QUINOLONES - OoCities
CHEMO NOTES FOR FINAL
Structures to know and notes to know are highlighted in yellow.
QUINOLONES
- Synthetic antimicrobials with N-alkylated 3-carboxypyrid-4-one fused with substituted aromatic ring.
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First-Generation Quinolones
- Nalidixic acid is the first marketed quinolone in 1965. It is still available for Gram (-) bacterial infections.
- Used for uncomplicated UT infections, mainly by E. coli.
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- Other 1st generation quinolones including oxolinic acid & cinoxacin are not common & mainly used UT disinfectants.
- They’re well absorbed orally & highly serum protein bound & hence have relatively high t½ .
- This restricts their use to protein free compartments e.g., UT.
- Used in high doses, because of their low potency, which leads to some side effects, e.g., GI upset, rash & visual disturbance.
- They are also proconvulsant & photosensitizers in susceptible patients.
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Second-Generation Quinolones
- Not used widely till the discovery of the first fluoroquinolone norfloxacin in 1986, which was equivalent in potency to fermentation antibiotics.
- Since the discovery of norfloxacin, thousands of 2nd-generation quinolones have been made & marketed in the US including:
- ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin, trovafloxacin, norfloxacin, enoxacin, lomefloxacin& gatifloxacin.
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- Ciprofloxacin is completely orally absorbed, not highly protein bound.
- Lomefloxacin has comparative longer t1/2 & hence administered less frequently.
- Levofloxacin is optically active isomer of ofloxacin & nearly 2-fold more active & more water soluble & became very popular.
- Sparfloxacin & trovafloxacin have better Gram (+) activity.
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Mechanism of action
- Quinolones are bactericidal due to their inhibition of DNA gyrase& topoisomerase IV which are key enzymes that dictate bacterial DNA conformation so that it can be stored unwounded, replicated, repaired & transcribed when needed.
- These enzymes change the conformation of DNA by catalyzing transient double strand cuts staggered by 4 base pairs, passing the uncut portion of the molecule back together.
- This change DNA twisting degree & release torsional stress in the molecule.
- Inhibition of DNA gyrase & topoisomerase IV renders a cell’s DNA inaccessible, leading to death, especially if the cell must deal with other toxic effects at the same time.
- Topoisomerase IV is more important to Gram (+) while DNA gyrase is important to Gram (-) bacteria.
- Humans shape their DNA with topoisomerase II which doesn’t bind quinolones at therapeutic doses.
- Resistance through reduced cellular uptake & mutation.
- Quinolones form chelate polyvalent with metal ions Ca2+, Mg2+, Al3+& Fe2+ to form less water soluble complexes & hence considerably lose their potency.
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- Hence, co-administration of certain antacids, hematinics, tonics & dairy products soon after quinolones administration is contraindicated.
Side Effects
- Proconvulsant, as in 1st-generation, especially in epileptics.
- Other CNS side effects: hallucinations, insomnia, visual disturbances.
- Diarrhea, vomiting, abdominal pain & anorexia.
- Fluroquinolones are much better tolerated.
- Quinolones are associated with erosion of the load bearing joints of young animals, hence they are not used before puberty or during pregnancy, since it can cause severe metabolic acidosis & hemolytic anemia.
- Concomitant use with theophylline increase its effect & toxicity.
- Some fluroquinolones have narrow safety margin, e.g., temafloxacin was removed from the market because it caused hemolysis, renal failure & thrombocytopenia.
- Recently, severe liver toxicity of trovafloxacin resulted in its removal from the market.
- Its use is restricted to severe infections involving institutional care where liver functions carefully monitored.
- Grepafloxacin marketed in 1997 & withdrawn in 1999 due to its cardiovascular toxicity. It prolonged QTc interval.
- These toxicity events reduced the popularity of quinolones& apparently these side effects were not revealed during animal & clinical studies.
Therapeutic uses
- 1st-Generation quinolones have relatively narrow anti-Gram (-) spectrum.
- 2nd-Generation quinolones are more widely used:
1. Norfloaxacin used for UT infections (enterobacter, enterococcus or P. aeruginosa).
2. Ciprofloxacin used for Bacillus anthrax, prostatitis, upper respiratory tract, chronic ear & bone infections, septicemia, staphylococcus &
pseudomonal endocarditis, meningitis, sexually transmitted diseases (gonorrhea & chlamydia) & purulent osteoarthritis.
- Anaerobes, Staph & Pseudomonas must be watched for emergence of resistance.
3. Lomefloxacin is used once daily for UT & upper respiratory tract infections.
- Quinolones are still under active investigation & newer agents are expected at regular intervals.
Nitrofurans
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- Oral antibacterial available since World War II.
- Used for prophylaxis & treatment of UTIs when kidney function is normal.
- It also inhibits kidney stone growth.
- It can cause nausea & vomiting which is avoided by slowing the drug’s rate of absorption through wax-coated large particles (Macrodantin).
- It inhibits DNA & RNA functions with unknown mechanism. Resistance is not common.
Methenamine
- Low molecular weight ammonia/formaldehyde polymer which hydrolyzes to its components under mild acid conditions.
- The drug is used for disinfections of acid urine & recurrent UTIs.
- HCHO is the active antimicrobial component.
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Phosphomycin
- Synthetic antimicrobial compound
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- Inhibits enolpyruvial transferase which catalyzes early bacterial cell wall synthesis step.
- This results in reduced synthesis of peptidoglycan & hence producing bactericidal effect.
- Effective against E. coli & Enterobacter faecalis.
SUMMARY
1. First-Generation Quinolones:
- Nalidixic acid, oxolinic acid & cinoxacin.
2. Second-Generation Quinolones:
- Norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin, trovafloxacin, norfloxacin, enoxacin, lomefloxacin& gatifloxacin
3. Nitrofurans
4. Methenamine
5. Phosphomycin
Cancer Chemotherapy
- Neoplasm: New & diseased form of tissue growth.
- The difference between benign & malignant tumors is the latter can metastasize.
- So benign tumors can be removed surgically since they have defined borders.
- Malignant tumors are invasive to surrounding tissue & their complete removal is difficult.
- They form secondary tumors at locations distant from that of primary tumors.
- So malignant tumor cells of primary tumor can be shed & distributed by the vascular or lymph system to other places.
- Hence, Cancer spreads by metastasis: ability to penetrate lymphatic & blood vessels, circulate through the bloodstream & then invade & grow in normal body tissues somewhere else, which makes cancer a potentially life-threatening disease
- Metastasis requires the growth of a new network of blood vessels.
- Angiogenesis is the recruitment of new blood vessels.
- Tumor angiogenesis is the proliferation of a network of blood vessels that penetrates into cancerous growths, supplying nutrients, oxygen & removing waste
products.
- Angiogenesis is directly related to metastasis.
- The highly vascular primary tumors having a higher incidence of metastasis than poorly vascular tumors.
- Shedding of cells from the primary tumor begins only after the tumor has a full network of blood vessels.
- Beside cancer, pathological angiogenesis also occurs in chronic inflammation, or
atherosclerosis vessels
- Normal Angiogenesis occurs during wound healing, new blood vessels are formed during tissue growth & repair & the development of the fetus during pregnancy
Angiogenesis
- In a mother’s womb, human fetus must create the vast network of arteries, veins
& capillaries through vasculogenesis, which creates the primary network of
vascular endothelial cells that will become major blood vessels
Angiogenesis Activator
- Walls of blood vessels are formed by vascular endothelial cells which only divide once every 3 years.
- Angiogenesis can stimulate them to divide when necessary.
- Endothelial cells are the source of new blood vessels & have the ability to divide & migrate.
- Many proteins & small molecules are released by normal & tumor cells as signals for angiogenesis.
- Examples for activator proteins:
- Vascular endothelial growth factor (VEGF), epidermal growth factor, angiogenin, tumor necrosis factor-a, interleukin 8, acidic, & basic fibroblast growth factor (bFGF).
- Examples for small molecules: Adenosine, nicotinamide, prostaglandins E1& E2
- Once VEGF & bFGF encounter endothelial cells, they bind to specific protein receptors on the outer surface of the cells, which activates a series of relay proteins that transmits a signal into the nucleus of the endothelial cells.
- Nuclear signal stimulates certain genes to make products needed for new
endothelial cell growth.
- Activated endothelial cells produce matrix metalloproteinases (MMPs) which are enzymes that facilitate the degradation of the extracellular matrix.
