University of Arizona



Class and NameMOAClinical usesAdverse effectsMechs of drug resistance & metabolismAntimetabolitesmethotrexate (MTX) Leukovorin (LV)PremetrexedInhibition of DHFR leading to partial depletion of reduced folatesGestational carcinoma, hydatidiform mole, ALL (prevents meningeal leukemia & combo tx), br ca, epidermoid ca’s of head & neck, adv’d mycosis fungoides, lung ca (esp sq & sm cell), advance NHLN/V, photosensitivity, myelosuppression –IV (nadir 7 -10 d, recover by 14-20d)-renal : direct to renal tubular cells & intratubular precipitation of methotrexate and metabolites (high dose IV)-hepatic: ↑ed transaminase (oral, esp daily dose)-mucositis (3-7d): IV-CNS: (intrathecal, iv sometimes)1. Acute chem. Arachnoiditis, arises imm after admin – severe HA, nuchal rigidity, vomiting, fever, and inflame cells in CSF2. subacute: ~10%, usu 3-4th course, m common in those w/ active meningeal leukemia – motor paralysis, CN palsies, seizure, coma; cont’d intrathecal tx may ->death3.chronic demyelinating encephalopathy: usu in kids mo-yrs after receiving intrathecal MTX-diarrhea-defective transport common (ALL & osteosarcoma)-glutamic acid residue 45-drug efflux pumps: multi resistant-asstd protein family (MRP -1,2,3, &4); 1 is primary route; overexp of efflux pump-↓ ability to form MTX polyglutamatesdiminish toxicity & counteract effects of impaired MTX elimination and of inadvertent overdosage of folic acid antagonistsAfter high dose MTX tx in osteosarcoma & in adv’d colorectal caAllergic sensitization, including anaphylactoid reactions and urticaria Met: liverElim: urine(90%) & fecesInhibits dihydrofolate reductase and thymidine synthetase-admin folic acid & B12 supplements 2 wks prior tx-solid tumors: malignant mesothelioma, breast, pancreatic, head & neck, non-sm cell lung, colon, gastric, cervical, bladder ca’s-myelosuppression (ANC nadir btwn 8-9.6 d w/ return to baseline 4.2-7.5 d later)-mucositis-GI toxicity-skin rash/desquamatn(40%)-hepatotoxicity: reversible transaminasemia-anorexia-N/V (84%/58%)-infusion rxn: shiveringExcreted 90% unchanged in urinePyrimidine AntagonistsAzacitidine (5 –Aza)DecitabineCapecitabine (oral 5-FU)Cytarabine(Ara-C, Cytosine, Arabosinide, Arabinosylcytosin)Flurorouracil(5-FU, 5-fluorouracil)Gemcitabine(difluorodeoxy-Cytidine, dFdC)Pyrimidine nucleoside analog of cydidine-hypomethylation of DNA & direct cytotoxicity on abn hematopoietic cells in BMMDS, CMMLMyelosuppression (dose limiting toxicity),- IV: ↑ed serum Cr, reanl failure, renal tubular acidosis, hypokalemia, hepatic coma-subQ: N/V, pancytopenia, pyrexia, , diarrhea, fatigue, injection site erythema, constipation, ecchymosisMet by liver and excreted in urine-direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosisMDSnonFDA: CMMLMyelosuppression is dose limiting, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, hyperglycemia-uncommon: A fib, cardiac arrest, HF, cerebreal hemorrhage, MI, intracranial hemorrhage, pneumonia, pulm edemaPro-drug of 5-FU; converted in tumor cell to 5-FUMet breast, met colonMyelosup (lymphonenia in 94%); diarrhea, N/V, stomatitis, hand-foot syndrome (45%) – pain, redness, scaling of skin of palms/soles; faigue, anorexia, paraesthesia, HA, cardiotoxicity in 3% can be fatal – MI, angina, dysrythmias, arrest, failure, ECG changes-as pass thru S phase, incorporates into cell & blocks polymerization