Feb. 17, 2014 Phase II, Foundation BlockAntineoplastics Faculty of Medicine, Kuwait University Prof. Saghir Akhtar RM 327, Phone: References 1. Integrated Pharmacology (3 rd Ed), Page et al 2. Pharmacology (6th ed), Rang et al.

Learning Objectives Basic concepts in cancer chemotherapy: cell cycle kinetics and relevance to the mode of action, log kill hypothesis, and mechanisms of resistance General toxic effects of anticancer drugs Major classes antineoplastic drugs Mechanism of action, important pharmacokinetic features, clinical uses and toxicity of the main drugs in each class of anticancer drugs

Cancer A disorder characterized by loss of normal cellular control of proliferation and differentiation Affects many organs/cell types e.g. breast, lung, brain, prostate.

Cancer - a genetic disease that involves abnormalities in three types of genes Oncogenes Tumour suppressor Stability genes CANCER Faulty Brake Bad Mechanic Faulty Accelerator

Gene-based Cancer Medicines 1. Advances in understanding role of genes in cancer have lead to better medicines e.g. Leukemia genomics have led to Imatinib, a specific tyrosine kinase inhibitor that targets a fusion gene (Bcr-Abl) only found in these tumours 2. New class of therapeutics that can very specifically turn on or off gene expression may be available in the future e.g. Gene Therapy/ Gene silencing

Approaches to Management of Cancer Surgery Radiation Chemotherapy (antineoplastic drugs) (approach depends on the type of cancer !)

The Principle of Cancer Chemotherapy To attain maximal therapeutic cytotoxic effects to cancer cells while causing lowest toxicity to normal cells.

Distinguished Characteristics of Cancer Cells Uncontrolled proliferation Immortalization Loss of function Invasiveness & Metastasis Neovascularization

Cancer cell growth is best described by Gompertzian Kinetics - Slow linear growth at smallest and largest tumor sizes - Exponential growth in between *A tumor is usually far advanced before diagnosed !

The Log Kill Hypothesis: The Log Kill Hypothesis: Drugs kill a constant fraction of tumor cells

The Log Kill Hypothesis A proportion of cancer cells can survive a course of treatment by chance without being specifically resistant Log kill varies with cell growth rate Short doubling times make cancer cells more susceptible to treatment by anti-neoplastic drugs. Log kill progressively decreases in the late stages of tumor when cells stop cycling Solution: combination therapy and repeated cycles of treatment

Combination Therapy Each individual drug or combination of drugs has certain cytotoxic activity. Therefore, combination therapy is more likely to provide a better cure than single-drug therapy. Different drugs may be effective against a particular tumor but via different mechanisms To avoid cumulative adverse effects, drugs of different toxicities can be used If more than one drug is used in the treatment regimen then this decreases the chance of resistance to the chemotherapy regimen

Problems of Anticancer Chemotherapy Lack of highly selective toxic agents Unlike viral, bacterial and fungal infections there are no obvious selective drug targets ***Remember !: Cancer cells, although altered, are host cells ! Adverse effects Resistance

Antineoplastic Drugs & Normal Cells Many anticancer agents affect rapidly dividing normal cells in: - bone marrow, - gut epithelium, - spermatogenic cells, - lymphoid tissue, - hair follicles, - foetus, etc. Therapeutic index of antineoplastic drugs are very low and serious adverse effects are observed at therapeutic dose

Common Adverse Effects of Antineoplastics Severe- vomiting, - nausea, - stomatitis, and/or - alopecia occur (from light to severe) with most of antineoplastic agents Some toxicities such as Myelosuppression & associated immunosuppression are common to many anti-neoplastic drugs

Some toxicities are specific for certain drugs: cardiotoxicity with doxorubicin pulmonary fibrosis with bleomycin hearing loss with cisplatin

Resistance to Antineoplastic Drugs May be innate or acquired Innate resistance: most of the cells in the tumor are resistant to initial treatment acquired resistance: initial treatment kills the cells in the tumor and cells later become resistant to same treatment (e.g. expression of mdr gene (p-glycoprotein efflux pump)