- This permits the migration of endothelial cells into the surrounding tissues, begin to divide & they finally organize into hollow tubes that gradually develop into a mature network of blood vessels.
- Hence, both angiogenesis & metastasis require MMPs during blood vessel formation & tumor invasion.
Angiogenesis Inhibitors
- Angiogenesis activators must overcome an array of natural angiogenesis inhibitors that normally restrain blood vessel growth.
- Naturally occurring angiogenesis inhibitor proteins include:
- angiostatin, interferons, tissue inhibitors of metalloproteinase-1-3, endostatin, platelet factor 4, interleukins 1 & 12, thrombospondin.
- The balance between the concentration of angiogenesis inhibitors & activators decides whether a tumor can induce the growth of new blood vessels.
- Angiogenesis is predominant if production of activators exceeds production of inhibitors.
- Angiogenesis is not only controlled by the quantity & quality of angiogenic stimuli
it also depends on the coordinated production of endogenous angiogenic & angiostatic factors.
- Angiogenesis may be induced by increased production of angiogenic factors or suppressed production of angiostatic factors
- Steps required for metastasis & angiogenesis are similar for all tumors regardless of their genetic origin, hence blocking both by inhibiting invasion is useful for all tumors of different origin.
- The use of anti-angiogenic compounds in cancer area started to attract more attention with the discovery of the first pro-angiogenic molecules bFGF& VEGF &
the development of in vitro methods to grow VE cells & in vivo assays of angiogenesis.
Cell Proliferation
- Cellular life is controlled by:
1. DNA synthesis/mitosis to produce new cells &
2. Cell differentiation to produce specialized cells.
- Normal (non-transformed) cells are able to modulate/control both processes using chemical signals as growth factors or inhibitors.
- They produce growth factors (GF) to stimulate growth & can counterbalance the effects of GF if necessary.
- If an organ is damaged, the level of inhibitor is reduced & proliferation rate increased.
- Cancer cells over produce GFs as epidermal growth factor (EGF) & under express growth inhibitors as p53 or over express GF receptors.
- This lead to loss of normal growth control & increase cell proliferation.
- Control loss is possibly through transformation of proto-oncogenes, which control normal proliferation into oncogenes which alter cellular control mechanisms.
Cell Cycle
- Gap 1 (G1) phase is the period when a newly created cell is born.
- If the cell is a proliferating cell, G1 phase will be very short & the cell will quickly moves into the synthesis (S) phase, where DNA is replicated resulting in 2 copies of DNA.
- Gap 2 (G2) phase is a preparation time for the final cell cycle phase M or mitosis.
- Cell cycle time is the time between mitoses.
- G1/S (when cells commit to replicate) & G2/M (when cells commit to divide) control the cell cycle.
- During G1 phase, a cell can either enter the S phase, enter the G0 phase (Gap 0 or quiescent) or the cell terminally differentiate & die.
- Normal cell populations may be proliferating, quiescent, or terminally differentiating, without net change in cells number.
- Tumor cells proliferation is higher at the expense of quiescent or terminally differentiating cells with net increase in cells number.
- In tumors, new cells are produced in hypoxic regions which are nearer to the tumor center & poorly perfused. These cells are usually in nonproliferative state & not sensitive to drugs.
- After the tumor is exposed to cancer chemotherapy drug, outermost cells which are mainly in the proliferative state are susceptible to the drug.
- Non-proliferative cells can be recruited into proliferative state.
- Hence to eradicate the tumor, several cancer chemotherapy rounds are required.
- Mutation
- Germ-line & somatic mutations
- Cells have many mechanisms for repairing damaged DNA, hence generally multiple
mutations are encountered for tumor promotion using the following sequence:
1. Initial mutation(s) (initiation)
2. Promotion, mutated cells proliferate, aided by exposure to non-genotoxic compounds.
3. Small benign tumor forms or mild dysplasia occurs with development of malignant phenotype.
4. Primary malignant tumor.
5. Secondary tumors (metastasis).
- Carcinogenesis is a multi-stage process that involves the initiation stage, in which the normal cells are transformed into tumor cells.
- Initiation is irreversible & momentary reaction.
- Initiated cell can then develop into tumors with prolonged exposure to promoters (promotion stage).
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- Promoters are not carcinogenic, but rather enhance the growth &/or survival of initiated cells.
- Example of promoters: organochlorine pesticides, estrogens, & phorbol esters (TPA).
- Tumors can then become more highly malignant leading to the progression stage.
- Cancer chemoprevention (anti-tumor promotion) agents targets the promotion stage unlike anti-tumor agents, which affects the progression stage.
Carcinogenic Chemicals
- Benzo[a]pyrene (a component of soot) was the first carcinogenic chemical to be identified.
- It is metabolized to reactive intermediates by CYP450 enzymes which react with guanine & other DNA bases to produce single mutations.
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- These mutations are either repaired or later misread when DNA is replicated producing transitions & permanent mutations & DNA adducts.
- Other similar examples:
- b-naphthylamine, asbestos, hydrocarbons, aflatoxins, tobacco smoke & alkylating agents.
- Ionizing radiation produce reactive oxygen species (ROS) as hydroxy radical which produce DNA adduct & single or double strand DNA damage.
Cancer Therapy
1. Surgery
- Cancer must be in 1ry tumor stage to make sure the entire tumor will be excised & without causing excessive damage to vital organs.
2. Radiation Therapy
- Used to shrink or destroy tumors by damaging DNA of tumor cells. X-ray radiation is used without anesthesia. Tumor must be localized for
successful therapy.
3. Immunologic Therapy
- Administration of interferons, mainly interferon-2 stimulate immune system to eradicate cancer by boosting the levels of lymphocytes, especially Tcells (destroy foreign malignant & premalignant cells) & B-cells (make antibodies in response to foreign protein expressed by cancer cells).
4. Chemotherapy
- Mainly targets the cure of a specific cancer type, reduce tumor size before surgery, sensitizing tumors to radiation therapy or destroy microscopic metastases after tumor surgical removal.
- Chemotherapeutic agents are complementary to either surgery or radiation therapy for metastasized or residual tumors.
- They are effective for small tumors because large tumors are not well perfused by blood & hence inner part of tumors is not accessible to drugs.
- Chemotherapeutic agents are basically cytotoxic & can kill both malignant & normal cells. Their selectivity is mainly rely on the faster proliferation rate & extracellular material uptake by malignant cells.
- However, few normal cells are rapidly proliferating, e.g., hair, bone marrow & GIT cell lining cells.
- Hence cancer chemotherapy usually causes hair loss, immune system depression, nausea or diarrhea.
- These side effects usually disappear once chemotherapy is discontinued.
- Early cancer detection is essential for cancer therapy success since tumor are likely to be small without secondary tumors.
- Complete remission rate of testicular cancer & Hodgkins disease is 80-85% with 5-year survival rate.
- Other cancer types could have lower remission rates like lung cancer (15%), liver & pancreas cancers (10% or less 5-year survival rates).
Anticancer Drugs:
1. Alkylating Agents
2. Antimetabolityes& Nucleoside Analogs
3. Antitumor Antibiotics
4. Antimitotic Agents
5. Miscellaneous Agents
6. Antiangiogenic Drugs
7. Hormonal Therapy
1. Alkylating Agents
- The use of sulfur mustard in World War I revealed that tissues of victims were damaged at sites distant from contact area.
- This included: leukopenia, bone marrow aplasia, lymphoid tissue suppression & GIT ulceration.
- Sulfur mustard has too nonspecific anti-tumor effect in animals.
- Nitrogen mustards were later synthesized, e.g., mechlorethamine, which has better selective toxicity especially to lymphoid tissue.
- Mechlorethamine was then used successfully for Hodgkin’s disease & certain lymphomas.
- Alkylation is the replacement of H by an alkyl group. Alkylation of nucleic acids or proteins includes a substitution reaction in which a nucleophilic atom (nu) of the biopolymer replaces a leaving group from alkylating agent.
nu-H + alkyl-Y( alkyl-nu + H+ + Y
Alkylating agents are classified into:
1. Nitrogen mustards
- The oldest example is mechlorethamine, approved by FDA in 1949.
- Other related compounds include:
- cyclophosphamide, ifosfamide, chlorambucil, estramustine phosphate & melphalan.
- They react with DNA through heterocyclic mechanisms.
2. Thiotepa & busulfan
3. Nitrosoureas, e.g., carmustine& lomustine.
- Alkylating agents act by alkylation of DNA, mostly at N-7 position of guanine. - Other DNA bases, e.g., adenine, thymine or cytosine or DNA backbone phosphate oxygens may also be alkylated.