of DNA by inhibiting DNA polymerase & leads to shortened DNA strandsAML, ALL, CML, CNS leukemia, HD, NHLMyelosuppression (14-21d), hepatic-jaundice and elevations in serum bilirubin, transaminases & alk phosphatase, alopecia, GI-diarrhea, anorexia, derm –marcopap rash, erythema, blistering/peeling of skin, esp on hands and feet), hand-ft syndrome->-High dose Ara-C toxicity:Cerebellar dysfxn (20%), usu w/in 2-8 days, accumulation of ara-U or ara-CTP causes nerve damage AND conjunctivitis/corneal toxicity (use steroid eye drops)Analog of pyrimidine uracil-inhibits thymidylate synthase (TS) by FdUTP ->affects DNA synthesisIncorporation into cell DNA and RNAColorectal, gastric, pancreatic, breast, basal cell carcinomanonFDA: liver, head & neck, ovarian, cervical-DPD deficiency:->rare, inherited disorder of pyrimidine degredation d/t low/deficien DPD in caucasion (~5%) and AA (~.1%); pts; no evidence of fluorouracil degredation in these pts--toxicities: diarrhea, stomatitis, myelopsuppression, N/V, rectal bleeding, vol depletion, skin changes, neurologic!-myelosuppression (7-14 d nadir w/ rapid recovery), possibility of febrile neutropenia- mucositis-diarrhea/nausea-skin: alopecia, maculopap rash of extremities-cardiac: myocardial ischemia & angina in 2%-CNS: somnolence & cerebellar ataxia in ~1%-ocular: conjunctivitis, lacrimation, blepharitis, photophobia-beware those w/ dihydro-pryrimidine DH deficiency!- tx w/ 5-FU can be life threatening for even partial deficiencies-incorporation into DNA strands, inhibiting replication and repair blocking nucleotide productionMet pancreatic, NSCLCnonFDA: bladder, breast, ovarian, malignant mesothelioma, NSCLCMyelosuppression (anemia 68%, leucopenia 62%, thrombocytopenia 24%)-N/V, Diarrhea, stomatitis, ↑es in serum transaminases, mild protein/hematuria ->can lead to irreversible renal failure (manifests as HUS), rash, fever/fluish sxs, dyspnea, peripheral edemaExcreted in urinePurine Antagonists1. .Adenosine Analogs-general a. Fludarabine b. Cladribine c. Pentostatin2.Guanine Analogs (Thiopurines) a. 6-mercaptopurine (6-MP) b.6-thioguanine (6-TG)-Inhibition of DNA repair & synthesis-Inhibition of RNA fxn-inhibiting synthesis of substrates needed for DNA synhthesis-cell-cycle specific for S phaseCLL, low grade NHL, AML, Waldenstrom’s macroglobinemia, cutaneous T-cell lymphoma, BM transplant-heme: myelosuppression (severe immunosuppression -> opp infections (OI’s) d/t ↓CD4’s -> herpes zoster, candida, PCP-CV: edema, chest pain, hypotension-fever (flu-like sxs in 25%)-derm: alopecia, rash->CNS:peripheral neuropathy, blindness, coma, death-GI: diarrhea, N/V-pulm: pna, pulm hypersensitivity, interstitial pneumonitisHariy cell leukemia, CLL, AML, NHL, Waldenstrom’s macroglobinemiaMyelosuppression, CD4 & 8↓ 6 mo, OI’s, candida /aspergillosis (use px abx)-fever-rash-fatigue/HA-mild nauseaHairy cell leukemia, NHL, CLL, T-cell leukemia/lymphomaMyelosuppression (esp T & B lymphocytes (esp CD4) – recovery prolonged & incomplete, fever & OI’s in 2nd and 3rd course)-dry skin, rash-fatigue, seizures-mild N/V-renal: tubular toxicity (↑ Sr CR) – use hydration-inhibit de novo purine synthesis & purine interconversion rxns by falsely incorporating into RNA/DNA-cell specic for S phaseMet in liver and excreted in urine-Results from decreased ability to form cytotoxic nuncleotide metabolites-resistant cells