Pharmacology Anti-Cancer Lec 11 PDF

Pharmacology Anti-Cancer Lec 11 Pharmacology | Anti-Cancer Contents : Anthracyclines 3 Bleomycin 10 Alkylating Agent 16 Cyclophosphamide and ifosfamide 23 Nitrosoureas 24 Dacarbazine and temozolomide 25 Other alkylating agents 28 Microtubule Inhibitors 30 Vincristine and vinblastine 33 Paclitaxel an...

Pharmacology Anti-Cancer Lec 11 Pharmacology | Anti-Cancer Contents : Anthracyclines 3 Bleomycin 10 Alkylating Agent 16 Cyclophosphamide and ifosfamide 23 Nitrosoureas 24 Dacarbazine and temozolomide 25 Other alkylating agents 28 Microtubule Inhibitors 30 Vincristine and vinblastine 33 Paclitaxel and docetaxel 34 Pharmacology | Anti-Cancer The antitumor antibiotics owe their cytotoxic action primarily to their interactions with DNA, leading to disruption of DNA function. In addition to intercalation, their abilities to inhibit topoisomerases (I and II) and produce free radicals also play a major role in their cytotoxic effect. They are cell cycle nonspecific, with bleomycin as an exception. Pharmacology | Anti-Cancer A. Anthracyclines: Doxorubicin, daunorubicin, idarubicin, epirubicin, and mitoxantrone Doxorubicin and daunorubicin are classified as anthracycline antibiotics. Doxorubicin is the hydroxylated analog of daunorubicin. Idarubicin, the 4-demethoxy analog of daunorubicin, epirubicin, and mitoxantrone are also available. Pharmacology | Anti-Cancer Pharmacology | Anti-Cancer Therapeutic uses for these agents differ despite their structural similarity and apparently similar mechanisms of action. Doxorubicin used in combination with other agents for treatment of sarcomas and a variety of carcinomas, including breast cancer, as well as for treatment of acute lymphocytic leukemia and lymphomas. Daunorubicin and idarubicin are used in the treatment of acute leukemias, and mitoxantrone is used in prostate cancer. Pharmacology | Anti-Cancer Mechanism of action Doxorubicin and other anthracyclines induce cytotoxicity through several different mechanisms. For example, doxorubicin-derived free radicals can induce membrane lipid peroxidation, DNA strand scission, and direct oxidation of purine or pyrimidine bases, thiols, and amines. Pharmacology | Anti-Cancer Pharmacokinetics These agents must be administered intravenously, because they are inactivated in the GI tract. Extravasation is a serious problem that can lead to tissue necrosis. The anthracycline antibiotics bind to plasma proteins as well as to other tissue components, where they are widely distributed. They do not penetrate the blood–brain barrier or the testes. Pharmacology | Anti-Cancer These agents undergo extensive hepatic metabolism, and dosage adjustments are needed in patients with impaired hepatic function. Biliary excretion is the major route of elimination. Because of the dark red color of the anthracycline drugs, the veins may become visible surrounding the site of infusion, and red discoloration of urine may occur. Pharmacology | Anti-Cancer Adverse effects Irreversible, dose-dependent cardiotoxicity is the most serious adverse reaction and is more common with daunorubicin and doxorubicin than with idarubicin and epirubicin. There has been some success with the iron chelator dexrazoxane in protecting against the cardiotoxicity of doxorubicin. The liposomal-encapsulated doxorubicin is reported to be less cardiotoxic than the standard formulation. Pharmacology | Anti-Cancer B. Bleomycin Bleomycin is a mixture of different copper-chelating glycopeptides that, like the anthracycline antibiotics, cause scission of DNA by an oxidative process. Bleomycin is cell cycle specific and causes cells to accumulate in the G2 phase. It is primarily used in the treatment of testicular cancers and Hodgkin lymphoma. Pharmacology | Anti-Cancer Mechanism of action A DNA–bleomycin–Fe2+ complex appears to undergo oxidation to bleomycin–Fe3+. The liberated electrons react with oxygen to form superoxide or hydroxyl radicals, which, in turn, attack the phosphodiester bonds of DNA, resulting istrand breakage and chromosomal aberrations. Pharmacology | Anti-Cancer Pharmacokinetics Bleomycin is administered by a number of routes. The bleomycin-inactivating enzyme (a hydrolase) is high in a number of tissues (for example, liver and spleen) but is low in the lung and absent in the skin, accounting for toxicity in those tissues. Most of the parent drug is excreted unchanged in the urine, necessitating dose adjustment in patients with renal failure. Pharmacology | Anti-Cancer Adverse effects Pulmonary toxicity is the most serious adverse effect, progressing from rales, cough, and infiltrate to potentially fatal fibrosis. The pulmonary fibrosis that is caused by bleomycin is often referred as “bleomycin lung.” Hypertrophic skin changes and hyperpigmentation of the hands are prevalent. Bleomycin is unusual in that myelosuppression is rare. Alkylating Agents Pharmacology | Anti-Cancer Alkylating Agents Alkylating agents exert their cytotoxic effects by covalently binding to nucleophilic groups on various cell constituents. Alkylation of DNA is probably the crucial cytotoxic reaction that is lethal to the tumor cells. Alkylating agents do not discriminate between cycling and resting cells, even though