1 HST-151 Principles of Clinical Cancer Chemotherapy and Drug Resistance Cancer Mortality: 2000 = 553,091; Est.2003 = 556,500 Cancer Chemotherapy -- Effectiveness by Disease 1. Curative • Acute Lymphocytic Leukemia, Hodgkin’s Disease, Diffuse Histiocytic Lymphoma, Burkitt’s Lymphoma • Testicular Cancer, Choriocarcinoma • Wilms’ Tumor,* Ewing’s Sarcoma,* Embryonal Rhabdomyosarcoma* 2. Probably Curative • Acute Myelogenous Leukemia • Small Cell Lung Cancer, Breast Cancer,* Osteogenic Sarcoma* 3. Major Therapeutic Benefit (Short of Cure) • Head and Neck Cancer, Cervical Cancer, Metastatic Breast Cancer, Ovarian Cancer • Soft Tissue Sarcoma • Nodular Lymphomas, Chronic Leukemias • Insulinomas 4. Limited Effectiveness • Lung Cancer • GI Cancer • Prostate Cancer • Melanoma * Adjuvant chemotherapy: Drugs administered after removal of all detectable disease. Harvard-MIT Division of Health Sciences and Technology HST.151: Principles of Pharmocology Instructor: Dr. Donald Kufe2 HST-151 Acute Lymphocytic Leukemia: Induction of Chemotherapy 1. First Order Kinetics 2. Host Toxicity 3. Selectivity 4. Combination Chemotherapy 1. First Order Kinetics A given dose/unit time of chemotherapy will kill a constant percentage of cells, not a constant number. This means that the same dose which decreases the tumor burden from 106 to 103 cells will be needed to decrease the burden from 103 to 100 cells. Drug Dose / Unit Time 0.0001 0.001 0.01 0.1 1 10 100 Percent Surviving Cells 10 0 10 1 10 2 10 3 10 4 10 5 10 6 Cell Number First Order Kinetics Assuming an initial tumor burden of 106 cells, a treatment which is 99.9% effective will still leave 103 cells untouched. Thus, treatment may eliminate clinical symptoms, but the tumor can recur. Treatment should aim for 10-1 cells or less remaining to ensure a high percentage of cures. “Log-kill hypothesis”3 HST-151 • Dashed line = no treatment. • Top solid line = moderate, infrequent dosing of chemotherapy which prolongs survival but results in recurrent symptoms and eventual death. • Middle line = aggressive treatment. Cell kill exceeds regrowth and treatment is sufficiently long to sterilize tumor (patient is cured). • Bottom line = primary tumor is surgically removed or debulked, and adjuvant chemotherapy is used to kill remaining occult tumor.4 HST-151 2. Host Toxicity Therapeutic effects on tumor (solid line) and toxicity (broken line) are related to drug dose. ent of the toxicity curve to the right reflects the therapeutic index (median toxic dose/median effective dose) which is usually low for antitumor agents. 0.1 1 10 100 1000Drug Concentration050100% of PatientsHost ToxicityTumor ResponseToxicity Both curves are steep, and displacem5 HST-151 3. Selectivity Normal bone marrow cell kill and recovery (solid line) are compared to tumor cell kill and recovery (broken line). Each chemotherapy course causes a similar destruction of normal bone marrow and tumor cells, Rate of recovery of normal bone marrow, however, is greater than that of tumor cells. Number of normal bone marrow progenitors does eventually decrease with continued therapy. Selectivity 10 12 10 11 10 10 10 9 10 8 10 7 Normal Marrow 10 6 10 5 Tumor Cells 10 4 10 3 10 2 10 1 10 0 0 1 2 3 4 5 6 Chemotherapy Course No. Cells Remaining6 HST-151 4. Combination Chemotherapy Combining drugs with different mechanisms of action and different dose-limiting toxicities can produce a bigger therapeutic effect at maximally tolerated doses of all drugs. Antitumor drugs may be placed into one of three classes based on the relationship of the effect to the mitotic cycle of the cell: 1. Cell cycle active, phase specific 2. Cell cycle active, phase non-specific 3. Non-cell cycle active Mitotic Cycle7 HST-151 Cell Cycle Active, S Phase Specific ANTIMETABOLITES Mechanisms • incorporation of nucleotide analog in DNA or RNA, resulting in abnormal nucleic acids • inhibition of certain enzymes involved in nucleotide biosynthesis Examples: • Pyrimidines Uracil: 5-fluorouracil (5-fluoro-2’-deoxyuridine) Thymine: 3’-azido-3’-deoxythymidine Cytosine: Cytosine arabinoside; 5-azacytidine • Purines Adenine: 6-mercaptopurine Guanine: 6-thioguanine ANTIFOLS (METHOTREXATE) Mechanism: competitive inhibition of dihydrofolate reductase, necessary for generation of methyl donors required for thymidine synthesis.8 HST-151 Toxicity (general) • interfere with replication of all rapidly proliferating cells • bone marrow --- myelosuppression • GI mucosa ---- diarrhea, stomatitis Toxicity (specific) • 6-mercaptopurine --- cholestatic jaundice • Methotrexate renal – high doses may block tubules and cause acute renal failure hepatic – usually seen with chronic daily administration of low doses (i.e., psoriasis treatment) CNS – encephalopathy in patients given prior irradiation Cell Cycle Active, G2/M Phase Specific BLEOMYCIN Mechanisms • induces single-strand and double-strand DNA breaks • selectivity for G2 phase, but cells in G1 can also be killed Toxicity • subacute or chronic pneumonitis • little myelosuppression PLANT ALKALOIDS: VINCRISTINE (VCR), VINBLASTINE (VBL), TAXOL, EPIDOPHYLLOTOXINS (VP-16, VM-26), CAMPTOTHECINS Mechanisms • Tubulin Binders VCR, VBL inhibit polymerization of tubulin Taxol blocks depolymerization; stabilizes microtubule • VP-16, VM-26 target topoisomerase II; non-intercalating • Camptothecins (topotecan, irinotecan) inhibit topoisomerase I Toxicity • neurotoxicity • paresthesias • constipation • decreased deep tendon reflexes • myelosuppression • SIADH (VCR, VBL)9 HST-151 Cell Cycle Active, Phase Non-Specific ALKYLATING AGENTS Mechanisms • base alkylation resulting in DNA cross-linking • single strand breaks • double strand breaks and strand misreading Examples: • Nitrogen Mustard • Cyclophosphamide • Nitrosoureas • Cis-platinum • Busulfan Toxicities (general) • myelosuppression • stomatitis • nausea/vomiting • alopecia • impaired ovulation and spermatogenesis • mutagenesis and carcinogenesis Toxicities (specific) • Cyclosphosphamide: hemorrhagic cystitis, bladder fibrosis, cardiotoxicity (reversible), SIADH • Busulfan: interstitial pulmonary fibrosis • Nitrosoureas: cumulative myelosuppression • Platinum: acute tubular necrosis, ototoxicity ANTHRACYCLINES