express either complete or partial deficiency of HGPRT (or altered affinity)ALL, CML, AML, NHLPancytopenia-hepatic: jaundice, cholestasis, ascites, hepatic encephalopathy, ↑ liver enzymes-GI: N/V/D, abd pain-derm; necrosis, rash, HAALL, AML, CML, NHLMyelosuppression (leucopenia, thrombocytopenia m com), ↑liver enzymes, VOD, jaundice, N/V/anrxa, stomatitis, severe diarrhea, rash/dermatitis, tumor lysis syndromeHydroxyureaS phase depEnzyme that inhibits ribonucleotide reductase (nec for DNA synthesis)AML (blast crisis), sickle cellMyelosuppression, skin: rash, hyperpigmentation, pruritis, radiation recall50% met in liver and 50% excreted unchanged in urineMicrotubule Targeting Agents: Vinca AlkyloidsNaturally occurring nitrogenous base in periwinkle plant-inhibit microtubule assembly-rapidly/reversibly binds alternative sites on tubulin & disrupts microtubule fxn leading to metaphase arrest-Pleitropic or multidrug resistance (MDR) -> results in decreased drug accumulation & retention-alteration in α & β tubulins: leads to ↓ed drug binding or ↑ed resistance to microtubule disassemblyVincristineVinblastineVinorelbineTaxanesPaclitaxelDocetaxelEpothilonesIxabepilone (Aza-epothilone B)ALL, HD, NHL, MMTesticular Ca, CLL, Aid’s-related Kaposi’s sarcoma, Ewing’s sarcoma, rhabdomyosarcoma, SCLC, medulloblastoma, cervical CA, CML-Neuro: peripheral neuropathy, parasthesia, ↓DTR’s, gait changes, pharyngeal/paratid pain(esp cristine/relbine)-adynamic ileus: mimics surgical abd-fatal ascending paralysis post intrathecal admin-> leads to resp failure/death-GI: abd cramps, wt loss, N/V/D, oral ulcerations, paralytic ileus, int necrosis, anorexcia-mucositis, pharyngitis, stomatitis-constipation (esp vinorelbine)-heme: .vincristine: mild anemia, leucopenia, thrombocytp.vinblastine: myelosup. (esp neutropenia).vinorelbine: neutropenia-derm: alopecia, photosentivity-CV: chest pain, htn, MIMet testicular ca, bladder, prostate, HL, NHL, Kaposi’s sarcoma, breast ca, mycosis fungoides, choriocarcinoma, CML, cutaneous T-cell lymphoma, head & neck, lung, melanoma, neuroblastoma, ovarianNSCLC, met br ca, hormone refractory prostate ca, cervical, ovarianPromotes assembly of microtubules from tubulin diamers, and stabilizes microtubules by preventing depolymerization resulting in inhibition-hypersensitivity rxn (HSR)-neutropenia-derm: alopecia-onycholyosis, hand-ft/palm-plantar dysesthesia syndrome, urticaria, alopecia-fluid retention (↑ed cap permeability allows leakage of fluid)-peripheral neuropathy-transient myalgia, myopathy-cardiac: hypotension, bradycardia, Docetaxel more water soluble (more potent) than paclitaxel -met: p450-resistance: same as vinca alkyloidsAbraxane: (alb bound paclitasel)-facilitates the admin of water insoluble contentsOvarian ca, br. Ca, NSCLC, Aids related Kaposi’s sarcoma, bladder, head & neckHypersensitivity: major in 25% and minor in 40% ->bronchospasm, urticaria, hypotension, rash, flush-N/V, mucositis- arrhythmias-neurotoxicityExcreted in bileBreast ca, NSCLC, Prostate Ca, Gastric aden-ocarcinoma, head and neckMaj and minor HSR’s in 31%-D/N/V-erythematous, prurtic maculopap rash of forearms and hands in 75%Excreted in feces-Epothalone A has similar tubular polymerization as paclitaxel-Epothalone B more potenet than A or paclitaxel-binds β-tubulin subunit of microtulbules-promotes prolif and resists breakdown of mitotic