Antineoplastics & Cell Cycle Certain antineoplastic drugs show phase-specific lethality. Anticancer drugs can be divided into 2 groups: Cell-cycle phase independent drugs - they kill cells in anywhere in cell cycle - as dose increases, cell kill increases Cell-cycle Phase Dependent Drugs - Act mainly on cells in certain phases of cell cycle - Further kill can be achieved by time not by dose

Principles of chemotherapy of Cancer DNA synthesis precursors DNA RNA Tumour blood supply Proteins Microtubule assembly for cell division and continued cancer cell growth Growth promoting hormones

Principles of chemotherapy of Cancer DNA synthesis precursors DNA RNA Tumour blood supply Proteins Microtubule assembly for cell division and continued cancer cell growth Growth promoting hormones Angiogenesis inhibitors Antimetabolites Anti-Hormones DNA alkylating agents Topoisomerase inhibitors Tubulin-binding drugs e.g. vinca alkaloids, taxanes Tyrosine kinase inhibitors Monocolonal antibodies

Major Classes of Antineoplastic Drugs I. Akylating agents & related compounds II. Cytotoxic antibiotics III. Hormones and hormone antagonists IV. Antimetabolites V. Tubulin/microtubule binding agents VI. Miscellaneous drugs e.g. Angiogenesis inhibitors Tyrosine kinase inhibitors Monoclonal antibodies

I. Alkylating Agents & Related Compounds Examples: I. Alkylating Agents & Related Compounds Examples: A. Nitrogen mustards (carmustine) B. Platinum compounds (cisplatin) Contain chemical groups that can form covalent bonds with particular substances (DNA, RNA, protein) in the cell Broad ‘alkylating’ properties are therapeutic but also give rise to side effects In addition to killing rapidly proliferating cells, they also kill non-proliferating cells as a result of alkylation of DNA, RNA, and essential proteins.

II. Cytotoxic Antibiotics *They owe their antineoplastic actions to their interactions with DNA Examples Major classes of antineoplastic antibiotics: A. Anthracyclins (doxorubicin) B. Bleomycins (bleomycin)

III. Hormones and Hormone Antagonists III. Hormones and Hormone Antagonists (Endocrine Therapy of Cancer) Tumors derived from hormone-sensitive tissues (eg. breast, prostate) might be hormone dependent Growth of hormone dependent tumors can be inhibited by: –hormones with opposing actions, –hormone antagonists (e.g. tamoxifen in breast cancer) –agents inhibiting the synthesis of relevant hormones Advantage of endocrine therapy: Advantage of endocrine therapy: generally far fewer serious adverse effects than cytotoxic agents

IV. Antimetabolites Examples: IV. Antimetabolites Examples: A. Folate antagonists (eg.methotrexate) B. Pyrimidine analogues (eg. 5-fluorouracil) C. Purine analogues (eg. 6-mercaptopurine) They are structurally related to normal cellular components e.g. metabolites for DNA synthesis Generally they interfere with the availability of normal metabolite. As a result, antimetabolites inhibit the utilization of the natural metabolite e.g. in DNA synthesis

V. Tubulin/Microtubule binding agents (Mitotic Inhibitors) A.Vinca alkaloids: They act by binding tubulin & preventing its polymerization into microtubules (This event prevents spindle formation in cells at mitosis stage: cells are arrested at metaphase. Cells cannot complete chromosomal segregation and hence mitosis, and die !) Vincristine and vinblastine are alkaloids found in periwinkle plant (Vinca rosea) They are used in combination with other drugs for many cancers

V. Tubulin/Microtubule binding agents continued… B. Taxanes (e.g. Paclitaxel) Microtubules are stabilized by taxanes: Taxanes bind to microtubules and inhibit their depolymerization into tubulin. (With the spindle still in place, the cell can't divide into daughter cells) Taxanes are extracted from the yew trees

a) Angiogenesis inhibitors (e.g. avastin) They are designed to stop tumors from developing a blood supply, a pre-requisite for tumor growth and metastasis b) Tyrosine kinase inhibitors (e.g. imatinib; gefitinib) Inhibit phosphorylation of growth promoting proteins c) Monoclonal antibodies (e.g. trastuzamab) Neutralize the actions of growth factor receptor signaling that promote cancer growth e.g. HER2 in Breast cancers VI. Miscellaneous Antineoplastic Drugs

ANTINEOPLASTICS Drug list None (need only to learn principles)