1. Anticancer Drugs Dr.Qamar Barakzai Department of Pharmacology Ziauddin Medical University Karachi.Pakistan

2. “CANCER” Refers to a Malignant neoplasm (New growth) Cancer cells can manifest: Uncontrolled Proliferation. Loss of function due to lack of ability to differentiate. Invasiveness. The ability to metastasize. Cancer arises as a result of a series of genetic changes in the cell, the main genetic lesions being: Inactivation of tumor suppressor genes. The activation of oncogenes.

3. Antineoplastic agents Are cytotoxic not tumoricidal Only kill cells during mitosis, and Not all cancer cells are dividing at the same time. SUCCESS DEPENDS ON: Stage of cancer at time of diagnosis Type of cancer Development of drug resistance Overall health of patient.

4. R Tumor Suppressor Genes -ve (p53) Growth Factors Oncogenes +ve S DNA Synthesis G 2 Premitotic Interval M PROPHASE METAPHASE ANAPHASE TELOPHASE MITOSIS G0G0 G1G1 S PHASE SPECIFIC Cytosine Arbinoside Hydroxyurea S PHASE SPECIFIC SELF LIMITING 6-Mercaptpurine Methotrexate. M PHASE SPECIFIC vincristine vinblastine paclitaxel PHASE NONSPECIFIC alkylating agents, cis-platinum nitrosoureas, dacarbazine antibiotics procarbazine G0G0 Differentiation

5. CELL GROWTH CYCLE 5 DISTINCT PHASES OF MITOSIS 1. G 0 - Resting - no mitosis 2. G 1 - Postmitotic - first growth 3. S - DNA synthesis phase 4. G 2 - Premitotic - second growth 5. M - Mitosis phase GENERATION TIME - one complete cycle different in all tumors, from hours to days

7. PENTOSTATIN Inhibits adenosine Deaminase PALA Inhibits Pyrimidine Biosynthesis Purine synthesis Pyrimidine synthesis Ribonucleotides Deoxyribonucleotides DNA HYDROXYUREA Inhibit Ribonucleotide Reductase 6-MERCAPTOPURINE 6-THIOGAUNINE Inhibit Puring ring biosynthesis Inhibit Neocleotide interconversions 5-FLOUROURACIL Inhibit TMP Synthesis METHOTREXATE Inhibit dihydrofolate reduction, blocks TMP and Purine synthesis

8. DNA RNA (Transfer, messenger, ribosomal) CYTARABINE FLUDARABINE 2-CHLORODEOXY ADENOSINE Inhibit DNA Synthesis ALKYLATING AGENTS MITOMYCETIN CISPLATIN PROCARBAZINE DACARBAZINE Form adducts w/ DNA BLEOMYCIN ETOPOSIDE TENIPOSIDE Damage DNA and Prevent repair DACTINOMYCINE DAUNORUBICIN DOXORUBICIN MITOXANTRONE Intercalate with DNA Inhibit RNA synthesis PROTEINS EnzymesMicrotubules A-ASPARAGINASE Deaminate asparagine Inhibits protein synthesis PACLITAXEL VINCA ALKALOIDS COLCHICINE Inhibit function of Microtubules

9. ANTINEOPLASTIC AGENTS DEFINITIONS:  ALKYLATION - chemical reaction that cleaves DNA and interferes with mitosis  BIFUNCTIONAL ALKYLATING AGENTS - have 2 alkyl groups and alkalate 2 DNA strands  DOSE-LIMITED SIDE EFFECTS - adverse effects that prevent an agent from being given in higher doses  EMETIC POTENTIAL - potential of an agent to cause N & V

10. ANTINEOPLASTIC AGENTS ADVERSE EFFECTS: Kills all fast growing cells Hair follicles GI tract mucosa Bone marrow suppression (BMS) causing anemiaand leukopenia All are pregnancy category D ! Most are nephro- hepato- and ototoxic Extravasation of IV can result in loss of limb

11. Antineoplastic Agents ADVERSE EFFECTS: (Contd) All have a BMS and emetic index All have wide interaction with other drugs. Special training required for nursing Most agents can be harmful to nurse administering them

12. DEFINITIONS: GROWTH FRACTION % of cells in mitosis at any given time LEUCOVORIN RESCUE - use of leucovorin to reverse methotrexate-induced toxicity MITOTIC INDEX number of cells per unit undergoing mitosis during a given time NADIR lowest point (as in blood count) after being depressed by chemotherapy PARANEOPLASTIC SYNDROME (PNS) S/S of cancer located distant from tumor or its metastatic sites

13. ANTINEOPLASTIC AGENTS 2 MAIN GROUPS OF AGENTS: CELL CYCLE - NONSPECIFIC (CCNS) ALKYLATING AGENTS cytotoxic in any phase of cell cycle effective against slowly growing tumors CELL CYCLE - SPECIFIC (CCS) 3 TYPES ANTIMETABOLITES - cytotoxic is S phase MITOTIC INHIBITORS - cytotoxic in M phase CYTOTOXIC ANTIBIOTICS (some are CCNS) effective against rapidly growing tumors

14. ALKYLATING AGENTS NITROGEN MUSTARDS first developed in 1940s CCNS killing ability mechlorethamine is the prototypical agent USES: Hodgkin’s disease & lymphomas. leukemias, CANCERS OF lung, breast, ovary, testes, brain, bladder, Most widely used agent, often in combination with other agents.