- Difunctional alkylating agents as mustards may alkylate 2 DNA sites, producing intra- or interstrand links.
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- Alkylated DNA site becomes liable to cleavage resulting in single strand breaks of nuclear DNA.
- Alkylating agents react with DNA & RNA & proteins.
- Bifunctional alkylating agents can produce inter & intra-strand cross-links.
- Inter-strand links formed by mechlorethamine aziridinium ions prevent DNA separation & cause cytotoxicity.
- Reaction with N-7 of guanine is highly favorable.
- Alkylating agents are effective in G1 or S phase.
- DNA alkylation repair could occur where an endonuclease cuts the damaged strand & the region is backfilled.
- Rapidly proliferating agents have insufficient time to repair.
- Hence, alkylating agents should be most effective against rapidly proliferating cells, & hence, somewhat selective to cancer cells.
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- Despite Cl atom, which is the leaving group in the mustards is not an easily replacable atom, the nitrogen atom in mustards activates the chloride by proceeding through an aziridinum ion intermediate.
- Hence, nitrogen mustards are very reactive agents & must be administered intravenously.
I. Nitrogen Mustards
1. Mechlorethamine (Mustargen)
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- Simplest nitrogen mustards.
- Aqueous injectable formulations of mechlorethamine HCl salt (pH 3-5) are triturated with NaCl at a conc. of 1mg/ml.
- In vivo hydrolysis of mechlorethamine is rapid (t1/2 ~15 min.) & the active drug form lasts for few minutes only.
- Used intravenously or intracavitary (10mg/vial) for lung carcinoma, chronic lymphocytic leukemia (CLL), Hodgkin’s lymphoma lymphosarcoma, chronic myelocytic leukemia.
- Toxicity
- Bone marrow depression
2. Melphalan (Alkeran, L-PAM, L-Phenylalanine Mustard)
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- Chemically related to the natural phenylalanine amino acid.
- The L-isomer is transported preferentially with the assistance of an L-amino acid active transporter.
- D-Phenylalanine mustards require a higher dose to reach the same cytotoxicity level against animal tumors than the marketed L-enantiomer.
- ~30% of administered dose is accounted for covalently bound form with plasma protein.
- Used orally as 2 mg tablets or intravenously (50mg/vial).
- Effective against ovarian carcinoma & multiple myeloma
- Toxicity:
- mainly bone marrow depression.
3. Cyclophosphamide (Cytoxan)
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- Despite it is chemically related to nitrogen mustards, its mustard nitrogen nucleophilicity is tremendously reduced with the amide-like phosphoramide linkage.
- Hence, it is less likely to form aziridinium ion, compared with nitrogen mustards.
- This increased its chemical stability.
- Cyclophosphamide contains several polarizable groups which improve its H2O solubility.
- Cyclophosphamide is a pro-drug that requires metabolic bioactivation started with cytochrome P450 hydroxylation to an unstable carbinolamine intermediate, which fragment to acrolein & phosphoramide mustard, an active alkylating agent.
- Phosphoramide mustard forms an aziridinum analog which is an effective DNA cross-linking & cytotoxic agent.
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- Cyclophosphamide is well absorbed orally as tablets (25 & 50 mg).
- It is also available as iv injections (100, 200, 500 & 1000 mg/vial).
- It is used for:
- breast & ovary carcinomas, all acute monocytic leukemia, acute myelogenous
leukemia, Hodgkin’s & non-Hodgkin’s lymphoma, mutiple myeloma, neuroblastoma & retinoblastoma.
- Toxicity: bone marrow depression, hemorrhagic cystitis (acrolein metabolite)
4. Ifosphamide (Ifex)
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- Analogue of cyclophosphamide.
- Metabolic activation by CYP450 is required for the cytotoxic activity.
- Similar to cyclophosphamide, hydroxylation at C-4 produces the active unstable carbinolamine metabolite, 4-hydroxyifosphamide, which degrades to additional cytotoxic metabolite.
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- Used for testicular carcinoma as iv or intracavitary injections, 1000mg & 3000mg/vial.
- Toxicity: bone marrow depression & hemorrhagic cystitis (caused by acrolein metabolite).
- 2-Mercaptoethanesulfonate (MESNA, Mesenex) is an anticancer adjunct co-administered with cyclophosphamide or ifosphamide to conjugate their toxic acrolein metabolites, which reduces the hemorrhagic cystitis & nephron & urotoxicities induced by these toxic metabolites.
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5. Chlorambucil (Leukeran)
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- Original nitrogen mustard in which an alternative approach was used to
reduce the reactivity of alkyl nitrogen mustards by attaching an aromatic group to them.
- This decreases the basicity & nucleophilicity of the mustard nitrogen.
- Well absorbed orally & metabolized in vivo into another active metabolite, phenylacetic acid mustard.
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- This 2-carbon loss from butanoic acid side-chain is reminiscent of a fatty acid metabolism pathway.
- Both chlorambucil& its metabolite are highly protein-bound, like any acidic compounds.
- Used orally as 2mg tablets for chronic lymphocytic leukemia, Hodgkin’s & non-
Hodgkins’lymphoma.
- Toxicity: bone marrow depression
6. Estramustine Phosphate (Emcyt)
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- An estradiol analog with phosphoric acid at C-17 & carabmoylated at C-3
with a nitrogen mustard analogue.
- Formulated as di-sodium salt imparted by the phosphate ester. Freely water soluble.
- Alkylating moiety is not a true mustard as the N is acylated as part of the carbamate ester.
- After oral administration, estramustine phosphate is rapidly dephosphorylated.
- The major metabolites are free estramustine, estrone& estradiol.
- Used orally as 140 mg capsules specifically for prostate carcinoma.
- Toxicity:
- Gynecomastia, nausea & vomiting.
II. Other Alkylating Agents
1. Busulfan (Myleran)
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- Sulfonic acid ester that is an electrophile with methane sulfonic acid acting as a leaving group.
- Hydrolysis or alkylation reactions are the major metabolic pathways of busulfan
- Determination of 3-hydroxytetrahydrothiophene- 1,1-dioxide as the major urinary
metabolite in animals suggested the electrophilic reactivity of busulfan is due to SH groups in the body.
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- Busulfan is a neutral molecule & poorly water soluble.
- Used as 2mg tablets for chronic myelocytic leukemia.
- Toxicity include bone marrow depression & pneumonitis/pulmonary fibrosis.
2. Thiotepa (Thioplex)
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- Less reactive drug with 3 aziridine ([pic]) moieties, which react with nucleophiles to relieve ring strains.
- At acidic pH, aziridine group is protonated to give reactive aziridinium
ion which is known to alkylate DNA.
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- At physiologic pH, aziridine with a pKa ~6, is mainly in the free base form which is less reactive alkylating species.
- Metabolic desulfuration of thiotepa give a toxic metabolite, TEPA (triethylenephosphoramide).
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- The drug is used as iv, intravesically & intracavitar injections, 15 mg/vial for breast, bladder & ovary carcinomas, Hodgkin’s & non-Hodgkin’s lymphoma, malignant effusions & lymphosarcoma.
- Toxicity: Bone marrow depression.
3. Procarbazine (Matulane)
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- DNA alkylation can be achieved by free radical intermediates. This can be done using substituted hydrazines which produce radical intermediate in vitro.
- Procarbazine is an example for this case.
- At physiologic pH, in presence of O2, procarbazine decomposes by autooxidation,
releasing H2O2.
- The formed azo derivative is further hydrolyzed to a benzaldehyde analog & methylhydrazine.
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- Methylhydrazine is oxidized to methyldiazene & then to a methyl radical, which methylate DNA guanine at C-8.
- The benzaldehyde derivative is excreted in urine after oxidation to an acid.
- Procarbazine inhibits alcohol & catecholamine metabolic enzymes, producing Antabuse (disulfuram)-like effect with alcohol intake.
- Monoamine oxidase is also inhibited by procarbazine.
- Hence, drug interactions with sympathomimetics drugs, tricyclic antidepressants & tyramine-containing food are expected.
- The drug is used orally as capsules (50 mg each) for Hodgkin’s lymphoma.
- Toxicity: Bone marrow depression
4. Dacarbazine (DTIC-Dome) & Temozolomide (Temnodal)
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- Dacarbazine is metabolically activated through series of reactions involving CYP450.