spindles-binds multiple sites on microtubulesMet breast cancer-neutropenia, HSR’s, cardia (LV dysfxn or supraventric arrhythmia)-sensory neuropathy, CN palsy, ocular/visual changes, athralgia, myalgia, increased transaminases, N/V/A/D, abd pain, alopecia, rashNot as susceptible to resistanceMet by liver; excreted in urine and fecesG1 specific agents:Asaparaginasehydrolyzes circulating L-asparagine to aspartic acid and ammonia resulting in inhibition of protein synthesisALLHSR, ↓clotting factors (IX, XI, PC, PS, antithrombin III, fibrinogen; pancreatitis, neurologic toxicity, fever, chills, N/VG2 Specific Agents: Topoisomerase IhibitorsCampto-thecin analogs (inhibit topo-isomerase I)-TopotecanEpipodophyllotoxins (inhibit topo-isomerase I)-IrinotecanEtoposide (VePeside, VP-16)-topoisomer-ase II inhibitorANthra-cyclinesDoxo-rubicinDauno-rubicinEpirubicinIdarubicinMitroxantroneLipsomal DoxrbicinTopoisomerases are nuclear enzymes which make transient breaks in DNA allowing the cell to manipulate its topology?Functions: DNA replication, DNA transcription, Chromosomal segregation, DNA repair->-topoisomeraseI: acts on one strand of DNA, removes negative supercoils, no involvement in DNA replication, expression continuous during G2 phase of the cell cycle & in quiescent cells, ATP independent-> Topoisomerase II: Acts on both strands of DNA, Removes positive supercoilsInvolved in DNA replicationExpression increases during S phase of cylcle ~absent in quiescent cellsATP dependent-alterations in topoisomeras I-inadequate accumulation of drug in tumor-P-glycoproteins and MDR efflux pumps-MOA: stabilizes cleavable complex where topoisom. I covalently bound to DNA at a single-stranded break site-conversion to lethal DNA damage follows when a DNA replication fork encounters these cleavable complexesOvarian ca, SCLCMyelosuppression (esp neutropenia), N/V, stomatitis, diarrhea, transient ↑s in liver enzymes, skin rash and alopeciapH conversion to active form; minimal liver metabolism–Excreted in urine-first converted by carbosylesterase to active metabolite SN-38, same mech as aboveMet colon ca->Can lead to dev of AMLMyelosuppression, neutropenic fever, diarrhea –acute cholinergic like sxs, D/N/V/A, chills, malaise, dizzy, visual disturbance, salivation, lacrimation, asx bradycardia, delayed-onset diarrhea, N/V, alopecia, fatigue, skin toxicity, increased liver transaminases–metabolized by the liver and intestinal mucosa–Excreted in fecestopoisomerase II inhibitor-single strand breaks in DNAand inhibits topoisom II-late S phase/early G II-production of free radicals-disrupt membrane transportSCLC, testicular ca (refractory), ALL, AML, BMT, MM, MDS, lymphoma, gastricMyelosuppression, N/V, alopecia, CHF, MI, stomatitis, 2? AML (<5yrs)S phase specific-inihibit topoisomerase II which leads to apoptosis-intercalation into DNA leading to inhibited synthesis Myelosuppression (can lead to AML)Neutropenia–GI toxicity: mucositis, diarrhea, delayed vomitting–Cardiotoxicity:?Acute: arrhythmias, pericarditis, myocarditis?Chronic: CHF, dilated cardiomyopathy–Red-orange urine discoloration–Radiation recall skin reaction, hand-foot syndrome*Dexrazoxane:-indicated for the reduction of cardiomyopathy asst’d w/ doxorubicin admin in women w/ met breast ca w/ high dose-may add to myelosuppressionBluish discoloration of sclera, urine, and finger nails; Less cardiotoxicity