15. ALKYLATING AGENTS SELECTED AGENTS: Mechlorethamine (Mustine, Mustargen) IV only (adult use only) Cyclophosphamide (Cytoxan, Neosar) IV and PO, adults and pediatric use Carmustine (BiCNU) IV, adult only, can cross blood-brain barrier, therefore used to tread brain lesions OTHER AGENTS: Chlorambucil, Streptozotocin

16. Hepatic cytochrome P 450 0xidase 4-Hydroxycyclophosphamide Aldophosphamide Enzymatic Non enzymatic Hepatic aldehyde oxidase 4-Ketocyclophosphamide (Inactive). Acrolein Cytotoxic Phosphamide Mustard Cytotoxic. Carboxyphosphamide (Inactive). Responsible for unwanted effects Cyclophosphamide (Inactive)

17. Hepatic cytochrome P 450 0xidase 4-Hydroxycyclophosphamide Aldophosphamide Enzymatic Non enzymatic Hepatic aldehyde oxidase 4-Ketocyclophosphamide (Inactive). Acrolein Cytotoxic Phosphamide Mustard Cytotoxic Carboxyphosphamide (Inactive). Responsible for unwanted effects

18. ANTIMETABOLITES ACTIONS: Antagonism of folate, purines, and pyrimidines needed for synthesis of nucleic acids - stops cell replication USES: Solid tumors (breast, lung, liver, brain, colon. Stomach, pancreas) Lymphomas, leukemias. Some agents also immunosuppressive, Useful in treating immune-mediated diseases

19. ANTIMETABOLITES SELECTED AGENTS: (FOLIC ACID ANALOG) METHOTREXATE (Folex, Rheumatrex, MTx) Folic acid antagonist PO & IM, adult and pediatric use Also used to treat immune-mediated diseases, Used incombination with misoprostol for therapeutic abortion Causes profound anemia (folate depletion) Therefore leucovorin “rescue” often used to counteract

20. ANTIMETABOLITES SELECTED AGENTS: PURINE ANALOG - MERCAPTOPURINE (6-MP, Purinethol) - Purine antagonist - PO only, adult and pediatric use PYRIMIDINE ANALOG - CYTARABINE (Ara-C, Cytosar-U) -Pyrimidine antagonist -IV and intrathecal (within spinal canal)

21. MITOTIC INHIBITORS ACTIONS: Plant alkaloids (periwinkle, yew tree, mandrake plant, etc.) Bind to and disrupt mitotic spindles USES: Lymphomas (Hodgkin’s and non-Hodgkin’s), Neuroblastoma Kaposi’s sarcoma, Solid tumors (breast, testicular, etc.)

22. MITOTIC INHIBITORS SELECTED AGENTS: ETOPOSIDE (VP-16, VePesid) IV and PO, adult use only PACLITAZEL (Taxol) IV only, adult use only drug of choice for ovary and breast ca VINCRISTINE (LCR, VCR,Oncovin) IV only, adult and pediatric use drug of choice for acute leukemia

23. CYTOTOXIC ANTIBIOTICS ACTIONS: Source: Streptomyces mold - work by intercalation (insertion of drug molecule between the 2 DNA strands causing it to (“unwind”) Kill some bacteria and viruses but are too toxic to use for infections IV extravasation constant danger ! USES: wide variety of solid tumors, always used in combination with other agents

24. CYTOTOXIC ANTIBIOTICS SELECTED AGENTS: DOXORUBICIN (ADR, Rubex, Doxil) IV only, adult use only BLEOMYCIN (BLM, Blenoxane) IM, IV, SQ, adult use only very toxic agents !!!

25. MISCELLANEOUS ANTINEOPLASTICS Various actions, Both CCNS and CCS Used in combinations with other agents SELECTED AGENTS: Cisplatin (Platinol) IV, adult and pediatric use ALTRETAMINE (Hexalen) PO only, adult use only, primarily used to treat ovarian cancer ASPARAGINASE (Elspar) IV only, adult and pediatric use HYDROXYUREA (Hydrea) PO only, adult use only

26. MISCELLANEOUS ANTINEOPLASTICS HORMONES AND ANTAGONISTS. 1. Adrenocortical Suppressant: Mitotane, Aminoglutethimide. (Adrenal Cortex) 2.Adrenocortical Steroids. Prednisone. (Lukemias, Lymphomas, Breast) 3.Progestins. Hydroxyprogestrone.(Endometrium, (Breast) Medroprogestrone, Megesterol acetate. 4.Estrogens. DES, Ethinylesterdiol.(Breast, Prostate) 5.Antiestrogens. Tamoxifen.(Breast) 6.Androgens. Testosterone (Breast) 7.Antiandrogens. Flutamide (Prostate). 8.Gonadotropin Releasing Hormone Analog. Leuprolide. (Prostate)