Cancer Chemotherapy

Cancer Chemotherapy Jillian H. Davis Department of Pharmacology Howard University Cell Cycle Cell Cycle Specific Agents • Antimetabolites • Bleomycin • Podophyllin Alkaloids • Plant Alkaloids Cell Cycle Non-Specific Agents • Alkylating Agents • Antibiotics •Cisplatin • Nitrosoureas Resistance to Cytotoxic Drugs     Increased expression of MDR-1 gene for a cell surface glycoprotein, P-glycoprotein MDR-1 gene is involved with drug efflux Drugs that reverse multidrug resistance include verapamil, quinidine, and cyclosporine MDR increases resistance to natural drug products including the anthracyclines, vinca alkaloids, and epipodophyllotoxins Schematic of P-glycoprotein Alkylating Agents Nitrogen Mustards Ethylenimines Alkyl Sulfonates Nitrosoureas Cyclophosphamide Thiotepa Busulfan Carmustine Legend Drug Class Sub-class Prototype Drug Alkylating Agents Mechanism of Action Alkylate within DNA at the N7 position of guanine  Resulting in miscoding through abnormal base-pairing with thymine or in depurination by excision of guanine residues, leading to strand breakage  Cross-linking of DNA and ring cleavage may also occur  Alkylating Agents Mechanism of Action Nitrogen Mustards Cyclophosphamide  Ifosfamide  Mechlorethamine  Melphalan  Chlorambucil  Cyclophosphamide Metabolism Nitrosoureas Carmustine  Lomustine  Semustine  Streptozocin-naturally occuring sugar containing  M.O.A.- cross-link through alkylation of DNA All cross the blood brain barrier Alkylating-Related Agents Procarbazine  Dacarbazine  Altretamine  Cisplatin  Carboplatin  Platinum Coordination Complexes These compounds alkylate N7 of guanine. They cause nephro- and ototoxicity. To counteract the effects of nephrotoxicity, give mannitol as an osmotic diuretic, or induce chloride diuresis with 0.1% NaCl. Alkylating Agents Toxicity  Bone marrow depression, with leukopenia and thrombocytopenia Cyclophosphamide/Ifosfamide - hemorrhagic cystitis  Reduced  by coadministration with MESNA  Cisplatin/Carboplatin - ototoxic and nephrotoxic  Nephrotoxicity reduced by chloride diuresis and hydration Alkylating Agents Therapeutic Uses      Used to treat a wide variety of hematologic and solid tumors Thiotepa – ovarian cancer Busulfan – chronic myeloid leukemia Nitrosoureas - brain tumors Streptozocin – insulin-secreting islet cell carcinoma of the pancreas Antimetabolites Folic Acid Analogs Methotrexate Purine Analogs Mercaptoguanine Pyrimidine Analogs Fluorouracil Legend Drug Class Sub-class Prototype Drug Folic Acid Analogs Methotrexate  Trimetrexate  Pemetrexed  Folate An essential dietary factor, from which THF cofactors are formed which provide single carbon groups for the synthesis of precursors of DNA and RNA  To function as a cofactor folate must be reduced by DHFR to THF  Methotrexate Mechanism of Action The enzyme DHFR is the 1º site of action  MTX prevents the formation of THF, causing an intracellular deficiency of folate coenzymes and accumulation of the toxic inhibitory substrate, DHF polyglutamate  The one carbon transfer reactions for purine and thymidylate synthesis cease, interrupting DNA and RNA synthesis  Major Enzymatic Reactions Requiring Folates as Substrates* GAR transformylase AICAR transformylase AMP GMP (2) Methionine GAR AICAR (3) 10-formylTHF Formate + b THF e 5,10-CH2THF c IMP DHF (1) dTMP a DNA *from Bowen 5-CH3THF d Homocysteine dUMP a,thymidylate synthase; b, dihydrofolate reductase; c, methylenetetrahydrofolate reductase; d, methionine synthase; e, serine hydroxymethyl transferase Resistance Methotrexate Mechanism of Resistance 1. 2. 3. 