Pharmacology of Chemotherapy Cancer Biology Dr Dean Willis Department of Pharmacology University College London Gower Street, London WC1 6BT dean.willis@ucl.ac.uk

Learning Objectives To know the basic phenotypic and biochemical differences between normal and cancer cells To understand the basic principal of cancer chemotherapy and its limitations To know the four main groups of anti-cancer cytotoxic drugs To understand the adverse effects of cancer chemotherapy To know the basic mechanisms that develop in tumour cells that leads to drug resistance Understand the pharmacological rational behind the new anti cancer chemotherapeutics To understand the scientific rational behind drug combination studies.

Nature Reviews in Cancer Learning Tasks & Further Reading Revise mammalian DNA replication and the biosynthesis of nucleotides. Read Pharmacology, Rang, Dale & Ritter. Anti-cancer Drugs Chemotherapy of Neoplastic Diseases. Section IX. Goodman & Gilman’s. The Pharmacological Basis of Therapeutics. 10th Edition. Nature Reviews in Cancer Recent reviews relating to chemotherapy CLINICAL TRANSLATION OF ANGIOGENESIS INHIBITORS MICROTUBULES AS A TARGET FOR ANTICANCER DRUGS NF-κB IN CANCER: FROM INNOCENT BYSTANDER TO MAJOR CULPRIT

Theory of Chemotherapy. The Man, the film? For the case of Chemotherapy bacteria, fungi, protozoa, helminths, viruses and cancer cell are considered parasites. Find Qualitative (preferable) or Quantitative Biochemical difference between Host and Parasite which when exploited by a selective drug results in a cytotoxic effect to the parasite but not host Theory Drug Host Parasite Paul Ehrlich 1854-1915 Nobel Laureate 1908 No effect Cytotoxic

Qualitative Quantitative CHEMOTHERAPY: The basis of anti-cancer chemotherapy and the problem Qualitative Quantitative The goal is to selectively kill malignant cells and spare normal host cells. Selective toxicity is not possible to the degree seen with antibacterial or even anti-viral chemotherapy, as malignant cells are derived from the host and the differences between normal and malignant cells are much more subtle. Therefore, successful treatment is dependent on killing malignant tumor cells with doses and strategies that allow recovery of normal proliferating cells.

Characteristics of tumour cells & sites of therapeutic intervention (present and future) Blood vessel Primary Tumour Normal organ/tissue Major Modalities for Treatment for cancer Surgery Irradiation Combination of the above (modality therapy) Chemotherapy

Problems associated with Anti-cancer chemotherapy Because cells are derived from self, most therapies rely on quantitative (usually proliferation/growth) rather than qualitative. Therefor host cells are invariably effected. Therapeutic Index= LD50/ED50 For anti-cancer drugs this tends to be low therefore Tox problems Bone Marrow (G-CSF shorten period of Leukopenia) Healing Alopecia Damage to gastrointestinal epithelium (nutritional state) Depression of growth (children) Sterility Teratogenicity Severe nausea (treat with 5-HT3-receptor antagonist)

Problems associated with Anti-cancer chemotherapy Growth fraction (percentage of cells actively dividing) RT is carried into the cell with the virus. Anti-cancer chemotherapy most effect against cells in cell fraction A. Cells in fraction B can re-enter fraction A.

Problems associated with Anti-cancer chemotherapy Exponential growth of a tumour Limit of diagnostic procedures.

Problems associated with Anti-cancer chemotherapy Cell cycle: Susceptibility of cancer cells to a given drug is often dependant on cell cycle

Problems associated with Anti-cancer chemotherapy Minimal immune response Because the tumour is self the immune response as difficulty recognizing the tumour The drug receives no help (or little help) from the immune system Many anti-cancer drugs are toxic to immune cells (Bone marrow) Cancer cells can hide Tumour cell heterogeneity & cell phenotype instability Drug Resistance Specfic drug Drug of same chemical class Multi-drug resistance:- P170 (mdr1 gene)

