Joseph A. De Soto M.D., Ph.D., F.A.I.C. Cancer Pharmacology Joseph A. De Soto M.D., Ph.D., F.A.I.C.

Why Cancer Pharmacology? A large number of surgeries are cancer-related. Treatment of primary neoplasm. Reconstructive procedures Staging Central line placements Debulking procedures Neuro-ablative procedures As a professional your knowledge needs to be broad as others will come to you for questions. You future responsibilities may become more than the operating room such as commanding a hospital.

Introduction Cancer is a term that describes several different disorders that have in common: 1) abnormal cellular growth 2) cellular atypia 3) cellular immortality 4) the ability to invade 5) the potential to metastasize. Cancer develops through a series of stages 1) Initiation where DNA damage occurs in a cell. 2) Promotion where the mutated cell undergoes a clonal expansion obtaining further mutations. 3) Progression where mutations expand exponentially and chromosomal instability occurs resulting in the duplication or loss of entire chromosomes. The main determinant of cancer growth is that more cells are produced than die at a given time. Frequently, the rate of growth is faster than normal tissue. Most cancers are not detectable until the mass reaches 1 cm3 in volume. This represents 108-109 cells. .

Epidemiology of Cancer 33% of Americans will develop cancer. 25% of males and 20 % of females will die from cancer % of Cancer % Death 1) 32% breast (women) 1) 28% lung 2) 32% prostate (men) 2) 18% breast (women) 3) 14.5% lung 3) 13% prostate (men) 4) 12.5 % colon 4) 10.5 colon 5) 6.5% urinary 5) 8% leukem/lymph 6.5% leukem/lymph

Cancer Treatment The pharmacological treatment of cancer currently consist of three classes of medications: 1) Chemotherapy – which tend to either interfere with DNA synthesis , damage DNA or interfere with mitosis. 2) Hormonal treatment – which blocks the stimulation of growth of tissue by hormones. Thus, hormonal treatment in a sense are anti-hormonal therapy 3) Biologicals – this is the newest class of compounds which are antibodies or small molecules that inhibit receptors on tumor cells or growth factors thus blocking the stimulation of tumor growth.

Cancer Treatment For the most part, most of our therapies eventually fail as cancer cells rapidly become resistant to treatment. In addition, we must remember that even if chemotherapy/hormonal/biological therapy kills 99.0% of cells in a 1 cm3 tumor (1 billion cells) that leaves 10 million cancer cells still alive. In a large tumor of 10 cm3 100 million cancer cell would be left alive.

Toxicity The toxicity of the cancer agents is directly due to their mechanism of action. Most chemotherapeutic agents act most efficiently during the cell cycle hence normal cells that are frequently in the cell cycle will also be damaged. The hair, the lining of the G.I. tract, the bone marrow, skin. Hormones, biologicals, chemo drugs may inhibit metabolism and energy usage and thus organs or systems with high energy needs may be damaged: Heart, kidneys, nervous system.

G0 Cell Cycle S DNA Synthesis G1 pre-DNA synthesis G2 Pre-Mitosis M mitosis Cell Cycle Anti-Metabolites Alkylating Agents, Alkylating Type Agents Hormonal Agents G0 Topoisomerase Inhibitors Anti-Mitotics Often prolonged in cancer

Anti-Metabolites Agents: Methotrexate, permetrexed, 5-fluorouracil, capecitabine, cytosine-arabinoside (ARA-C), gemcitabine, 6-mercaptopurine. Mechanism of Action: Anti-metabolites interfere with the synthesis of DNA by mimicking nucleotides or nucleosides. These drugs are most active in the S phase of the cell cycle. Methotrexate and permetrexed inhibit dihydrofolate reductase and thus inhibit purine synthesis. 5-Flourouracil and capecitabine inhibit thymidylate synthase and thus inhibit thymidine production. Ara-C mimics cytosine is incorporated into the DNA and inhibits DNA polymerase. Gemcitabine acts in a similar fashion to ARA-C. 6-Mercaptopurine inhibits glycolysis and purine synthesis

Anti-Metabolites Toxicity: Methotrexate, permetrexed – Myelosuppression and mucocytosis. Occasional alopecia and interference with gametogenesis. 5-Fluorouracil, capecitabine- fulminant diarrhea, mucositosis. ARA-C, gemcitabine – severe leukopenia, seizures when given intra-thecally. 6-Mercaptopurine – moderate bone marrow suppression

Alkylating Agents Agents: Cyclophosphamide, mitomycin, dacarbazine, nitrosoureas, thiotepa, chlorambucil. Mechanism of Action: These agents cause inter-strand and intra-strand cross linking of DNA. Alkylating agents are active when a cell is not in the cell cycle and thus are useful for slow growing cancers. However, they do work best when a cell is cycling. Toxicity: Acute myelosuppression is the most common toxicity of these agents with a nadir of peripheral blood counts occurring 6-10 days after the last dose and recovery occurring at 14-21 days. Gastrointestinal damage is the next most common toxicity resulting in diarrhea and sometimes loss of blood. These agents are well know for causing alopecia Hypocalcemia, hypokalemia, hypomagnesemia may also occur. Note: Cyclophosphamide tends to spare platelets.