- Initial demethylation to MTIC followed by formation of diazomethane, a potent
methylating agent which methylate N-7 of DNA guanine.
- The major urine metabolite is 5-aminoimidazole-4-carboxyamide, which supports the proposed mechanism.
- Temozolomide is a pro-drug which is non-enzymatically converted to MTIC (N-demethyl dacarbazine), which then alkylate DNA similar to DTIC.
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- It is recently approved by the FDA for brain tumors.
- Unlike DTIC, which must be administered intravenously, temozolomide is administered & rapidly absorbed orally, which is an advantage over DTIC.
- Used orally as a 5, 20, 100 & 250 mg capsules. Common side effects include bone marrow depression, nausea, vomiting, constipation, headache & fatigue.
III. Nitrosoureas
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- These compounds produce reactive alkylating vinyl cations& isocyanate species by
reactions with water.
- In water, urea NH is deprotonated & negatively charged oxygen displaces Cl
to give the cyclic oxazolidine.
- This intermediate fragments to vinyl diazohydroxide& 2-chloroethylisocyanate.
- Both are reactive alkylating species & give the very reactive vinyl cation& 2-chloroethylamine.
1. Carmustine (BiCNU, 1,3-bis(chloroethyl)-1-nitrosourea,)
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- Neutral molecule, highly lipophilic, H2O insoluble which allow efficient crossing of blood-brain barrier& provide higher CSF/plasma ratios, compared with other alkylating agents.
- Alkylate DNA & RNA though no cross resistance with nitrogen mustards.
- Enzyme inhibition by carbamoylation of proteins have been suggested as an alternate mechanism of anti-neoplastic activity.
- Rapidly metabolized after iv injection to form active metabolites.
- Carmustine is a low melting solid, as it decomposes, its melting point drops such that partially degraded preparations may be in liquid forms at room temperature.
- Vials of carmustine that show an oily film indicate that the drug has decomposed & these vials should not be used.
- Carmustine is administered as a 10% aqueous ethanolic solution for iv use (100 mg/vial) for Hodgkin’s & non-Hodgkin’s lymphoma, multiple myeloma, primary brain tumor.
- The main side effect includes bone marrow depression.
2. Lomustine (CeeNU, CCNU, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea)
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- Similar to carmustine in solubility & activity.
- Used orally as capsules (10, 40 & 100 mg) for Hodgkin’s lymphoma, primary & metastatic brain tumors.
- Toxicity: bone marrow depression.
3. Streptozocin (Zanosar)
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- Combination of amino sugar& nitrosourea.
- The sugar moiety improves water solubility (compared with other anti-neoplastic
nitrosoureas)& it exists in both a & b-anomeric forms.
- Inhibits DNA synthesis & cell proliferation
- It also induces diabetes-like syndrome in animals.
- This is mediated by lowering of β-cell concentrations of NAD.
- Indicated as iv injections (1000 mg/vial) for pancreatic carcinoma.
- The main side effect is renal damage.
4. Cisplatin (Platinol)
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- Platinum complex containing 2 NH3 molecules & 2 Cl atoms in cis configuration.
- It is nominally soluble in water or saline at 1mg/ml.
- Reactivity with cellular nucleophiles or H2O is much faster than its metabolic reactions.
- Injectable formulation is at a concentration near its solubility in saline & it should not be refrigerated because it will precipitate out.
- After administration, most platinum becomes tightly bound to plasma proteins including albumin, transferring & g-globulin.
- Dose must be carefully administered because even hemodialysis after 4-hours of administration will have little effect in cases of overdoses because of its tight protein binding.
- Pt is detectable in tissue even after 180 days after the last dose.
- Needles or intravenous sets containing aluminium parts should never be used because cisplatin reacts with Al resulting in a precipitate & loss of activity.
- The effect of cisplatin is associated with its ability to alkylate N-7 of DNA guanine, forming intrastrand & interstrand cross links.
- Use as iv injections (1mg/ml, 50 & 100 ml) particularly for bladder, ovary & testes
carcinoma.
- Toxicity: Renal damage
5. Carboplatin (Paraplatin)
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- Similar to cisplatin in containing cis-diammine group & platinum (II)
with organometallic cyclobutane replacing 2Cl groups in cisplatin.
- Carboplatin is soluble in water (14 mg/ml) & hence can be used as iv injections (50, 150 & 450 mg/vial).
- It is insoluble in organic solvents as ethanol & acetone.
- Replacement of Cl with water in carboplatin forms a monohydroxy derivative which retain the anticancer activity with slower reaction rate, which justify why carboplatin is less potent than cisplatin.
- Used for ovaries carcinoma
- Toxicity: bone marrow depression.
SUMMARY
Alkylating Agents:
I. Nitrogen Mustards:
- Mechlorethamine, melphalan, cyclophosphamide, ifosphamide, chlorambucil & estramustine
II. Other Alkylating Agents:
- Busulfan, thiotepa, procarbazine, dacarbazine & temozolomide
III. Nitrosoureas:
- Carmustine, lomustine, streptozocin, cisplatin & carboplatin
2. Antimetabolites & Nucleoside Analogs
- Antimetabolites are compounds that competitively inhibit the biosynthesis of normal cellular metabolites usually due to close structure similarity between antimetabolites & natural metabolites.
- The well known examples are methotrexate & 5-fluorouracil (5-FU), the suicide-substrate enzyme inhibitor.
Antimetabolites:
I. Pyrimidine antimetabolites:
- 5FU, cytarabine (Ara-C), Gemcitabine
II. Purine antimetabolites:
- 6-Mercaptopurine, 6-Thioguanine, Fludarabine & cladribine
III. Other antimetabolites:
- Methotrexate
I. Pyrimidine antimetabolites:
1. 5-Fluorouracil (5-FU, Adrucil)
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- Substituted pyrimidine analog, one of the oldest antimetabolites, designed by Heidelberger in 1957.
- Some tumors preferentially use uracil rather than using orotic acid for the biosynthesis of DNA pyrimidines.
- Thymidine synthesis from uracil involves thymidylate synthetase
- A thiol group of a cysteine residue in the enzyme (E-SH) adds to the C-6 position of deoxyuridylic acid with subsequent addition of C-5 carbon to the N-5,N-10-methylene tetrahydrofolate.
[pic]
- The resulting intermediate transfers the C-5 H to folate N-10 to give deoxythymidylic acid, dihydrofolate& regenerated enzyme.
[pic]
- 5-FU must be first activated in vivo by conversion to 5-fluoro-2’-deoxyuridine monophosphate (5-FdUMP) through formation of 5FU riboside which is then transformed into 5-FdUMP catalyzed by ribonucleotide reductase.
- 5-FdUMP binds to thymidylate synthetase to give an intermediate similar to that of uridylic acid but with C-5 F atom instead of H.
- Hence the enzyme is inhibited because this intermediate will not be able to break down to give deoxythymidine monophosphate (dTMP).
- The overall result is a deficiency in thymidine which is essential for DNA synthesis.
- 5-FU can also be metabolized & reduced by dihydropyrimidine dehydrogenase which give the inactive 5-F-5,6-dihydrouracil.
- This enzyme can be inhibited by 5-ethynyluracil, which doubles the therapeutic index of 5-FU by 2-4 folds.
[pic]
- 5-FU is used (iv, 500 mg/vial or topically 1-5%) for breast, colon, rectum, skin, pancreas & stomach carcinoma.
- Toxicity: bone marrow depression & oral/GI ulceration.
- Remember: The antifungal flucytosine: 2- 5-Fluorodeoxyuridine (floxuridine, FUDR)
[pic]
2. 5-Fluorodeoxyuridine (floxuridine, FUDR)
[pic]
- Prodrug of 5-FU, which can be used alternatively.
- Deoxyribose rapidly cleaved metabolically to give 5FU.
- Floxuridine is freely water soluble unlike 5-FU.
- Used intra-arterially (500 mg/vial) as a palliative therapy of GI adenocarcinoma metastatic to liver.
- Toxicity: similar to 5-FU
3. Cytarabine (Ara-C, Cytosar-U)
- Pyrimidine nucleoside with arabinose (C-2’ b-OH & not a as in 5FUR).
[pic]
- The change in the C-2’ configuration results in a notable broadening of the activity spectrum.
- Similar to 5FU, Ara-C has to be converted to its mono- followed by
triphosphate derivative (Ara-CTP).
[pic]
- Ara-CTP inhibits the conversion of cytidylic acid to 2’-deoxycytidylic acid.