and N/V than, doxorubicin, HSR, Hand/foot syndromePresence of efflux pumps, P-glycoprotein and multiple-resistance associated protein, which belongs to the ATP binding cassette family of transporters-pt mutations to binding site of DNA topoisomerase gen-increased inactivation of superoxide free radicals breast, soft tissue sarcomas, ovarian, NHL, HD, ovarian, ALL, AML (and a million other things)ALL, AML, BreastALL, AMLBreastSlightly dif MOA, ↓ed free radical production, DNA-reactive agent that intercalates into DNA thru hydrogen bonding causing cross links and strand breaksAML, ALL, Prostate Ca –hormone refractory phase,AMLevades detection and destruction by the immune system–increases the time the drug is in the body–majority of the drug staysinside the liposome while in the blood (at least 90%)Kaposi’s sarcoma, ovarian caCell Cyle Specific Drugs:PlatinumsCisplatinCarboplatinOxaloplatinAlkylating AgentsCyclphos-phamideIfosphamideMelphalanChlorambucilCarmustineBusulfanNon classic alkylating agentAntitumor AbxBleomycinMitomycinArsenic TrioxideTrentinoin (ALL-transretinoic acid)Cell cycle nonspecific-form DNA intrastrand adducts as opposed to DNA interstrand cross linksHSRAltered cell accumulation of drug d/t impaired influx or enhanced efflux-cytosolic inactivation of drug-increased DNA repair-altered apoptotic process: drug induced apoptosis may be altered in cells that have MMR defects ->results in enhanced tumor cell survival and ↑ed resistance-widely distributed thru body and excreted in urinecervical, esophageal, gastric, head/neck, lung, testicular, ovarian, bladder, breast, NHLPeripheral neuropathy, nephrotoxicity, tinnitus, delayed N/V, myelosuppressioncarboplatin induces same adduct formation as cispllatin, but must use 10x higher concentrationBreast, lung, ovarian, NHL, bladder, testicular, head/neckAnemia > thrombocytopenia, delayed N/VColorectal, ovarian, gastricAcute-neuropathy (parasthesia, dsysthesia, of hands, ft, throat), chronic, cumulative neurotoxicity, N/V-Alkylator attatches to alkyl groups to DNA bases resulting in the DNA being fragmented by repair enzymes preventing DNA synthesis and RNA transcription-Crosslinks w/ DNA resulting in inhibition of DNA synthesisIncreased risk of 2?malignanciesNitrogen mustardBreast, ovarian, NHL, sarcomas, endometrial, CLLMyelosuppression(risk of MDS), hemorrhagic cycstitis, SIADH, hyperpigmentation, delayed vomiting , Nitrogen mustardGerm cell tumors, sarcomas, lymphoma, lungMyelosuppresion(risk of MDS) ,delayed N/V, dysuria, neurotox, SIADH, hemorrhagic cystitisNitrogen mustardMMMyelosup, N/V/D, mucositis, HSRNitrogen mustardCLL, HD, NHL, MMUricaria, myelosup, pulm fibrosis, neurotoxicityNitrosurea Brain tumors, HD, NHLMyelosup, pulm fibrosis, N/V, renal and hepatotoxicityAlkyl sulfonates BM transplantMyelosuppression, N/V, hepatotox, VOD, electrolyte abn’s, interstitial pneumonitisnon-classice alkylating agent–Methylation of guanine residues in DNA which inhibit DNA, RNA, and protein synthesisLeukopenia, thrombocytopenia–N/V, anorexia–Headache, and dizziness–Elevated LFTs (40%)–Skin: rash, itching, photosensitive–Increased incidence of PCP (prophylactic treatment with Bactrim)From fungus-activation by oxidized iron to form oxygen free radicals resulting in DNA breaksTesticular, HDsubacute and chronic pulmonary fibrosis, mucositis, skin (erythema/ hyperpig), HSR, vascul