Pharmacology Cancer Chemotherapy Lec 10 PDF

Pharmacology Cancer Chemotherapy Lec 10 Pharmacology | Cancer Chemotherapy Contents : Principles of Cancer Chemotherapy 3 Treatment strategies 6 Treatment regimens and scheduling 10 Resistance and toxicity with chemotherapy 15 Toxicity 18 Antimetabolites 23 Pharmacology | Cancer Chemotherapy Princip...

Pharmacology Cancer Chemotherapy Lec 10 Pharmacology | Cancer Chemotherapy Contents : Principles of Cancer Chemotherapy 3 Treatment strategies 6 Treatment regimens and scheduling 10 Resistance and toxicity with chemotherapy 15 Toxicity 18 Antimetabolites 23 Pharmacology | Cancer Chemotherapy Principles of Cancer Chemotherapy Cancer chemotherapy aims to cause a lethal cytotoxic event or apoptosis in the cancer cell that can arrest tumor progression. The attack is generally directed toward DNA or against metabolic sites essential to cell replication. Ideally, these anticancer drugs should interfere only with cellular processes that are unique to malignant cells. Pharmacology | Cancer Chemotherapy Indeed, most anticancer drugs do not specifically recognize neoplastic cells and affect all kinds of proliferating cells including the normal cells. Therefore, almost all antitumor agents have a steep dose–response curve for both therapeutic and toxic effects. Newer agents are being developed that take a different approach to cancer treatment by blocking checkpoints and allowing the patient’s own immune system to attack cancer cells. Pharmacology | Cancer Chemotherapy Chemotherapeutic agents also used in non-cancer diseases, e.g. methotrexate in rheumatoid arthritis and psoriasis, azathioprine in organ transplantation, and hydroxyurea in sickle cell anemia. Pharmacology | Cancer Chemotherapy Treatment strategies Goals of treatment Chemotherapy reduces neoplastic cell burden to maintain “normal” existence of the disease with the patient as a chronic disease, accordingly three goals intended depending upon complicated factors mainly the type and stage of cancer: First fundamental goal of cancer chemotherapy is to cure the disease. Cure means long-term disease-free survival. True cure requires the eradication of every neoplastic cell. Pharmacology | Cancer Chemotherapy Second goal becomes control of the disease by stopping the cancer from enlarging and spreading to extend survival and maintain the “best quality” of life. In advanced stages of cancer, controlling the disease is not possible. Third goal is palliation. Palliation means alleviation of symptoms and avoidance of life threatening toxicity. This means that chemotherapeutic drugs may be used to relieve symptoms caused by the cancer and improve the quality of life, even though the drugs may not extend survival. The goal of treatment should always be kept in mind, as it often influences treatment decisions. Pharmacology | Cancer Chemotherapy Indications for treatment Chemotherapy is indicated in the following cases: a) Initial chemotherapy: indicated when the neoplasm is disseminated and are not suitable to surgery, e.g esophageal, head and neck cancers, and leukemia. b) Adjuvant chemotherapy: is indicated as supplemental treatment to attack micro metastases following surgery or radiation, e.g in breast and colorectal cancers. Pharmacology | Cancer Chemotherapy c) Neo-adjuvant chemotherapy: given prior to surgery in an attempt to shrink the cancer in solid tumors. d) Maintenance chemotherapy: given in low doses to cancer patients to assist in prolonging remission. Pharmacology | Cancer Chemotherapy Treatment regimens and scheduling Drug dosages are usually calculated on the basis of body surface area, in an effort to tailor the dosage to each patient. Destruction of cancer cells by chemotherapeutic agents follows first-order kinetics (that is, a given dose of drug destroys a constant fraction of cells). Combination chemotherapy is more successful than singledrug treatment in most cancers for which chemotherapy is effective. Pharmacology | Cancer Chemotherapy Cytotoxic agents with different toxicities, and with different molecular sites and mechanisms of action, are usually combined at full doses. This results in higher response rates, due to additive and/or potentiated cytotoxic effects, and nonoverlapping host toxicities. In contrast, agents with similar dose-limiting toxicities, such as myelosuppression, nephrotoxicity, or cardiotoxicity, can be combined safely only by reducing the doses of each. Pharmacology | Cancer Chemotherapy The advantages of combination chemotherapy are that it: 1) Provides maximal cell killing within the range of tolerated toxicity. 2) Is effective against a broader range of cell lines in the heterogeneous tumor population. 