Summary anti-cancer chemotherapy's Cytotoxic drugs Alkylating agents Cyclophosphamide, Busulfan, Carmustin, Chloramabucil, Ifosfamide, lomustine, Melphan, Treosulfan Cisplatin, Carboplatin, Oxaliplatin Anti-metabolites Methotrexate, Fluoruracil, Cytarabine, Cladribine, Fludarabine phosphate, Gemcitabine, Mercaptopurine Cytotoxic Antibiotics Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitomycin Plant derivatives Etoposide, Vinblastine, Vincristine Hormone Tamoxifen, Anastrozole, Letrozole Miscellaneous Imatinib, Bortezomib, Bevacizumab, Trastuzumab, Taxol, Cristaspase, Arsenic

Summary of cytotoxic drug action

Action of Alkylating drugs (methlorethamine) Mustine Other nitrogen mustards Cycloposphamide Chlorambucil Melphalan

Action of Alkylating drugs Resistance Decreased permeability Increased production of glutathione Increase DNA repair Increased metabolism of drugs Nitrosoureas carmustine, lomustine Busulphan Cisplatin Administered orally or i.v. tumours of testes & ovary

Anti-metabolites (methotrexate) Resistance Decreased transport into cells Decreased affinity of DHF reductase Increase levels of DHF reductase Administered orally or i.v. Non-Hodgkin’s lymphoma Burkitt’s lymphoma Childhood acute lymphoblastic leukemia

Anti-metabolites (5-Fluorouracil) Resistance Decreased levels of thymidine phosphorylase or affinity for 5FU Administered parentally Breast, ovarian, prostate, pancreatic, hepatic carcinomas

Anti-metabolites (Cytosine arabinoside, Cytarabine) Resistance Decreased levels of deoxycytidine kinase Increase in dCTP Administered oral and i.v. Chronic granulocytic leukemia

Cytotoxic antibiotics Doxorubicin, Dactinomycin, Etoposide (VA) Resistance Multidrug resistance Increased glutathione peroxidase decreased topoisomerase Administered i.v. Acute lymphocytic leukemia Acute granulocytic leukemia

Cytotoxic antibiotics (Dactinomycin, Bleomycin) Resistance not characterized Parentally administered Used in combination with other modalities Dactinomycin Minor groove Bleomycin Major groove Resistance due to increase anti-oxidant, and DNA repair mechanisms Parentally administered Treatment of testicular and ovarian cancer Note cytotoxic antibiotics do share some modes of action DNA binding and topoisomerase II inhibition

Vincristine & vinblastine Plant alkaloids (vincristine & vinblastine, Taxol) Vincristine & vinblastine Resistance due to multidrug resistance, altered tublin molecules Administered I.v. Childhood leukemia's, Hodgkin's and non-Hodgkin's lymphoma, testicular, ovarian carcinomas and brain tumours Taxol Resistance altered tublin molecules Administered i.v. Metastatic ovarian and breast cancer

Resistance to chemotherapeutic agents

New anti-cancer drugs: Imatinib Treatment Chronic myelogenous leukaemia CML caused by reciprocal translocation between chromosomes 9 and 22 Philadelphia chromosome BCR-ABL gene which encodes a protein with high tyrosine kinase activity Fast drug to be approved by FDA, Approx 80% remission in IFNg refractory patients Activity against c-kit & PDGF receptor

New anti-cancer drugs: Bortezomib Treat multiple myeloma ( current drugs 5 year survival is approx 29%) In MM (and other tumors ) NF-kB is constitutively expressed

Combination therapy Knowledge of the pharmacokinetics of each cytotoxic agent is less important than knowing the maximal dose and the duration of that drug can be administrated before adverse side effects become unacceptable Bleomycin Etoposide Curative therapy testicular cancer (BEP) Cisplatin Individual drugs must be active against the tumour Drugs must have different modes of action Minimize drug resistance Hit cancer cells in different parts of cell cycle Drugs must have limited overlapping toxicity Individuals should be optimally scheduled Renal & hepatic Function Bone Marrow reserve Immune status Previous Treatments Likely natural History of Tumor Patients Wishes to undergo treatment Patients Physical & emotional Tolerance Long term gains & Risks