Anti Kanker

Cancer is the second leading cause of death Each year there are 2,300,000 deaths in the US: ◦ Heart disease 730,000 ◦ Cancer 530,000 ◦ Cerebrovascular diseases 150,000 ◦ HIV infection 40,000

Cancer incidence and death by organ sites Most common new cancer cases: Male:Female: Prostate (29%) Breast (30%) Lung (15%) Lung (13%) Colon/rectum (10%) Colon/rectum (11%) Leading cancer deaths: Male:Female: Lung (32%) Lung (25%) Prostate (13%) Breast (16%) Colon/rectum (9%) Colon/rectum (11%)

Treatment of cancer patients Treatment of cancer patients Therapeutic modalities include surgery, radiotherapy and chemotherapy. Requires a skillful interdigitation of these forms of treatment. Chemotherapy is the general term for any treatment involving the use of chemical agents to stop cancer cells from growing.

Therapeutic index Therapeutic effects on tumor and toxicity are related to drug dose. The therapeutic index (median toxic dose/median effective dose) is usually low for antitumor agents.

Selectivity Each chemotherapy causes a similar destruction of normal bone marrow and tumor cells. Rate of recovery of normal bone marrow is greater than that of tumor cells.

Chemotherapy used to prolong life and/or to palliate symptoms (~70%): A majority of anticancer drugs are being used to prolong life and relieve symptoms ◦ chronic leukemias, multiple myeloma, and most of advanced solid tumors of the lung, prostate, breast and colon, which are not curable with current therapy

Major classes of anti-cancer drugs Alkylating agents Antimetabolites Antibiotics Antimitotics Hormones and antagonists Molecularly-targeted therapy

Alkylating agents Mechanism of action: cross-link 2 strands of DNA leading to impairment of DNA replication and RNA transcription.

Alkylating agents: examples cyclophosphamide: creates guanine adducts that block cell proliferation. cisplatin and its analogues, such as oxaliplatin: form DNA adducts and create inter or intrastrand crosslinks that disrupt DNA synthesis.

Antimetabolites Analogues of normal metabolites, incorporated into DNA or RNA, resulting in abnormal nucleic acids and inhibition of enzymes involved in nucleotide biosynthesis Purine Synthesis Pyrimidine Synthesis Ribonucleotides Deoxyribonucleotides DNA RNA

Antimetabolites: examples Methotrexate: a folate analog inhibits dihydrofolate reductase (DHFR), the enzyme essential for nucleic acid synthesis. 5-fluorouracil (5-FU): a pyrimidine analog that inhibits thymidylate synthase and also interferes with RNA synthesis and function. Gemcitabine: a pyrimidine analog that inhibits DNA polymerase.

FH2: dihydrofolate FH4: tetrahydrofolate TMP: thymidine monophosphate dUMP: deoxyuridine monophosphate 5-FU Methotrexate DNA

Antibiotics Bacterial or fungal derivatives, interfere with cellular processes such as DNA or protein synthesis. Examples ◦ Doxorubicin: fungal anthracycline that intercalates within the DNA, causes single and double strand breaks, and inhibits topoisomerase II. ◦ Mitomycin C: binds to DNA and form cross-links and DNA adducts. ◦ Bleomycin: a small peptide that binds to DNA, which results in single-strand and double-strand breaks.

Inhibitors of topoisomerases Topoisomerases: Cleavage, unwinding and re-annealing of DNA, necessary for DNA replication and RNA transcription Etoposide (VP-16): Inhibits topoisomerase II, leading to double-strand DNA breaks Etoposide

Antimitotics Mechanism of action: ◦ natural products that interfere with microtubule synthesis and degradation, leading to inhibition of cell division. Examples: ◦ Paclitaxel (Taxol): stabilizes microtubules, inhibit the cell cycle during mitosis. ◦ Vinblastine: plant alkaloid that causes depolymerization of microtubules.

Mechanism of antimitotics Paclitaxel Vinblastine

Hormones and antagonists Mechanism of action: ◦ inhibits synthesis or effects of the steroid hormones that are necessary for growth of certain tumors, such as breast and prostate tumors. Examples: ◦ Tamoxifen: binds to estrogen receptors (ER) as an antagonist inhibitor of estrogen. ◦ Anastrozole: inhibits aromatase, the enzyme that catalyzes the final step in estrogen production.

Mechanisms of Tamoxifen

The development and testing process of a drug

Clinical trials for anticancer drugs Phase I: To define the maximal tolerated dose and pharmacokinetics of a new anticancer drug. Phase II: To test the efficacy and side effects of a new anticancer drug or a new combined anticancer regimen in patients with a specific tumor type. Phase III: To compare a new drug or regimen with a standard therapy in patients with a specific tumor type.

Hallmarks of cancer

STI-571 (Gleevec, Imatinib) A small molecule that inhibits Bcr-Abl tyrosine kinase Targets this enzyme which is over-expressed in CML (chronic myeloid leukemia) Taken by mouth daily for treatment of refractory CML

Gefitinib (Iressa) It inhibits the intracellular tyrosine kinase (TK) domain of epidermal growth factor receptor (EGFR). Recent research indicates that it inhibits growth of cancer cells with mutations of the TK domain of EGFR. It is approved for treatment of non-small cell lung cancer refractory to standard chemotherapy. (~10% patients have EGFR mutations)

Cytotoxic effects of anticancer drugs

Cell cycle A process of division allowing the duplication of cells A cycle: end products (daughter cells) are the same as starting products (mother cells). An essential mechanism by which living things reproduce Malfunction in cell cycle regulation results in cancer and other diseases.