- It also inhibits DNA dependant DNA polymerase.
- Ara-C causes miscoding after its incorporation into DNA & RNA.
- It is rapidly metabolized (oxidative deamination) into the inactive arabinofuranosyluracil.
- Ara-C is water soluble, used as iv, intrathecal or subcutaneous injections (20, 50, 100 mg/100ml) for acute lymphocytic leukemia, meningeal leukemia, acute myelogenous leukemia, chronic myelocytic leukemia.
- Toxicity: bone marrow depression.
4. Gemcitabine (Gemzar)
[pic]
- Recent C-2’ difluoro pyrimidine analog.
- Unlike Ara-C, it shows excellent activity against murine solid tumors.
- It has to be bioactivated to the active triphosphate metabolite which then incorporated into DNA causing cell toxicity.
- The drug incorporates into RNA & inhibits both DNA & RNA synthesis.
- Active against locally advanced or metastatic pancreatic adenocarcinoma, human T-lymphoblastoids & human chronic myelogenous leukemia.
- Used intravenously (200 & 1000 mg/vial).
- Extensively metabolized into the inactive metabolite 2’-deoxy-2’,2’ -diflurouridine (dFdU).
II. Purine antimetabolites
1. 6-Mercaptopurine (Purinethol, 6-MP)
[pic]
- 6-MP is bioactivated in vivo to the corresponding ribouncleotide, 6-thioinosinate (6-MPMP), catalyzed by hypoxanthine-guanine phosphoribosyltransferase (HGPRT).
6-MPMP is a potent inhibitor of the conversion of 5-phosphoribosyl pyrophosphate into 5-phosphoribosylamine, which is the first step in purine biosynthesis.
- 6-Thioinosinate also inhibits the conversion of inosinic acid to xanthylic acid.
- The overall effect of 6-MP is the inhibition of purine biosynthesis.
[pic]
Cellular Targets of 6-MP
[pic]
- 6-Thioinosinate di & triphosphate anabolites further inhibit biosynthesis & incorporation of guanine in DNA & RNA chains, hence inhibiting chain elongation.
- 6-Thioinosinate can also be a substrate for adenosylmethionine, converted to 6-methylthioinosinate, which also have antimetabolic activity.
- 6-MP is orally active as 50 mg tablets although its oral absorption erratic.
- Urinary metabolites include thiouric acid, formed by xanthine oxidase & many methylthiopurines.
- Concurrent administration of mercaptopurine with uricosouric xanthine oxidase inhibitors like allopurinol requires dose adjustment of mercaptopurine.
- Cross resistance with other purine drugs, e.g., thioguanine is expected.
- Used for acute lymphocytic, myelomonocytic & myelogenous leukemia.
- Toxicity: Bone marrow depression
2. 6-Thioguanine (6-TG)
[pic]
- An antimetabolite structurally related to 6-MP.
- Similar to MP, it has to be ribosylated catalyzed by HPGRT to monophosphate (6-TGMP), diphosphate (6-TGDP) & triphosphate (6-TGTP).
- Each of these anabolites inhibit several enzymes similar to 6-MP.
- Also 6-TGTP can be incorporated into RNA or into DNA after reduction of C-2’ OH.
- This inhibits DNA replication due to the inability of replication enzymes to recognize 6-TG.
- Activity margin & toxicity are comparable with 6-MP but 6-TG deactivation is not dependant on xanthine oxidase which is an advantage over 6-MP.
3. Fludarabine Phosphate (Fludara) & Cladribine (Leustatin)
[pic][pic]
- Structurally related antimetabolites to adenine with modified sugars.
- Fludarabine is a derivative of the Antiviral & antimetabolite Ara-A
(adenosine 2’-b-anomer).
- Fludarabine is more effective than vidarabine because it is less susceptible to adenosine deaminase.
- It is converted in vivo to its 5’-triphosphate which is inhibitor of ribonucleotide
reductase.
- Cladribine (2-chloro analogue) mainly inhibits DNA repair enzymes.
- Fludarabine is used for chronic lymphocytic leukemia while cladribine is useful against hairy–cell leukemia.
- They both can cause bone marrow depression & used intravenously 10-50 mg/vial
III. Other antimetabolites
Methotrexate (Folex, MTX)
[pic]
- Pteridine analog that compete with normal folic avid & dihydrofolate substrates for the active site on dihydrofolate reductase (DHFR).
- DHFR is responsible for the reduction of folic acid (FA) to dihydro FA & then to tetrahydroFA, which is essential for the next round of uridylic to thymidylic acids biosynthesis.
- This prevents DNA synthesis & kill cells by depleting thymidylic acid.
- Hence MTX is cytotoxic due to its ability to inhibit DNA synthesis & inhibit thymidine synthesis from uridylic acid.
- Inhibition of DHFR can also inhibit purine synthesis, since the biosynthesis of N10-formyltetrahydrofolic acid will be inhibited. The latter is an essential formyl (C1) donor in purine biosynthesis.
[pic]
- N5-formyl-tetrahydrofolic acid (leucovorin) is used as “rescue” therapy to prevent the lethal effects of methotrexate on normal cells.
- Leucovorin also inhibits active transport of methotrexate into the cells.
- MTX is metabolized in liver & intracellularly to polyglutamate forms, which hydrolyze back to methotrexate.
- MTX is largely excreted unchanged.
- Methotrexate is indicated for Trophoblastic neoplasms, breast, head, neck &
lung carcinoma, acute & menigeal leukemia, lymphosarcoma, nonmetastatic osteosarcoma & Burkitt’s lymphoma.
- Toxicity:
- Bone marrow depression, pneumonitis/pulmonary fibrosis & oral & GI
ulcerations.
SUMMARY:
Antimetabolites:
I. Pyrimidine antimetabolites:
- 5-FU, cytarabine (Ara-C), Gemcitabine
II. Purine antimetabolites:
- 6-Mercaptopurine, 6-Thioguanine, Fludarabine & cladribine
III. Other antimetabolites:
Methotrexate
3. Antitumor antibiotics
- Several microbial fermentation products that were originally rejected as antibiotics for their toxicity have become clinically useful antitumor drugs.
1. Bleomycin (Blenoxane)
- Cytotoxic glycopeptide antibiotics discovered in 1966 from Streptomyces verticillus.
- Current preparation is composed of a mixture of bleomycins A2& B2.
[pic]
- Natural bleomycins occur as Cu chelates with ligands provided by pyrazine, imidazole, amide & amine functional groups.
- Although Cu++ is removed during isolation, the tendency to form chelates is the key of its cytotoxic activity.
- Bleomycins chelate in cells with Fe++. This alters the redox potential of iron & reduce bound oxygen into reactive radical species, hydroxyl radical (OH ), which reacts with nuclear DNA, degrading it & causing cytotoxicity.
- Bleomycins are used as intramuscular, subcutaneous, intravenous or intrapleural
injections (15-30 units/vial).
- Bleomycins are used for cervix, head, neck, penis, skin, testes carcinoma.
- It is also used for Hodgkins& non-Hodgkin’s lymphoma.
- Toxicity: Pneumonitis & pulmonary fibrosis.
2. Dactinomycin D (Actinomycin D, Cosmegen)
[pic]
- Dactinomycins are peptide antibiotics isolated from Streptomyces parvullus.
- They consist of tricyclic phenoxazone ring in the quinone oxidation state
(3-phenoxazone-1,9-dicarboxylic acid, actinocin) & 2 identical pentapeptide lactone appendages.
- Dactinomycin’s phenoxazone ring system is planar & can intercalate or insert into DNA between base-pair steps.
- Intercalation of actinocin moiety needs space & hence the helix must unwind. - Once inserted, actinocin moiety is held in DNA helix by p-p stacking interactions with DNA bases.
- This causes local distortion which affects the action of topoisomerase II, which normally regulates unwinding of coiled double-stranded DNA.
- This ultimately leads to interference with DNA replication & transcription which causes cell death.
- Actinomycins also cause DNA cleavage by nucleases.
- Dactinomycin is light sensitive.
- It is minimally metabolized & doesn’t cross blood-brain barrier.
- It is used as intravenous injections, 0.5 mg/vial.
- The drug is used for testes carcinoma, Ewing’s sarcoma, trophoblastic& Welm’s tumors, rhabdomycosarcoma & sarcoma botryoides.
- Toxicity:
- Bone marrow depression, stomatitis & oral/GI ulcerations.