3) may delay or prevent the development of resistant cell lines. Pharmacology | Cancer Chemotherapy Treatment protocols Many cancer treatment protocols have been developed, and each is applicable to a particular neoplastic state. They are usually identified by an acronym. For example, a common regimen called R-CHOP, used for the treatment of nonHodgkin lymphoma, consists of rituximab, cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), and prednisone. Therapy is scheduled intermittently to allow recovery or rescue of the immune system, which is also affected by the chemotherapeutic agents, thus reducing the risk of serious infection. Pharmacology | Cancer Chemotherapy Resistance and toxicity with chemotherapy Resistance one of the major difficulties in cancer therapy is the development of resistance to cancer chemotherapy. Resistance could be categorized into two forms: 1. Inherited or primary resistance: were some types of neoplasms are inherently resistant to some anticancer drug (e.g. melanoma) even when the chemotherapy treatment used for the first time. 2. Acquired resistance: were the tumor cells that previously sensitive will develop resistance during treatment with chemotherapy. This type of resistance developed by modulations made by the tumor cells to overcome the lethal effect of the drug. Pharmacology | Cancer Chemotherapy including decreased accumulation of drug (e.g. Pglycoprotein), insufficient activation of the drug (e.g. 5- FU, mercaptopurine), decreased taking up the drug (e.g. methotrexate), increased the concentration of target enzyme (e.g. methotrexate), utilization of alternative metabolic pathway (e.g. antimetabolites), increased repair of drug-induced lesions (e.g. alkylating agents), and mutations in various genes that giving rise to resistant target site (e.g. overexpression of antiapoptotic genes). Pharmacology | Cancer Chemotherapy Resistance to chemotherapy commonly developed with: 1. Long-term, continuous. 2. Suboptimal doses. 3. Single drug regimens. Therefore, to minimize resistance, it is advised to use short-term, intermittent, and intensive and drug combination regimens. Pharmacology | Cancer Chemotherapy Toxicity Therapy aimed at killing rapidly dividing cancer cells also affects normal cells undergoing rapid proliferation (for example, cells of the buccal mucosa, bone marrow, gastrointestinal [GI] mucosa, and hair follicles), contributing to the toxic manifestations of chemotherapy. Common adverse effects Most chemotherapeutic agents have a narrow therapeutic index. Severe vomiting, stomatitis, bone marrow suppression, and alopecia occur to varying extents during therapy with most antineoplastic agents. Pharmacology | Cancer Chemotherapy Vomiting is often controlled by administration of antiemetic drugs. Some toxicities, such as myelosuppression that predisposes to infection, are common to many chemotherapeutic agents, whereas other adverse reactions are confined to specific agents, such as: bladder toxicity with cyclophosphamide. cardiotoxicity with doxorubicin. pulmonary fibrosis with bleomycin. The duration of the adverse effects varies widely. For example, alopecia is transient, but the cardiac, pulmonary, and bladder toxicities can be irreversible. Pharmacology | Cancer Chemotherapy Pharmacology | Cancer Chemotherapy Antimetabolites Pharmacology | Cancer Chemotherapy Antimetabolites Antimetabolites are structurally related to normal compounds that exist within the cell. They generally interfere with the availability of normal purine or pyrimidine nucleotide precursors, either by inhibiting their synthesis or by competing with them in DNA or RNA synthesis. Their maximal cytotoxic effects are in S phase and are, therefore, cell cycle specific. Pharmacology | Cancer Chemotherapy Pharmacology | Cancer Chemotherapy Methotrexate, pemetrexed, and pralatrexate The vitamin folic acid plays a central role in a variety of metabolic reactions involving the transfer of onecarbon units and is essential for cell replication. Folic acid is obtained mainly from dietary sources and from that produced by intestinal flora. Methotrexate, pemetrexed, and pralatrexate are antifolate agents. Pharmacology | Cancer Chemotherapy Mechanism of action MTX is structurally related to folic acid and acts as an antagonist of the vitamin by inhibiting mammalian dihydrofolate reductase (DHFR), the enzyme that converts folic acid to its active, coenzyme form, tetrahydrofolic acid (FH4). The inhibition of DHFR can only be reversed by a 1000-fold excess of the natural substrate, dihydrofolate (FH2), or by administration of leucovorin, which bypasses the blocked enzyme and replenishes the folate pool. Pharmacology | Cancer Chemotherapy Folinic acid (leucovorin) could restore MTX inhibition by replenishing THF pool as it bypasses the MTX inhibition sites. Pemetrexed is an antimetabolite similar in mechanism to methotrexate. However, in addition to inhibiting DHFR, it also inhibits thymidylate synthase and other enzymes involved in folate metabolism and DNA synthesis. Pralatrexate is an antimetabolite that also inhibits DHFR. Pharmacology | Cancer Chemotherapy Therapeutic uses MTX, usually in combination with other drugs, is effective