they are most toxic for rapidly dividing cells. Pharmacology | Anti-Cancer They are used in combination with other agents to treat a wide variety of lymphatic and solid cancers. In addition to being cytotoxic, all are mutagenic and carcinogenic and can lead to secondary malignancies such as acute leukemia. Pharmacology | Anti-Cancer A. Cyclophosphamide and ifosfamide These drugs are very closely related mustard agents that share most of the same primary mechanisms and toxicities. These agents have a broad clinical spectrum and are used as single agents or in combinations in the treatment of a wide variety of neoplastic diseases, such as non-Hodgkin lymphoma, sarcoma, and breast cancer. Pharmacology | Anti-Cancer Mechanism of action Cyclophosphamide is the most commonly used alkylating agent. Both cyclophosphamide and ifosfamide are first biotransformed to hydroxylated intermediates primarily in the liver by the CYP450 system. Pharmacology | Anti-Cancer The hydroxylated intermediates then undergo metabolism to form the active compounds, phosphoramide mustard and acrolein. Reaction of the phosphoramide mustard with DNA is considered to be the cytotoxic step. Pharmacology | Anti-Cancer Pharmacology | Anti-Cancer Pharmacokinetics Cyclophosphamide is available in oral and IV preparations, whereas ifosfamide is IV only. Cyclophosphamide is metabolized in the liver to active and inactive metabolites, and minimal amounts are excreted in the urine as unchanged drug. Ifosfamide is metabolized primarily by CYP450 3A4 and 2B6 isoenzymes. It is mainly renally excreted. Pharmacology | Anti-Cancer Adverse effects A unique toxicity of both drugs is hemorrhagic cystitis, which can lead to fibrosis of the bladder. Bladder toxicity has been attributed to acrolein in the urine in the case of cyclophosphamide and to toxic metabolites of ifosfamide. Adequate hydration as well as IV injection of mesna (sodium 2-mercaptoethane sulfonate), which neutralizes the toxic metabolites, can minimize this problem. Pharmacology | Anti-Cancer Neurotoxicity has been reported in patients on high-dose ifosfamide, probably due to the metabolite, chloroacetaldehyde. Pharmacology | Anti-Cancer B. Nitrosoureas Carmustine and lomustine are closely related nitrosoureas. Because of their ability to penetrate the CNS, the nitrosoureas are primarily employed in the treatment of brain tumors. Pharmacology | Anti-Cancer Mechanism of action The nitrosoureas exert cytotoxic effects by an alkylation that inhibits replication and, eventually, RNA and protein synthesis. Although they alkylate DNA in resting cells, cytotoxicity is expressed primarily in cells that are actively dividing. Therefore, nondividing cells can escape death if DNA repair occurs. Nitrosoureas also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins in the targeted cells. Pharmacology | Anti-Cancer Pharmacokinetics Carmustine is administered IV and as chemotherapy wafer implants, whereas lomustine is given orally. Because of their lipophilicity, these agents distribute widely in the body and readily penetrate the CNS. The drugs undergo extensive metabolism. Lomustine is metabolized to active products. The kidney is the major excretory route for the nitrosoureas. Pharmacology | Anti-Cancer C. Dacarbazine and temozolomide Dacarbazine is an alkylating agent that must undergo biotransformation to an active metabolite, methyltriazenoimidazole carboxamide (MTIC). The metabolite is responsible for the alkylating activity of this agent by forming methyl carbonium ions that attack the nucleophilic groups in the DNA molecule. The cytotoxic action of dacarbazine has been attributed to the ability of its metabolite to methylate DNA on the O-6 position of guanine. Pharmacology | Anti-Cancer Dacarbazine has found use in the treatment of melanoma and Hodgkin lymphoma. Temozolomide is related to dacarbazine, because both must undergo biotransformation to an active metabolite, MTIC, which is likely responsible for the methylation of DNA on the O-6 and N-7 position of guanine. Unlike dacarbazine, temozolomide does not require the CYP450 system for metabolic transformation, and it undergoes chemical transformation at normal physiological pH. Pharmacology | Anti-Cancer Temozolomide also inhibits the repair enzyme, O-6guanine-DNA alkyltransferase. Temozolomide differs from dacarbazine in that it crosses the blood brain barrier and, therefore, is used in the treatment of brain tumors such as glioblastomas and astrocytomas. It is also used in metastatic melanoma. Pharmacology | Anti-Cancer Temozolomide is administered intravenously or orally and has excellent bioavailability after oral administration. The parent drug and metabolites are excreted in urine. Pharmacology | Anti-Cancer D. Other alkylating agents Mechlorethamine was developed as a vesicant (nitrogen mustard) during World War I. Its ability to cause lymphocytopenia led to its use in lymphatic cancers. Melphalan, a phenylalanine derivative of nitrogen mustard, is used in the treatment of multiple myeloma. Pharmacology | Anti-Cancer This is a bifunctional alkylating agent that can be given orally, although the plasma concentration differs from patient to patient due to variation in intestinal absorption