DRUG METABOLISM



ANTITUMOR AGENTS

I. Cell Cycle

II. Antimetabolites

III. Alkylating Agents

IV. Topoisomerase Inhibitors

V. Antimitotic Agents

VI. Endocrine Agents

A. Adrenocorticosteroids (Glucocorticoids)

B. Antiandrogens

C. Antiestrogens

VII. Biological Response Modifiers, Chemoprotectants, and Others

A. Biological Response Modifiers

B. Chemoprotectants

C. Monoclonal Antibodies

D. Cell Growth Inhibitors

E. Antisense Drugs

F. Gene Therapies

G. Vaccines

VI. Endocrine Agents

A. Adrenocorticosteroids (Glucocorticoids)

Prednisone and Dexamethasone

B. Antiandrogens

1. Leuprolide (Lupron)

Goserelin (Zoladex)

Abarelix (Plenaxis)

| |[pic] |

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|2. Flutamide (Eulexin) | |

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|Bicalutamide (Casodex) | |

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|Nilutamide (Nilandrone) | |

C. Antiestrogens

1. Tamoxifen Citrate

[Nolvadex]

[pic] [pic]

Toremifene

[Fareston]

Fulvestrant

[Faslodex]

2. Anastrozole Letrazole

[Arimidex] [Femara]

[pic] [pic]

| |[pic] |

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|3. Exemestane | |

|[Aromasin] | |

VII. BIOLOGICAL RESPONSE MODIFIERS, CHEMOPROTECTANTS, AND OTHERS

A. Biological Response Modifiers

1. Cyclosporin - Cyclic peptide used as an immunosuppressive agent in bone

Tacrolimus - marrow transplant patients. It binds to immunophilin receptors on T-lymphocytes thereby decreasing their activation.

A major dose-limiting toxicity is nephrotoxicity (and sometimes hepatotoxicity).

Cyclosporin is metabolized by CYP3A isoforms to inactive products and CYP3A inducers can increae its rate of metabolism and cause organ rejection. Inhibitors of CYP3A can increase cyclosporin drug concentrations and lead to nephrotoxicity.

2. BCG - A live, attenuated strain (Bacillus of Calmette and Guérin) of Mycobacterium bovis that when instilled into the bladder (intravesical administration) causes an inflammatory response leading to an infiltration of granulomatous cells (neutrophils, monocytes, etc.) that kill bladder cancer cells.

Cannot be used with immunosuppressive therapy.

3. Interferons - These are glycoproteins synthesized by lymphocytes, macrophages and fibroblasts that bind to cellular receptors leading to activation of RNAases that degrade RNA produced by, e.g., oncogenes.

Major toxicities are flu-like anaphylaxis, hypotension and tachycardia; sometimes liver failure.

They are P450 inhibitors.

Interferon-(-2a (Roferon-A) is used primarily for CML, non-Hodgkins lymphomas, multiple myeloma and hemangiomas. Interferon-(-2b (Intron-A) is used primarily for malignant melanoma and Kaposi's sarcoma.

4. Interleukins - Cytokines produced by a variety of cells as an inflammatory response.

IL-1 enhances platelet recovery, e.g., after carboplatin therapy.

IL-2 is produced by altered T-lymphocytes and transforms them to Lymphokine Activated Killer (LAK) cells. Use IL-2/LAK therapy for renal cells carcinomas and melanoma. Can cause life-threatening hypotension and pulmonary/peripheral edema (decrease by giving lower doses in combo with IFN-(-2b).

5. Granulocyte Colony Stimulating Factor (G-CSF) and Granulocyte Macrophage

Colony Stimulating Factor (GM-CSF)

These are recombinant hematopoietic growth factor proteins that stimulate the bone marrow to produce granulocytes (G-CSF) or graulocytes and monocytes (GM-CSF). They are used to increase white blood cell production in chemotherapy regimens that cause BMD and in patients undergoing bone marrow transplants.

They can cause fever and severe flu-like symptoms.

6. Retinoic Acids - All trans-retinoic acid (Tretinoin) causes normalization of an abnormal retinoic acid nuclear receptor found in promyelocytic leukemia.

7. Arsenic Trioxide (Trisenox) - An old poison that in the right doses preferentially kills promyelocytic leukemia cells by apoptotic and other mechanisms.

B. Chemoprotectants (see previous discussion of Leucovorin and Mesna)

1. Dexrazoxane (Zinecard) -

| | |

|[pic] |A piperidinedione that chelates iron and protects cardiac cells against |

| |free radical formation. Used to protect against cardiotoxicity caused by|

| |anthracycline antibiotics |

2. Amifostine (Ethyol) -

| |A thiophosphonate prodrug that is hydrolyzed by alkaline phosphatase in |

|[pic] |tissues to an aminothiol that protects some cells from toxic effects of |

| |antitumor agents, e.g., cisplatin nephrotoxicity, and leads to less BMD |

| |with carboplatin, paclitaxel, cyclophosphamide, and melphalan. |

C. Monoclonal Antibodies - Antibodies directed against specific proteins associated with some tumors.

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|1. Trastuzumab (Herceptin) - |MAb directed against the HER 2/neu protein (erB2), an oncogenic protein found in |

| |some advanced breast cancers that causes aggressive spread of the cancer. |

|Problems: Has caused some deaths due to immunotoxicities (allergic | |

|shock, pulmonary edema) and weakens heart muscle ( CHF | |

|Contraindicated with anthracyclines. | |

| 2. Rituximab (Rituxan) - |MAb that binds to CD-20 antigens on B-lymphocytes ( their destruction - Use in |

| |refractory non-Hodgkins B-cell lymphomas. |

|Problems: Anaphylaxis, infusion reaction (hypotension, chills) | |

| | |

|3. Ibritumomab (Zevalin) - |A radioimmunoconjugate with the same MAb as Rituximab plus a chelated Yttrium-90 |

| |(-emitter ( radioactive destruction of B-lymphocytes |

|Problems: Same as Rituximab | |

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|4. Bexaar |Same as Ibritumomab but with I131 (-emitter |