Platinum Type Alkylating Agents Agents: Cisplatin, oxaliplatin, carboplatin Mechanism of Action: Intra-strand and inter-strand cross linking. Especially A-G cross linkage. Toxicity: Ototoxicity, nephrotoxicity, marked nausea and vomiting, hypocalcemia, hypokalemia, hypomagnesemia. Cisplatin- ototoxicty and nephrotoxicity, Carboplatin- myelosuppression, mild neuro and nephrotoxicity. Most mild of the platinum alkylating agents. Oxaliplatin- peripheral neuropathy.

Anti-Mitotic Agents Agents: Paclitaxel, docetaxel, vincristine, vinblastine. Mechanism of Action: These agents either stabilize or destabilize microtubules interfering with mitosis and the intracellular transport of organelles. Paclitaxel and docetaxel stabilize microtubules inhibiting depolymerization. Vincristine and vinblastine de-stabilize microtubules inhibiting polymerization. Toxicity: Paclitaxel – Edema, neutropenia at 8-11 days after last dose. Stock and glove neuropathy, allergic reactions, anaphylaxis. Docetaxel – Edema, peripheral neuropathy, bone marrow suppression, severe fatigue, allergic reactions, anaphylaxis. Vinblastine- Leukopenia at 7 days after last dose, diarrhea. Vincristine – Progressive neurological toxicity, constipation, bowel obstruction.

Topoisomerase Inhibitors Agent: Doxorubicn, daunorubicin, etoposide, mitoxantrone, irinotecan. Mechanism of action: These agents inhibit topoisomerase and hence the unwinding of DNA during DNA replication. They may also cause strand breakage. Toxicity: Doxorubicin may cause CHF in 30% of patients occurring months or years later. In 5% more immediate cardiotoxicity. Daunorubicin and mitoxantrone may also cause cardiotoxicity. Irinotecan 35% suffer from severe diarrhea. Etoposide causes leukopenia at 10-14 days recovering at 3 weeks and diarrhea in 55% who receive the drug orally.

Hormonal Agents Agents: Tamoxifen, raloxifene, faslodex, letrozole, anastrazole, flutamide, nilutamide, bucalutamide, goserelin, leuprolide. Mechanism of Action: Tamoxifen, raloxifene and faslodex block the estrogen receptor. Letrozole and anastrazole inhibit the production of estrogen by inhibiting aromatase. Flutamide, nilutamide and bucalutamide block the androgen receptor and goserelin and leuprolide over stimulate the gonadotropin releasing hormone receptor (GRH) thereby inhibiting the release of GRH.

Hormonal Agents Toxicity: The anti-androgens may cause impotence, gynecomastia, muscle wasting, bone loss, fatigue. Tamoxifen causes an increase risk of endometrial cancer and thromboembolism. Faslodex may cause osteoporosis and increased risk of thromboembolisms. Raloxifene, thromboembolisms. The aromatase inhibitors may cause bone thinning and severe joint pain. The GRH inhibitors may initially cause cardiac ischemia, and edema. Later they may cause fatigue, impotence, muscle wasting and bone loss.

Biologicals Agents: Trastuzumab, bevacizumab, cetuximab, gefitinib Mechanism of action: Trastuzumab is an antibody that inhibits the her2/neu receptor. Bevacizumab is an antibody that inhibits vascular endothelial growth factor. Gefitinib is a small molecule that inhibits the epidermal growth factor receptor. Cetuximab is an antibody that also inhibits the epidermal growth factor receptor. Toxicity: Trastuzumab is cardiotoxic in 5% of patients. Long term effects are not known. Bevacizumab may cause hypertension and bowel perforation (ovarian cancer). Gefitinib and cetuximab cause a skin rashes and occasionally elevated liver enzymes.

Standard Regimens for Prostate Cancer Hormonal Treatment (considered first) A) Luprolide with one of the following: Flutamide, nilutamide, bucalutamide B) Goserelin with one of the following: Flutamide, nilutamide, bucalutamide Chemotherapy (if hormonal treatment fails) A) Docetaxel and Prednisone B) Mitoxantrone and Prednisone

Standard Regimens for Breast Cancer A) Doxorubicin, Cyclophosphamide followed by Paclitaxel . B) Doxorubicin, Cyclophosphamide followed by Docetaxel C) Methotrexate, Cyclophosphamide, 5-Fluorouracil followed by Taxane D) Carboplatin and Taxane Add Trastuzumab for her2/neu positive breast cancer. Add Tamoxifen or Letrozole for estrogen receptor positive breast cancer

Breast Cancer

Standard Regimens for Colon Cancer A) (FOLFOX) Folinic acid, 5-fluorouracil,oxaliplatin B) (FOLFIRI) Folinic acid, 5-flourouracil,irinotecan C) (CAPOX) Capecitabine, oxaliplatin Add cetuximab , bevacuzimab, gefitinib

Colon Cancer

Standard Regimens for Lung Cancer Non-Small Cell Lung Cancer A) Cisplatin, gemcitabine B) Cisplatin, docetaxel C) Cisplatin, etoposide Consider Bevacizumab Small Cell Lung Cancer Cisplatin, etoposide Cyclophosphamide, doxorubicin, and vincristine

Leukemia Treatment Acute Lymphocytic Leukemia Induction Prednisone, L-asparaginase, and vincristine Consolidation Methotrexate and 6-mercaptopurine Acute Myelocytic Leukemia Daunomycin, cytosine arabinoside, etoposide Cytosine – arabinoside (ARA-C) and etoposide Cytosine – arabinoside (ARA-C) and mitoxantrone