4. Decreased drug transport Altered DHFR Decreased polyglutamate formation Increased levels of DHFR Methotrexate Therapeutic Uses  Methotrexate- psoriasis, rheumatoid arthritis, acute lymphoblastic leukemia, meningeal leukemia, choriocarcinoma, osteosarcoma, mycosis fungoides, Burkitt’s and non-Hodgkin’s lymphomas, cancers of the breast, head and neck, ovary, and bladder Trimetrexate Therapeutic Uses  Trimetrexate- Pneumocystis carinii pneumonia, metastatic colorectal carcinoma, head and neck carcinoma, pancreatic carcinoma, non-small cell carcinoma of the lung Pemetrexed Therapeutic Uses  Pemetrexed- Mesothelioma Methotrexate Toxicity   Bone marrow suppression  Rescue with leucovorin (folinic acid) Nephrotoxic  give sodium bicarbonate to alkalinize the urine Purine Antagonists Mercaptopurine  Thioguanine  Fludarabine Phosphate  Cladribine  Mercaptopurine/Thioguanine Must metabolized by HGPRT to the nucleotide form  This form inhibits numerous enzymes of purine nucleotide interconversion  Fludarabine Phosphate M.O.A.- phosphorylated intracellularly by deoxycytidine kinase to the triphosphate form  The metabolite inhibits DNA polymerase-α and ribonucleotide reductase  Induces apoptosis  Tx- non-Hodgkin’s lymphoma and chronic lymphocytic leukemia  Cladribine M.O.A. -phosphorylated by deoxycytidine kinase and is incorporated into DNA  Causes DNA strand breaks  Tx- hairy cell leukemia, chronic lymphocytic leukemia, and non-Hodgkin’s lymphoma  Pyrimidine Antagonists Fluorouracil - S-phase  Cytarabine  Gemcitabine  Capecitabine  MTX X 5-FU X Figure 2. This figure illustrates the effects of MTX and 5-FU on the biochemical pathway for reduced folates. Mechanism of Action 5-FU  5-FU inhibits thymidylate synthase therefore causing depletion of Thymidylate 5-FU is incorporated into DNA 5-FU inhibits RNA processing   Activation of 5-FU Therapeutic Uses of 5-FU Metastatic carcinomas of the breast and the GI tract  hepatoma  carcinomas of the ovary, cervix, urinary bladder, prostate, pancreas, and oropharyngeal areas  Combined with levamisole for Tx of colon cancer  Cytarabine It is activated to 5’ monophosphate (AraCMP) by deoxycytidine kinase  Through a series of reactions it forms the diphosphate (AraCDP) and triphosphate (AraCTP) nucleotides  Accumulation of AraCTP potently inhibits DNA synthesis  Inhibition of DNA synthesis is due to competitive (-) of polymerases and interference of chain elongation  Cytarabine It is a potent inducer of tumor cell differentiation  Fragmentation of DNA and evidence of apoptosis is noticed in treated cells  AraC is cell-cycle specific agent, it kills cells in the S-phase  Cytarabine Mechanisms of Resistance deficiency of deoxycytidine kinase  increased CTP synthase activity  increased cytidine deaminase activity  decreased affinity of DNA polymerase for AraCTP  decrease ability of the cell to transport AraC  Cytarabine Therapeutic Uses Induction of remissions in acute leukemia  Treats meningeal leukemia  Treatment of acute nonlymphocytic leukemia  In combination with anthracyclines or mitoxantrone it can treat non-Hodgkin’s lymphomas  Cytarabine Toxicities Nausea  acute myelosuppression  stomatitis  alopecia  Gemcitabine Gemcitabine is S-phase specific  it is a deoxycytidine antimetabolite  it undergoes intracellular conversion to gemcitabine monophosphate via the enzyme deoxycytidine kinase  it is subsequently phosphorylated to gemcitabine diphosphate and gemcitabine triphosphate  Gemcitabine Gemcitabine triphosphate competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA strands  do to an addition of a base pair before DNA polymerase is stopped, Gemcitabine inhibits both DNA replication and repair  Gemcitabine-induced cell death has characteristics of apoptosis  Gemcitabine Therapeutic Uses Gemcitabine treats a variety of solid tumors  very effective in the treatment of pancreatic cancer  small cell lung cancer  carcinoma of the bladder, breast, kidney, ovary, and head and neck  Cancer Chemotherapy Jillian H. Davis Department of Pharmacology Howard University Plant Alkaloids Vinca Alkaloids Vinblastine Podophyllotoxins Etoposide Camptothecins Topotecan Taxanes Paclitaxel Vinca Alkaloids    Vinblastine Vincristine Vinorelbine Vinca Alkaloids Inhibit microtubules (spindle), causing metaphase cell arrest in M phase. 