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|5. Gemtuzumab (Mylotarg) - |Monoclonal Ab - Toxin conjugate in which MAb binds to CD33 antigen on |

| |myeloblastic leukemia cells and linker toxin (calicheamycin) kills the cells. |

|Problems: BMD and hepatotoxicity from toxin plus severe hypersensitivity|Used to treat AML. |

|reaction (flu-like) | |

| | |

|6. Denileukin Diftitox (Ontak) - |MAb - toxin conjugate that binds to CD25 anti–gens of the IL-2 receptor expressed|

| |on lymphoma T-cells and linker diphtheria toxin kills the cells. Use in |

|Problems: Allergic reactions and hypotension |non-Hodgkins T-cell lymphomas. |

| | |

|7. Alemtuzumab (Campath) - |MAb that binds to the CD52 antigen on the surface of malignant lymphocytes ( cell|

| |lysis (use in CLL) |

|Problems: Hematological toxicities | |

| 8. Bevacizumab (Avastin) - |Monoclonal antibody binds to vascular endothelial growth factor (VEGF) ( |

| |inhibits angiogenesis in colorectal cancer |

|Problems: Bleeding, GI perforations, stroke, cardiotoxicity with | |

|anthracyclines | |

| 9. Cetuximab (Erbitux) - |Monoclonal antibody binds to and inhibits the epidermal growth factor (EGF) |

| |receptor ( blocks angiogenesis and tumor invasion |

|Problems: Rash and severe N/V/D | |

| 10. Panitumumab (Vectibix) |A MAb similar to Cetuximab with same activity in treating colorectal cancers |

D. Cell Growth Inhibitors -

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|1. Imatinib Mesylate (Gleevec) - |Inhibits Bcr - Abl tyrosine kinase that phosphorylates proteins that cause cell |

| |proliferation in myeloid cells which contain the mutated Philadelphia chromosome |

|Problems: Edema, N/V/D, BMD and hepatotoxicity; plus inhibits and is |found in >90% of CML patients |

|metabolized by CYP3A4, + some cardiotox | |

| | |

|2. Dasatinib (Sprycel) - |Same mechanism but binds to more and different conformers of the enzyme |

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|3. Gefitinib (Iressa) - |Inhibits phosphorylation of tyrosine kinases, especially the Epidermal Growth |

| |Factor Receptor tyrosine kinase, thereby blocking tumor invasion and |

|Problems: Interstitial lung disease, rash, N/V/D; plus metabolized by |angiogenesis. Approved use in Non-Small cell lung cancer. |

|CYP3A4 | |

| | |

|4. Erlotinib (Tarceva) |Similar to Gefitinib, but apparently more effective in non-small-cell lung cancer|

| |and also in pancreatic cancer. |

| | |

|5. Bortezomib (Velcade) - |Inhibits the 26S proteosome that normally degrades signal transduction and cell |

| |cycle regulatory proteins ( ( activity of factors for cell growth. Approved for |

|Problems: Peripheral neuropathy, BMD, N/V/D |use in multiple myeloma. |

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|6. Sunatinib (Sutent) |Tyrosine kinase inhibitor that decreases activity of vascular endothelial growth |

| |factor and platelet-derived growth factor ( blocks angiogenesis in renal cells |

|Sorafenib (Nevaxar) | |

| | |

|Problems: Skin rashes, diarrhea, hypertension | |

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E. Antisense Drugs - Antisense oligonucleotides are short pieces of DNA that are complementary to a segment of messenger RNA (mRNA) that bind to the oncogenic RNA of interest and block translation of its oncogenic protein.

In development - Antisense oligos to bcl-2 mRNA overexpressed in melanoma cells and BCR-ABL mRNA overexpressed in CML cancer cells.

F. Gene Therapies - Goal is to modify the cellular genome for therapeutic benefit by:

1. Insertion of cancer fighting genes (e.g., gene for tumor necrosis factor) into cancer cells or into a virus that only infects cancer cells.

2. Insert enzyme-activating genes into cells (GDEPT = gene-directed enzyme prodrug therapy) or via viruses (VDEPT = virus-directed enzyme prodrug therapy) that encode enzymes that convert prodrugs to their toxic products. Examples - trials with a carboxypeptidase (CPG2) gene that cleaves a prodrug of doxorubicin, and a P450 gene that converts cyclophosphamide to its toxin.

G. Vaccines - 1. HPV Vaccine (Gardasil) - Active against 2 HPV strains that cause cervical cancer, +2 strains that cause genital warts.

2. Melacine( by Corixa, a Seattle-based company. Mixture of modified melanoma tumor cells and an immune stimulant ( production of Abs that kill melanoma cells.

Other reports of successes with fusion of renal tumor cells with dendritic cells to treat renal carcinoma.

Ongoing studies with vaccines to treat breast, prostate and lymphoma cancers.

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