3. Mitomycin C (Mutamycin)
[pic]
- Antitumor antibiotic from Streptomyces caespitosus first discovered in 1950’s & approved as anticancer agent in 1970’s.
- The compound is containing multiple anticancer functional groups, e.g., quinone, aziridine & carbamate.
- The drug is a bioreductive alkylating agent.
[pic]
- It is first bio-reductive activated then one molecule of methanol is eliminated to give a highly reactive alkylating agent capable of mono & dialkylation (cross-linking) of cytosine/guanine rich regions of DNA.
- Mitomycin is blue-violet crystals (due to quinone moiety.
- It is poorly absorbed in GIT & hence it must be used as iv injections (20-30 mg/vial).
- It is rapidly & extensively metabolized.
- It is specifically indicated for gastric & pancreatic carcinoma.
- Toxicity: bone marrow depression.
4. Anthracyclines
[pic]
- Cytotoxic anthracycline antibiotics isolated from Streptomyces caeruleorubidus
or Streptomyces peuceticus var. caesius.
- They have tetracyclic quinone-containing ring aglycone attached to the unique daunosamine sugar.
- Due to the presence of conjugated anthraquinone nucleus, anthracycline are reddish in color & their administration imparts red urine coloration.
- The main problem of anthracyclines is their cardiotoxicity.
- Due to their molecule’s flatness, anthracyclines are able to intercalate with DNA perpendicular to its long axis.
- The aminosugar daunosamine increases the stability of this binding through its interaction with the DNA sugar phosphate backbone.
- This intercalation lead to a single or doublestranded DNA breaking.
- This may be the result of repair process initiated by topoisomerase.
- Anthracyclines also are able to produce reactive oxygen species as hydroxyl radical (OH.) & superoxide radical anion (.O-O-), which damage & destroy cellular DNA.
- Generation of these free radicals may account for anthracyclines’ cardiotoxicity.
- Recently, anthracyclines are reported to show angiogenesis inhibitory activity at a non-toxic concentration.
- Anthracyclines are not orally active & have to be administered as iv injections (5-100 mg/vial).
- Anthracyclines hydroxylated in vivo to the active daunorubinols.
- Other biotransformations include reductive cleavage of the glycosidic bond, O-demethylation, conjugation with glucouronic acid & sulfate esetrifation.
- Doxorubicin HCl (adriamycin) liposome injection (Doxil) has a smaller distribution volume & slower clearance.
-It is used as 20 mg/vial iv injection for acute lymphoblastic& myeloplastic leukemia, Welm’s tumor, breast, ovarian, thyroid & gastric carcinoma,
malignant lymphoma, bronchogenic carcinoma, Hodgkin’s disease, soft tissue & bone sarcomas, neuroblastoma
- Daunorubicin (Cerubidine) is used for acute lymphocytic leukemia, acute myelogenious leukemia & acute monocytic leukemia.
- Both doxorubicin & daunorubicin can induce bone marrow depression & cardiotoxicity.
- Epirubicin (Ellence) has a different C-4’ configuration.
- It is much less commonly used & it is mainly used as an adjunct therapy in axillary node tumor after resection of primary breast cancer.
- Idarubicin (idamycin) is a synthetic analog which has improved cellular uptake, lipid solubility & hence penetrates CSF.
[pic]
- It also lacks cardiotoxic side effect.
- The major metabolite of idamycin, is its 13 hydroxy derivative (idarubicinol) is also active & has a longer t1/2 (45 hr), compared with idarubicin (22 hr).
- Idarubicin is used for acute lymphocytic& myelogeous leukemia.
- Toxicity: bone marrow depression
Valrubicin (Valstar)
- It is recently approved by the FDA for intravesical injection (40 mg/vial) therapy of BCG-refractory carcinoma in situ of the urinary bladder (CIS) for which immediate cystectomy is not an option.
[pic]
5. Pentostatin (Nipent, 2’deoxycoformycin, DCF)
[pic]
- Adenosine deaminase inhibitor from Streptomyces antibioticus.
- Structurally related to purines with unusual 7-membered ring (tetrahydrodiazepine).
- Marketed as iv injections (10 mg/vial), used for a-interferon-refractory hairy-cell leukemia in adults.
- Toxicity: bone marrow depression
6. Mitoxantrone HCl (Novantrone)
[pic]
- Antitumor anthracenedione, highly conjugated, intense blue color & causes urine blue pigmentation.
- The mechanism of action is similar to anthracyclines.
- Its acidic (pH 3-4.5) parentral preparations should not be mixed with heparin because it can be precipitated.
- Used for acute monocytic, promyelocytic& myelogenous leukemia.
- Used as iv injections (20-30 mg/vial).
- Toxicity: Bone marrow depression.
4. Antimitotic Agents
- Drugs that prevent cellular mitosis & specially interfere with mitotic spindle formation.
- During mitosis, the protein tubulin undergo polymerization to form the mitotic spindle.
- Antimitotic drugs interfere with this process either by depolymerization of the microtubules or by causing structures other than the normal mitotic spindle to form. Lack of properly formed mitotic spindle will cause incorrect chromosomal
segregation which leads to cell death.
- Recently, the potential antiangiogenic & antimigration effects of paclitaxel&
other microtubule disruptors on tumor cells at a non-cytotoxic concentration is reported.
- Concomitant use of paclitaxel & thalidomide in the treatment of highly vascular colorectal tumors in mice xenograft model also showed effective decreased expression of angiogenic growth factors.
1. Vinca Alkaloids
[pic]
- First antimitotic drugs are alkaloids (vincristine & vinblastine) isolated from
periwinkle flower, Vinca rosa.
- The related semisynthetic analog vinorelbine was also introduced.
- Vinca alkaloids contain 3ry amine group which makes water soluble salts.
- They metabolized by CYP450.
- Treatment of cells with vinblastine results in the formation of 1:1 binded complex of vinblastine & tubulin.
- Vincristine (oncovin) is used as iv vials (10mg/vial) for acute lymphocytic leukemia,
Hodgkin’s & non-Hodgkin’s lymphoma, neuroblastoma& Wilm’s tumor.
- Vinblastine (Velban) is used as iv injections (10mg/vial) for breast & testicular carcinoma, Hodgkin’s & non-Hodgkin’s lymphoma, mycosis fungoides& Kaposi sarcoma.
- Vinorelbine (Navelbine) is specifically indicated for non-small cell lung cancer as iv injections (10 & 50 mg/vial).
- All vinca alkaloids cause bone marrow depression
2. Taxanes: Paclitaxel & Docetaxel
[pic]
- Paclitaxel is natural product isolated from the Pacific yew tree in the early 1960’s & only used & approved as anticancer in the mid 1990’s.
- Paclitaxel binds to tubulin but doesn’t cause depolymerization like Vinca alkaloids.
- Paclitaxel causes microtubules to arrange themselves in a parallel array rather than the required arrangement of mitotic spindle, causing mitotic arrest.
- The final outcome is similar to vinca alkaloids.
- Paclitaxel is highly lipophilic, doesn’t form stable salts with acids & bases & it is water insoluble.
- Intravenous infusion of paclitaxel is prepared a non-aqueous solution in polyoxyethylated castor oil & dehydrated alcohol.
- Paclitaxel is hydroxylated in vivo catalyzed by CYP450 enzymes to give 6-hydroxypaclitaxel, 3’-p-hydroxypaclitaxel & 6,3’-p-dihydroxypaclitaxel.
- Docetaxel is a related semisynthetic compound with different acyl moieties.
- It is formulated in polysorbate 80 & must be diluted by 13% ethanol in water before use.
- Paclitaxel (Taxol) is used as iv injections (30 mg/5ml & 100 mg/16.7 ml) for metastatic breast cancer & refractory metastatic ovary carcinoma.
- Docetaxel (Taxotere) is used as iv injections 920 & 80 mg/vial) for locally advanced or metastatic breast cancer & non-small cell lung cancer.
- Both drugs can cause bone marrow depression
Antitumor antibiotics:
1. Bleomycins
2. Dactinomycin or dactinomycin D
3. Mitomycin C
4. Anthracyclines: doxorubicin, daunorubicin, idarubicin, epirubicin
5. Pentostatin
6. Mitoxantrone
Antimitotic agents
1. Vinca alkaloids: vincristine, vinblastine, vinorelbine.
2. Taxanes: Paclitaxel & docetaxel.
5. Miscellaneous/natural products
1. Epipodophyllotoxins
[pic]
- Podophyllotoxinsare natural products obtained from the May Apple plant & were
used by Native Americans & early settlers for their GI, emetic & cathartic
effects.