3 3 Vinca Alkaloids Mechanism of Action      Binds to the microtubular protein tubulin in a dimeric form The drug-tubulin complex adds to the forming end of the microtubules to terminate assembly Depolymerization of the microtubules occurs Resulting in mitotic arrest at metaphase, dissolution of the mitotic spindle, and interference with chromosome segregation CCS agents- M phase Vinblastine Toxicity Nausea  Vomiting  Marrow depression  Alopecia  Vinblastine Therapeutic Uses Systemic Hodgkin’s disease  Lymphomas  Vincristine Toxicity Muscle weakness  Peripheral neuritis  Vincristine Therapeutic Uses  With prednisone for remission of Acute Leukemia Vinorelbine Toxicity  Granulocytopenia Therapeutic Uses  non-small cell lung cancer Podophyllotoxins   Etoposide (VP-16) Teniposide (VM-26)  Semi-synthetic derivatives of podophyllotoxin extracted from the root of the mayapple Podophyllotoxins Mechanism of Action Blocks cells in the late S-G2 phase of the cell cycle through inhibition of topoisomerase II  Resulting in DNA damage through strand breakage induced by the formation of a ternary complex of drug, DNA, and enzyme  Podophyllotoxins Toxicity     Nausea Vomiting Alopecia Hematopoietic and lymphoid toxicity Podophyllotoxins Therapeutic Uses Monocytic Leukemia  Testicular cancer  Oat cell carcinoma of the lung  Camptothecins   Topotecan Irinotecan Camptothecins Mechanism of Action Interfere with the activity of Topoisomerase I  Resulting in DNA damage   Irinotecan- a prodrug that is metabolized to an active Top I inhibitor, SN-38 Camptothecins Toxicity  Topotecan  Neutropenia, thrombocytopenia, anemia  Irinotecan  Severe diarrhea, myelosuppression Camptothecins Therapeutic Uses Topotecan- metastatic ovarian cancer (cisplatin-resistant)  Irinotecan- colon and rectal cancer  Taxanes Paclitaxel (Taxol)  Docetaxel   Alkaloid esters derived from the Western and European Yew Taxanes Mechanism of Action  Mitotic “spindle poison” through the enhancement of tubulin polymerization Taxanes Toxicity  Paclitaxel  Neutropenia, thrombocytopenia  Peripheral neuropathy  Docetaxel  Bone marrow suppression  Neurotoxicity  Fluid retention Taxanes Therapeutic Uses Paclitaxel- ovarian and advanced breast cancer  Docetaxel- advanced breast cancer  Antibiotics Anthracyclines- Doxorubicin & Daunorubicin  Dactinomycin  Plicamycin  Mitomycin  Bleomycin  Anthracyclines Doxorubicin  Daunorubicin  Anthracyclines Mechanism of Action High-affinity binding to DNA through intercalation, resulting in blockade of DNA and RNA synthesis  DNA strand scission via effects on Top II  Binding to membranes altering fluidity  Generation of the semiquinone free radical and oxygen radicals  Anthracyclines Toxicity Bone marrow depression  Total alopecia  Cardiac toxicity  Anthracyclines Therapeutic Uses  Doxorubicin- carcinomas of the breast, endometrium, ovary, testicle, thyroid, and lung, Ewing’s sarcoma, and osteosarcoma Daunorubicin- acute leukemia  Dactinomycin Mechanism of Action Binds to double stranded DNA through intercalation between adjacent guaninecytosine base pairs  Inhibits all forms of DNA-dependent RNA synthesis  Dactinomycin Toxicity Bone marrow depression  Oral ulcers  Skin eruptions  Immunosuppression  Dactinomycin Therapeutic Uses Wilms’ tumors  Gestational choriocarinoma with MTX  Plicamycin Mechanism of Action Binds to DNA through an antibiotic-Mg2+ complex  This interaction interrupts DNA-directed RNA synthesis  Plicamycin Toxicity Hypocalcemia  Bleeding disorders  Liver toxicity  Plicamycin Therapeutic Uses Testicular cancer  Hypercalcemia  Mitomycin Mechanism of Action  Bioreductive alkylating agent that undergoes metabolic reductive activation through an enzyme-mediated reduction to generate an alkylating agent that crosslinks DNA Mitomycin Toxicity Severe myelosuppression  Renal toxicity  Interstitial pneumonitis  Mitomycin Therapeutic Uses Squamous cell carcinoma of the cervix  Adenocarcinomas of the stomach, pancreas, and lung  2nd line in metastatic colon cancer  Bleomycin Acts through binding to DNA, which results in single and double strand breaks following free radical formation and inhibition of DNA synthesis  The DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations  CCS drug that causes accumulation of cells in G2  Bleomycin Toxicity