events: MI/ CVA/ RaynaudsIntracell met; excreted in urineAntitumor antibiotic –isolated from Streptomyces caespitosus–Cross-link DNA resulting in inhibition of synthesis–Inhibits transcription by targeting RNA polymeraseAnal cancer & gastiric caLeucopenia, N/V, mucositis, HUS, interstitial pneumonitis, HSRMet by liver, spleen, kidney, heart; excreted in bileApoptosis of APL cells–Degradation of the fusion protein PML/RAR-aAcute promyelocytic leukemiaCV: Prolonged QT interval–GI: N/V/D/C–HA, myalgias, and bone pain–Leukocytosis (50% of pts)–neuropathy, tremors, insomnia–cough, sob, pleural effusions–Electrolyte abnormalitiesinduces maturation of promyelocytes to myelocyte; thus decreasing proliferationAPLVitamin A toxicity symptoms: HA, fever, bone pain, nausea, vomiting, sweating, dry skin, mucositis, rash–abdominal pain–Neuro: dizziness, confusion, depression–Increasing leukocyte countHormonal Agents: TamoxifenAromatase Inhibitors-Anastrozole, Letrozole, etcFulvestrantLHRH Agonists-Leuprolide, GoserelinAnti-Androgens-bicalutimide, nilutamide, flutamideCompletely binds ER, inhibiting transcriptional processes-SERM: selective E receptor modulatorPremenopausal breast ca ptsMenopausal sxs, vaginal bleeds, peripheral edema, DVT/PE, endometrial hyperplasia/ca (2%)?Strong inhibitors of CYP2D6?SSRI’s: Paxil>Prozac>Zoloft>>EffexorInactivates aromatase and blocks the conversion of adrenal androgens to estrognPost menopausal br caHot flashes, arthralgias, HA, flu-like sxsER antagonits and downreg ER expressionMet br caAsthenia, hot flashes, flu-like sxs, HABr/prostate caHot flashes, impotence, decreased libido, tumor flare – increasing bone pain, urinary retention, back painBinds androgen receptor and inhibits androgen uptakeProstate caHot flashes, decreased libido, gynecomastia, myalgias, hepatotoxicity*monoclonal Ab’s(traztusumab): HSR*Gleevec: Imatinib*procarbazine: an alkylating agent used for HL (part of MOPP) inhibits monamine oxidase so avoid cheese, wine, smoked meat) food and drug interactions*MOPP and ABVD (tx’s for HL): can lead to MDS*ABVD: tx for HL: Adriamycin (doxorubicin), bleomycin, vinblastine and dacarbazine*MOPP for HL: nitrogen mustard(cyclophosphamide), vincristine, procarbazine, prednisone*R-CHOP: tx for NHL: Rituximab+ cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), and prednisone/prednisoloneCommon acute toxicities:Myelosupression: leucopenia, thrombocytopenia, and anemia (lowest portion (nadir) is usu 7-10 d)Febrile Neutropenia: Neutropenia: <0.5 *10^9 cell/L and <1 *10^9 cells/L w/ predicted decrease in 48 hrFever: >101 F (38.3C), and sustained tem >100 F (38 C)Infection risk correlates w/ depth and duration of neutropeniaN/V: stimulation of chemoreceptor trigger zone (CTZ) in medulla; stimulation excites dopaminergic paths which converge on adjacent emetic centerOther paths also converge on this center including cortical and peripheral cholinergic neurons and vestibular serotonin and histaminergic neuronsChemotherapy induced diarrhea:GI epithelial lining replace Q 3-5 dToxicity to epith cells leads to inflame and secretory diarrheaChemo most implicated: 5-FU, methotrexate, cytarabine, HD chemoIrinotecan causes dose limiting diarrheaEarly onset: cholinergic-mediateLate-onset: resistant to antidiarrheal tx and may be life threatening ................
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