Relationship of antitumor drug action to the cycle

Many anticancer drugs induces apoptosis Programmed cell death, a mechanism used by an organism to selectively remove cells that are no longer needed, damaged or are dangerous. Regulated by Bcl-2 family proteins and executed by caspases. Apoptotic cellsNormal cells

DNA damage ATM/ATR/Chk2 p53 p21,  PUMA/Noxa/Bax Cell Cycle Arrest Apoptosis IR, anticancer drugs P53: central mediator of cellular response to DNA damage

Side effects of chemotherapy

Common toxicities Bone marrow suppression: ◦ Leukopenia, thrombocytopenia and anemia ◦ Caused by most anti-cancer drugs except: Bleomycin, vincristine, hormones, and most of the molecularly- targeted agents.

Common toxicities Gastrointestinal toxicity: ◦ Nausea and vomiting: cisplatin and anthracyclines ◦ Diarrhea: 5-FU, topotecan ◦ Mucositis: 5-FU Alopecia (Hair loss): Paclitaxel, carboplatin, anthracyclines. Renal toxicity: Cisplatin Pulmonary toxicity: Bleomycin (pulmonary fibrosis) Peripheral neuropathy: Cisplatin, oxaliplatin and paclitaxel

Long-term complications Cardiomyopathy: ◦ Anthracyclines (Incidence exceeds 5% for high- dose of doxorubicin) Leukemia: ◦ high-dose etoposide Infertility: ◦ Alkylating agents

Management of side-effects Use antiemetics to prevent nausea/emesis ◦ e.g. Zofran; a serotonin antagonist Anemia ◦ Blood transfusion and/or erythropoietin (Epogen) Neutropenia: ◦ Granulocyte-colony-stimulating factor (G-CSF, Neuprogen) ◦ To shorten duration of neutropenia Thrombocytopenia: ◦ Platelet transfusion and/or thrombopoietin

Principles for choice of anticancer drugs Histology and stage of cancer ◦ Histologic diagnosis is mandatory, and staging is essential for therapeutic choice and prognosis. Patient status ◦ Patients should have acceptable performance status and organ functions. Combined chemotherapy is the choice

Principles of Combined Chemotherapy Synergism and safety –Each drug is active against the cancer –Each drug has a different mechanism of action –Each drug has a different mechanism of resistance –Non-overlapping toxicities among the drugs

Combination chemotherapy: an example Oxaliplatin/5-FU/leucovorin (LV) combination ◦ Approved by FDA for first-line treatment for advanced colorectal cancer ◦ Patients treated had significantly longer progression-free-survival (9 vs. 6.2 months) and better response rates (50.7% vs. 22.3%) compared with the control 5-FU/LV. Benefits ◦ Each drug is given at full dose. ◦ The rate of cell kill increases. ◦ The chance of emergence of a drug-resistant clone decreases.

Resistance to anticancer drugs: tumor host resistance Changes in the tumor ◦ Location of tumor cells ◦ Effect of tumor size ◦ Growth characteristics Changes in the host ◦ Altered absorption, distribution or excretion of a drug so that less reaches the tumor ◦ Increased synthesis of enzymes from non-malignant cells which inactivate the drug ◦ Increased sensitivity of normal tissues to the effect of a drug

Resistance to anticancer drugs: cellular resistance Natural drug resistance ◦ lack of sensitivity of a tumor cell to drugs prior to therapy Acquired drug resistance ◦ genotypic and phenotypic changes during therapy that render a tumor cell insensitive to the lethal effects of a drug

Mechanisms of acquired drug resistance Defects in drug transporting and drug metabolizing enzymes ◦ Alterations in cytochrome p450 (CYP) Increased expression of drug targets ◦ Methotrexate resistance associated with DHFR amplification Multidrug or pleotropic resistance: tumor cells exposed to a single drug develop cross-resistance to other drugs. ◦ Overexpression of P-glycoprotein, the protein product of Multi Drug Resistance 1 (MDR1) gene ◦ Defective apoptosis regulation: Bcl-2 overexpression

Response to targeted anticancer drugs Mutations of drug targets can cause drug resistance ◦ Resistance to Gleevec is frequently associated with genetic mutations in the Bcr-Abl tyrosine kinase gene. Target status determines drug response ◦ Activating mutations in EGFR underlies responsiveness of non-small-cell lung cancer to Iressa.

Chemoprevention Chemoprevention refers to the use of pharmacologic or natural agents to inhibit or even reverse of the process of cancer development. An ideal chemopreventive agent should intervene early in the process of cancer development before premalignant cells become malignant.

COX-2 selective inhibitors Examples: Celecoxib (Celebrex), Rofecoxib (Vioxx) Also called “Coxibs”, developed to inhibit prostacyclin synthesis by COX-2 at sites of inflammation without affecting the constitutively active COX-1. Selectively bind to and block the active site of the COX-2 enzyme much more effectively than that of COX-1. Have similar analgesic, antipyretic, and anti-inflammatory effects as non-selective NSAIDs, but fewer GI side effects, no impact on platelet aggregation.

NSAIDs as chemopreventive agents In epidemiological studies, use of Aspirin decreases the risk of colon cancer. In clinical trials, NSAIDs reduce the size and number of colon ployps in FAP patients (Sulindac, Aspirin, Celebrex ……). In animal studies, NSAIDs reduce the size and number of ployps in APC +/min mice (Sulindac, Aspirin, Indomethacin, Celebrex ……).

COX-2 and Cancer COX-2 is overexpressed in a number of GI malignant and premalignant tissues. In COX-2 deficient mice, tumor yield is increased. Treatment with COX-2-specific pharmacologic inhibitors reduce tumor yields.

Apoptosis: a critical mechanism of NSAIDs mediated chemoprevention NSAIDs COX 2 ApoptosisTumor formation Colon cancer lines Animal models (APC +/Min mice) Normal mucosa of FAP patients