Lethal anaphylactoid reactions  Blistering  Pulmonary fibrosis  Bleomycin Therapeutic Uses Testicular cancer  Squamous cell carcinomas of the head and neck, cervix, skin, penis, and rectum  Lymphomas  Intracavitary therapy in ovarian and breast cancers  Hormonal Agents Estrogen & Androgen Inhibitors Gonadotropin-Releasing Aromatase Inhibitors Hormone Agonists Tamoxifen Leuprolide Aminogluthethimide Legend Drug Class Sub-class Prototype Drug Anti-Estrogens Tamoxifen (SERMs)  Raloxifene (SERMs)  Faslodex  Tamoxifen        Selective estrogen receptor modulator (SERM), have both estrogenic and antiestrogenic effects on various tissues Binds to estrogen receptors (ER) and induces conformational changes in the receptor Has antiestrogenic effects on breast tissue. The ability to produce both estrogenic and antiestrogenic affects is most likely due to the interaction with other coactivators or corepressors in the tissue and the binding with different estrogen receptors, ER and ER Subsequent to tamoxifen ER binding, the expression of estrogen dependent genes is blocked or altered Resulting in decreased estrogen response. Most of tamoxifen’s affects occur in the G1 phase of the cell cycle Tamoxifen Toxicity Hot flashes  Fluid retention  nausea  Tamoxifen Therapeutic Uses  Tamoxifen can be used as primary therapy for metastatic breast cancer in both men and postmenopausal women Patients with estrogen-receptor (ER) positive tumors are more likely to respond to tamoxifen therapy, while the use of tamoxifen in women with ER negative tumors is still investigational   When used prophylatically, tamoxifen has been shown to decrease the incidence of breast cancer in women who are at high risk for developing the disease Anti-Androgen  Flutamide  Antagonizes androgenic effects  approved for the treatment of prostate cancer Gonadotropoin-Releasing Hormone Agonists Leuprolide  Goserelin  Gonadotropoin-Releasing Hormone Agonist Mechanism of Action Agents act as GnRH agonist, with paradoxic effects on the pituitary  Initially stimulating the release of FSH and LH, followed by inhibition of the release of these hormones  Resulting in reduced testicular androgen synthesis  Gonadotropoin-Releasing Hormone Agonist Toxicity Gynecomastia  Edema  thromboembolism  Gonadotropoin-Releasing Hormone Agonist Therapeutic Uses Metastatic carcinoma of the prostate  Hormone receptor-positive breast cancer  Aromatase Inhibitors Aminogluthethimide  Anastrozole  Aminogluthethimide Mechanism of Action Inhibitor of adrenal steroid synthesis at the first step, conversion of cholesterol of pregnenolone  Inhibits the extra-adrenal synthesis of estrone and estradiol  Inhibits the enzyme aromatase that converts androstenedione to estrone  Aminogluthethimide Toxicity Dizziness  Lethargy  Visual blurring  Rash Therapeutic Uses   ER- and PR-positive metastatic breast cancer Anastrozole A new selective nonsteroidal inhibitor of aromatase  Treats advanced estrogen and progesterone receptor positive breast cancer that is no longer responsive to tamoxifen  Miscellaneous AntiCancer Agents Asparaginase  Hydroxurea  Mitoxantrone  Mitotane  Retinoic Acid Derivatives  Amifostine  Asparaginase An enzyme isolated from bacteria  Causes catabolic depletion of serum asparagine to aspartic acid and ammonia  Resulting in reduced blood glutamine levels and inhibition of protein synthesis  Neoplastic cells require external source of asparagine  Treats childhood acute leukemia  Can cause anaphylactic shock  Hydroxyurea An analog of urea  Inhibits the enzyme ribonucleotide reductase  Resulting in the depletion of deoxynucleoside triphosphate pools  Thereby inhibiting DNA synthesis  S-phase specific agent  Treats melanoma and chronic myelogenous leukemia  Mitoxantrone Structure resembles the anthracyclines  Binds to DNA to produce strand breakage  Inhibits DNA and RNA synthesis  Treats pediatric and adult acute myelogenous leukemia, non-Hodgkin’s lymphomas, and breast cancer  Causes cardiac toxicity  Mechanisms & Actions of Useful Chemotherapeutic Drugs in Neoplastic Disease