and metabolism. The dose of melphalan is carefully adjusted by monitoring the platelet and white blood cell counts. Chlorambucil is another bifunctional alkylating agent that is used in the treatment of chronic lymphocytic leukemia. Pharmacology | Anti-Cancer Busulfan is an alkylating agent that is effective against chronic myelogenous leukemia. This agent can cause pulmonary fibrosis (“busulfan lung”). Like other alkylating agents, all of these agents are leukemogenic. Pharmacology | Anti-Cancer Microtubule Inhibitors Pharmacology | Anti-Cancer Microtubule Inhibitors The mitotic spindle is part of a larger, intracellular skeleton (cytoskeleton) that is essential for the movements of structures occurring in the cytoplasm of all eukaryotic cells. The mitotic spindle is essential for the equal partitioning of DNA into the two daughter cells that are formed when a eukaryotic cell divides. Several plant-derived substances used as anticancer drugs disrupt this process by affecting the equilibrium between the polymerized and depolymerized forms of the microtubules, thereby causing cytotoxicity. Pharmacology | Anti-Cancer Pharmacology | Anti-Cancer Pharmacology | Anti-Cancer A. Vincristine and vinblastine Vincristine (VX) and vinblastine (VBL) are structurally related compounds derived from the periwinkle plant, Vinca rosea. They are, therefore, referred to as the Vinca alkaloids. A less neurotoxic agent is vinorelbine (VRB). Pharmacology | Anti-Cancer Although the Vinca alkaloids are structurally similar, their therapeutic indications are different. They are generally administered in combination with other drugs. VX is used in the treatment of acute lymphoblastic leukemia in children, Wilms tumor, Ewing soft tissue sarcoma, and Hodgkin and non-Hodgkin lymphomas, as well as some other rapidly proliferating neoplasms. Pharmacology | Anti-Cancer VBL is administered with bleomycin and cisplatin for the treatment of metastatic testicular carcinoma. It is also used in the treatment of systemic Hodgkin and non-Hodgkin lymphomas. VRB is beneficial in the treatment of advanced non–small cell lung cancer, either as a single agent or with cisplatin. Pharmacology | Anti-Cancer Mechanism of action These agents are cell cycle specific and phase specific, because they block mitosis in metaphase (M phase). Their binding to the microtubular protein, tubulin, blocks the ability of tubulin to polymerize to form microtubules. Instead, paracrystalline aggregates consisting of tubulin dimers and the alkaloid drug are formed. Pharmacology | Anti-Cancer Pharmacology | Anti-Cancer The resulting dysfunctional spindle apparatus, frozen in metaphase, prevents chromosomal segregation and cell proliferation. Pharmacokinetics IV injection of these agents leads to rapid cytotoxic effects and cell destruction. This, in turn, can cause hyperuricemia due to the oxidation of purines that are released from fragmenting DNA molecules. Pharmacology | Anti-Cancer The Vinca alkaloids are concentrated and metabolized in the liver by the CYP450 pathway and eliminated in bile and feces. Dosage adjustment is required in patients with impaired hepatic function or biliary obstruction. Pharmacology | Anti-Cancer Adverse effects VX and VBL are both associated with phlebitis or cellulitis if extravasation occurs during injection, as well as nausea, vomiting, diarrhea, and alopecia. VBL is a potent myelosuppressant, whereas peripheral neuropathy (paresthesias, loss of reflexes, foot drop, and ataxia) and constipation are more common with VX. These agents should not be administered intrathecally. This potential drug error can result in death, and special precautions should be in place for administration. Pharmacology | Anti-Cancer B. Paclitaxel and docetaxel Paclitaxel was the first member of the taxane family to be used in cancer chemotherapy. Substitution of a side chain resulted in docetaxel, which is the more potent of the two drugs. Paclitaxel has good activity against advanced ovarian cancer and metastatic breast cancer, as well as non– small cell lung cancer when administered with cisplatin. Docetaxel is commonly used in prostate, breast, GI, and non–small cell lung cancers. Pharmacology | Anti-Cancer Mechanism of action Both drugs are active in the G2/M phase of the cell cycle, but unlike the Vinca alkaloids, they promote polymerization and stabilization of the polymer rather than disassembly, leading to the accumulation of microtubules. The microtubules formed are overly stable and nonfunctional, and chromosome desegregation does not occur. This results in cell death. Pharmacology | Anti-Cancer Pharmacokinetics These agents undergo hepatic metabolism by the CYP450 system and are excreted via the biliary system. Dosages should be reduced in patients with hepatic dysfunction. Pharmacology | Anti-Cancer Adverse effects The dose-limiting toxicities of paclitaxel and docetaxel are neutropenia and leukopenia. Peripheral neuropathy is also a common adverse effect with the taxanes. Note: Because of serious hypersensitivity reactions (including dyspnea, urticaria, and hypotension), patients who are treated with paclitaxel should be premedicated with dexamethasone and diphenhydramine, as well as with an H2 receptor antagonist.