- Etoposide (VePesid) & teniposide (Vumon) are semisynthetic analogs that are used for small-scale carcinomas of lung & Hodgkin’s disease.
- Original podophyllotoxins have 1,4-cis orientation unlike the semisynthetic
etoposide & teniposide, which have 1,4-trans configuration.
[pic]
- The main functional groups in etoposide (lactone, phenol, ether, acetal & glucoside) are not salt-forming groups.
- Salts have better water solubility.
- Injections of both compounds are non-aqueous preparations & contain polysorbate 80/Tween 80, polyethylene glycol 300 & alcohol as diluents.
- They must be diluted right before administration because refrigerated solutions may precipitate.
- Etoposide phosphate is a prodrug which quickly hydrolyzed to etoposide after iv administration.
- Etoposide & teniposide bind to tubulin at a different site from that of vinca alkaloids & they do not change normal microtubular structure.
- Etoposide & teniposide target G2 phase & cause protein-DNA links & DNA strand breakage by inhibiting topoisomerase II.
- Etoposide stabilize DNA-topoisomerase II complex.
- Etoposide’s major urinary metabolites are the lactone hydrolysis products, glucouronides & sulfate esters.
- Catechol & O-demethyl metabolites are also possible.
- Teniposide is also extinsively metabolized mainly by CYP3A4.
- Etoposide (VePesid) is indicated for refractory testicular cancer & small cell lung cancer.
- It is used as iv injection (5-50 mg/vial) & as capsules (50 mg)
- Teniposide (Vumon) is specifically indicated for refractory childhood acute lymphoblastic leukemia as non-aqueous iv injections (50 mg/5 ml diluent).
- Both drugs may cause bone marrow depression.
2. Hydroxyurea (Hydrea)
[pic]
- Small neutral molecule that is well absorbed orally & excreted in urine un-metabolized.
- It acts by inhibiting ribonucleotide diphosphate reductase, causing decreased level of deoxyribouncleotide required for DNA synthesis.
- It also chelate an Fe2+ cofactor.
- It is cell-cycle specific for the S-phase & causes cell arrest at the G1-S-interface.
- Hence, it is useful for radiation therapy as cells in G1 phase are particularly sensitive to radiation.
- Hydroxyurea is used orally as capsules (500 mg) for head & neck & ovarian carcinomas, chronic myelocytic leukemia, malignant melanoma.
- Toxicity: Bone marrow depression.
3. Mitotane (Lysodren, o,p’-DDD)
[pic]
- It is an adrenal cytotoxic agent chemically related to the insecticide DDT.
- Most of the drug is stored in tissue & not excreted in urine.
- Terminal plasma t1/2 18-159 days after drug discontinuations.
- It is metabolized to the polar, water-soluble phenylacetic acid metabolite through acyl chloride intermediate.
- It is used for adrenal cortex carcinoma as 500 mg tablets.
- Toxicity: CNS depression
4. Retinoids
- Tretinoin & Alitretinon
[pic]
- Tretinoin (all-trans retinoic acid) is a natural metabolite of vitamin A (retinol).
- It induces the differentiation of acute promyelocytic leukemia cells.
- It is well absorbed orally & highly protein-bound. CYP450 oxidative metabolism of tretinoin give 4-oxo trans retinoic acid & its glucuronide.
- Tretinoin also isomerizes to 13 cis retinoic (isotretinoin) which is oxidized to 4-oxo cis retinoic acid.
- Alitretinoin (9-cis-retinoic acid) is also a natural product which inhibits
Kaposi’s sarcoma cells by activating intracellular retinoid receptors which activate genes which regulate cell growth, differentiation & apoptosis.
- It is also topically used for cutaneous lesions in AIDS-related Kaposi’s sarcoma.
- Topical use pose minimum toxicity.
- Its systemic use is still under investigation.
- Tretinoin (Vesanoid) is indicated as 0.1% gel for acute promyelocytic leukemia.
- Alitretinoin (Panretin) is useful as 0.1% gel for cutaneous lesions in AIDS-related Kaposi’s sarcoma.
5. Camptothecins
[pic]
- Topotecan & Irinotecan
- Topotecan HCl is a semisynthetic compound derived from the natural product camptothecin by addition of the phenolic OH & dimethylaminoethyl groups improved
water solubility & reduced side effects without reducing the effectiveness.
- Topotecan lactone is pharmacologically active although the equilibrium between the hydrolysis product & lactone favors the ring-opened at physiologic pH.
- Both camptothecin & topotecan are inhibitors of topoisomerase I & cause single strand breaks in DNA which is cytotoxic.
- Irinotecan HCl is a semisynthetic piperidine analog of camptothecin.
- It is activated in vivo by hydrolysis of the carbamate functionality.
- Topotecan (Hycamtin) is indicated for ovarian metastatic carcinoma as iv (4mg/vial) injections.
- It can cause bone marrow depression.
- Irinotecan (Camptosar) is used as iv injections (100 mg/5ml) for colon or rectum metastatic carcinoma.
- Toxicity: late diarrhea.
6. Porfimer Sodium
- Photosensitizing agent used in photodynamic therapy (PDT) of tumors.
- It is an oligomeric mixture of up to 8 porphyrin units linked together by ester & ether linkages.
- It is dark red color.
- It is cleared from tissues other than tumors, e.g., skin, reticuloendothelial system tissues quickly.
- After the drug accumulates in tumor tissue, tumor is illuminated with a laser at l 630 nm.
- Laser light promotes the porfimer polymer to an excited state which initiates & propagates radical reactions.
- Single oxygen (O•), superoxide anion (•O-O) & hydroxyl radical (OH•) formed in the reaction by spin transfer from profimer polymer to molecular oxygen.
- Patients experience photosensitivity for ~30 days & cautioned to avoid skin & eyes exposure to direct sun light or bright indoor light.
- Visible light causes photoactivation, hence UV sunscreens are of no value against porfimer photosensitivity.
6. Hormonal Therapy
- Hormonal therapy is common specially in breast cancers with antiestrogens & prostate cancer with gonadotropin-releasing hormone (GnRH) agonists & antiandrogens.
1. Antiestrogens
- Tamoxifen & toremifene are prototype antiestrogens with a complex
mechanism not limited to its antiestrogenic activity; for breast cancer
[pic]
- Tamoxifen (Novaldex) is used orally as tablets (10 & 20 mg) for breast cancer.
- Toxicity: Hot flashes, nausea & vomiting.
- Toremifene (Fareston) is also used orally for breast cancer as tablets (88.5 mg/tab) & it has a similar toxicity profile as tamoxifen.
- Tamoxifen and toremifene in breast cancer: comparison of safety and efficacy. Buzdar, Aman U.; Hortobagyi, Gabriel N. Dep. Beast and Gynecology Med. Oncology, Univ. Texas, MD Anderson Cancer Center, Houston, TX, USA. Journal of Clinical Oncology (1998), 16(1), 348-353.
- Tamoxifen is currently the std. hormonal treatment of breast cancer, both for metastatic disease and in the adjuvant setting.
- A new antiestrogen, toremifene, was approved recently for use in managing metastatic breast cancer in postmenopausal women.
- Both agents have shown a significant hypocholesterolemic effect after
long-term administration. Tamoxifen has been assocd. with maintenance of bone mineral d., a reduction in cardiac events, & a slightly increased risk of endometrial
cancer. Toremifene is not likely to be used as second-line therapy after tamoxifen failure due to crossresistance.
2. Aromatase inhbitors
- A key step in estrogen biosynthesis include the conversion of androstenedione to esterone catalyzed by aomatase enzyme.
- Blocking aromatase significantly lowers circulating estradiol.
- Anstrazole & letrozole are nonsteroidal aromatase inhibitors approved recently by FDA as first-line treatment of postmenopausal women with hormone receptor positive locally advanced or metastatic breast cancer.
- They competitively inhibit aromatase by binding to CYP450 subunit of the
enzyme.
[pic]
- Both drug are used orally as 1-2.5 mg Tablets.
- Letrozole metabolized slowly in humans by CYP34A & found to be in vitro
inhibitor of CYP2C19, an isoform of CYP which is linked to aromatase enzyme.
- Anastrazole (Arimidex) & letrozole (Femara) are used for advanced breast cancer.
- They can cause hot flashes, nausea & vomiting.
3. GnRH Agonists & Antiandrogens
- Hormonal therapy of prostate cancer targets the removal of stimulatory effects of male hormones (testosterone & dihydrotestosterone) on the prostate cancer cells.
- Example of this is the use of agonists of gonadotropin-releasing hormone (GnRH), also known as Luteinizing Hormone Releasing Hormone, LHRH.
- Although these agents initially increase testosterone level, they later decline its level through down-regulation (desensitizing), which take up to 4 weeks & leads to castrate testosterone level.
- Combination of GnRH agonists with antiandrogens will minimize the initial
testosterone level & prostate growth increase (flare phenomenon).
- The two most common GnRH agonists are leuprolide & goserelin.
- These are non-peptides differing from the natural hormone GnRH only at 2 locations.
- Leuprolide acetate (Lupron, Lupron Depot) is used as palliative therapy of prostate carcinoma & endometrosis as iv injections (5 mg/ml).
- It can cause gynecomastia, impotence, hot flashes, nausea & vomiting.
- Goserelin (Zoladex) is indicated for advanced prostate carcinoma as iv injections (3.6 mg/vial) or implants (10.8 mg). Toxicity: similar to lupron.
4. Antiandrogen Drugs
- Flutamide, bicalutamide & nilutamide are nonsteroidal antiandrogens which inhibit
androgen receptor translocation to the nucleus in target tissue, hypothalmus & prostate, which block the action of testosterone & DHT.
- Flutamide & bicalutamide are used in combination with GnRH agonists to prevent
the flare phenomenon in treating prostate cancer.
- Flutamide (Eulexin) & bicalutamide (Casodex) are well absorbed orally.
- Flutamide is activated by metabolic oxidation to it’s a-hydroxy derivative,
an active metabolite.
[pic]
- Flutamide & bicalutamide are indicated for metastaic prostate carcinoma, used as capsule (125 mg) or tablets (50 mg), respectively.
[pic]
- Toxicity: Gynecomastia, impotence, hot flashes, nausea & vomiting.
- Nilutamide (Nilandron) is another antiandrogen drug used as a single drug therapy with surgical castration to block the action of testosterone & DHT.
[pic]
- It is used as tablets (50 mg each) for metastatic prostate carcinoma.
- Toxicity: Hot flashes, nausea & vomiting.
5. GnRH Antagonists
- A new drug application was submitted for Abarelix which is a GnRH antagonist.
- It is a peptide with some structure similarity to the natural GnRH.
[pic]
6. Combination Therapy
- Common & highly effective in cancer therapy.
- It depends on using drugs which individually are effective against a special cancer type & using the individual agent at an effective dose.
- Each drug in the combination should have a unique mechanism of action & the combination will be particularly useful if the drugs did not have overlapped toxicities.
- The intent is to totally destroy cancer cells.
- Table: Text Book, pages 947-949.
- Metastasis requires the growth of a new network of
blood vessels. Angiogenesis is the recruitment of new blood vessels.
- Tumor angiogenesis is the proliferation of a network of blood vessels
that penetrates into cancerous growths, supplying nutrients, oxygen & removing waste products.
- Angiogenesis is directly related to metastasis.
- Angiogenesis may be induced by increased production of angiogenic factors
or suppressed production of angiostatic factors
- The use of anti-angiogenic compounds in cancer area started to attract more attention with the discovery of the first pro-angiogenic molecules bFGF & VEGF
7. Angiogenesis & Oncology
- Angiogenesis inhibitors were found to restrain the growth of primary tumors and reduce their metastasis rate by 20-folds.
- Several anti-angiogenic compounds currently undergoing evaluation in phase I- III clinical trials either alone or combined with cytotoxic therapeutics.
- Certain tumor dormancy for several years is attributed to the lack of angiogenesis.
- Unlike standard cancer drugs, angiogenesis inhibitors target dividing endothelial cells rather than tumor cells & other angiogenesis mediators.
- Anti-angiogenic drugs are not likely to cause bone marrow suppression, gastrointestinal symptoms, or hair loss side effects.
- Anti-angiogenic drugs may not necessarily kill tumors, but rather hold them in check indefinitely, increasing the survival time &/or time of disease progression.
- Drug resistance is a major problem with conventional chemotherapy because most cancer cells are genetically unstable & more susceptible to mutations &
hence, they likely tend to produce drug resistant cells.
- Angiogenic modulators target normal endothelial cells, which are genetically stable, drug resistance may not develop.
- Anti-angiogenic therapy aims at stopping tumor growth which reduces the tumor burden of the body & may increase the efficacy of other therapies.
- Limiting tumor number will enhance chemotherapy, hyperthermia, radiation, &
immune therapy & hence their com bination with anti-angiogenic therapy is indicated.
Mechanisms of anti-angiogenic drugs
[pic]
- The FDA approved Avastin (Bevacizumab) in February 2004.
- Avastin is approved for use in combination with intravenous 5-Fluorouracil-based chemotherapy as a treatment for patients with first-line, or previously untreated, metastatic cancer of the colon or rectum.
- The Avastin FDA approval is based on data from a large, placebo controlled, randomized study demonstrating prolongation in survival of patients treated with Avastin plus the IFL(5- FU/Leucovorin/CPT-11) chemotherapy regimen by
approximately 5 months, compared to patients treated with the IFL chemotherapy regimen alone (20.3 months versus 15.6 months).
- AVASTIN™ (Bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that binds to & inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in in vitro & in vivo assay systems.
- Bevacizumab has a molecular weight of approximately 149 kilodaltons.
- AVASTIN is a clear to slightly opalescent, colorless to pale brown, sterile, pH 6.2 solution for intravenous (IV) infusion.
- AVASTIN is supplied in 100 mg & 400 mg preservative-free, single-use vials to deliver 4 ml or 16 ml of AVASTIN (25 mg/ml).
- Toxicity: Gastrointestinal perforations/wound healing complications, hemorrhage, hypertensive crises, nephrotic syndrome & congestive heart failure.
Summary
5. Miscellaneous Agents/natural products:
- Epipodophyllotoxins: etoposide & teniposide
- Hydroxyurea, mitotane
- Retinoids: tretinoin, alitretinoin
- Camptothecins: topotecan & irinotecan
- Profimer
6. Hormonal Therapy:
- Antiestrogens: Tamoxifen & toremifene
- GnRH Agonists: Leuprolide acetate, Goserelin
- Antiandrogens: Flutamide, bicalutamide & nilutamide
- GnRH Antagonists: Abarelix
7. Antiangiogenic Drugs: Avastin
Angiogenesis inhibitors in clinical trials
|Drug |Angiogenesis Mechanism |Origin |
|BMS-275291 |Blocks matrix breakdown |Synthetic |
|Dalteparin (Fragmin) |Blocks matrix breakdown |Natural origin |
|Suramin |Blocks matrix breakdown |Synthetic |
|2-Methoxyestrdiol |Inhibits endothelial cells |Natural product |
|Thalidomide |Inhibits endothelial cells |Synthetic |
|CC-5013 (thalidomide analog) |Inhibits endothelial cells |Synthetic |
|Combretastatin A4 phosphate |Inhibits endothelial cells |Natural product |
|LY31761 |Inhibits endothelial cells/ Protein kinase |Synthetic |
| |C β inhibitor | |
|Genistin (Soy isoflavone) |Inhibits endothelial cells |Natural product |
|AE-941 (Neovastat) |Block angiogenesis activators |Natural product |
|Anti-VEGF antibody (Avastin, |Block angiogenesis activators |Natural product |
|Bevacizumab) | | |
|Interferon-α |Block angiogenesis activators |Natural product |
|PTK787/ZK 222587 |Block angiogenesis activators |Synthetic |
|VEGF-Trap |Block angiogenesis activators |Natural product |
|ZD6474 |Block angiogenesis activators |Synthetic |
|EMD 121974 |Inhibits endothelial-specific |Natural origin |
| |integrin/survival signaling | |
|Anti-Anb integrin antibody |Inhibits endothelial-specific |Natural product |
|(Medi-522, Vitaxin) |integrin/survival signaling | |
|Carboxyamidotriazole |No specific mechanism |Synthetic |
|Celecoxib (Celebrex) |COX-2 inhibitor/no specific |Synthetic |
| |angiogenesis mechanism | |
|Rofecoxib (Vioxx) |COX-2 inhibitor/no specific |Synthetic |
| |angiogenesis mechanism | |
|Halofuginone HBr |No specific mechanism |Synthetic |
|(Tempostatin) | | |
|Interleukin-12 |No specific mechanism |Natural product |
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