against acute lymphocytic leukemia, Burkitt lymphoma in children, breast cancer, bladder cancer, and head and neck carcinomas. In addition, low-dose MTX is effective as a single agent against certain inflammatory diseases, such as severe psoriasis and rheumatoid arthritis, as well as Crohn’s disease. Pemetrexed is primarily used in non–small cell lung cancer Pralatrexate is used in relapsed or refractory T-cell lymphoma. Pharmacology | Cancer Chemotherapy Pharmacokinetics MTX is variably absorbed orally at low doses from the GI tract, it can also be administered by intramuscular, intravenous (IV), and intrathecal routes. Small amounts of MTX undergo hydroxylation at the 7th position to form 7-hydroxymethotrexate. This derivative is less water soluble than MTX and may lead to crystalluria. Excretion of the parent drug and the 7-OH metabolite occurs primarily via urine. Pharmacology | Cancer Chemotherapy Adverse effects MTX, Pemetrexed and pralatrexate should be given with folic acid and vitamin B12 supplements to reduce hematologic and GI toxicities. Pretreatment with corticosteroids to prevent cutaneous reactions is recommended with pemetrexed. However, it may cause ocular toxicity, including irreversible retinal damage and corneal deposits, CNS disturbances, GI upset, and skin discoloration and eruptions. Pharmacology | Cancer Chemotherapy Purine analogs Drugs belong to this category are guanine analogs (6-mercaptopurine, 6-thioguanine), and adenosine analogs (fludarabine, and cladribine). Some drugs in this category dose not used in cancer chemotherapy but as immunosuppressant (e.g. azathioprine), antiviral (e.g. acyclovir, zidovudine) and hypouricemic agent (allopurinol). Pharmacology | Cancer Chemotherapy 6-Mercaptopurine 6-Mercaptopurine (6-MP), a purine antimetabolite, is the thiol analog of hypoxanthine. 6-MP and 6-thioguanine were the first purine analogs to prove beneficial for treating neoplastic disease. 6-MP is used principally in the maintenance of remission in acute lymphoblastic leukemia. 6-MP and its analog, azathioprine, are also beneficial in the treatment of Crohn's disease. Pharmacology | Cancer Chemotherapy Adenosine analogs Fludarabine and Cladribine, both agents are adenosine analogs used in leukemia’s and lymphomas. Fludarabine is the 5′-phosphate of 2-fluoroadenine arabinoside, a purine nucleotide analog. It is useful in the treatment of chronic lymphocytic leukemia, hairy cell leukemia, and indolent nonHodgkin lymphoma. Pharmacology | Cancer Chemotherapy Fludarabine is a prodrug, and the phosphate is removed in the plasma to form 2-F-araA, which is taken up into cells and again phosphorylated (initially by deoxycytidine kinase). Although the exact cytotoxic mechanism is uncertain, the triphosphate is incorporated into both DNA and RNA. This decreases their synthesis in the S phase and affects their function. Pharmacology | Cancer Chemotherapy Resistance is associated with: reduced uptake into cells lack of deoxycytidine kinase decreased affinity for DNA polymerase, as well as other mechanisms. Fludarabine is administered IV rather than orally, because intestinal bacteria split off the sugar to yield the very toxic metabolite, fluoroadenine. Pharmacology | Cancer Chemotherapy Pyrimidine analogs This category of chemotherapeutic agents designed as a false metabolite to inhibit pyrimidine nucleotide synthesis, thus inhibit DNA synthesis, and to lesser extent inhibit RNA synthesis. Pyrimidine analogs could be divided into two groups according to the nucleotide target: thymidine and cytosine inhibitors. Thymidine inhibitors include: 5-fluorouracil (5-FU), capecitabine while the cytosine inhibitors include cytarabine, 5azacytidine and gemcitabine. Pyrimidine Pharmacology | Cancer Chemotherapy 1. ( 5-Fluorouracil) 5-Fluorouracil (5-FU), a pyrimidine analog, has a stable fluorine atom in place of a hydrogen atom at position 5 of the uracil ring. The fluorine interferes with the conversion of deoxyuridylic acid to thymidylic acid, thus depriving the cell of thymidine, one of the essential precursors for DNA synthesis. 5-FU is employed primarily in the treatment of slowgrowing solid tumors (for example, colorectal, breast, ovarian, pancreatic, and gastric carcinomas). Pharmacology | Cancer Chemotherapy When applied topically, 5-FU is also effective for the treatment of superficial basal cell carcinomas. Mechanism of action 5-FU itself is devoid of antineoplastic activity. It enters the cell through a carrier-mediated transport system and is converted to the corresponding deoxynucleotide (5fluorodeoxyuridine monophosphate [5-FdUMP]), which competes with deoxyuridine monophosphate for thymidylate synthase, thus inhibiting its action. Pharmacology | Cancer Chemotherapy DNA synthesis decreases due to lack of thymidine, leading to imbalanced cell growth and “thymidineless death” of rapidly dividing cells. 5-FU is also incorporated into RNA, and low levels have been detected in DNA. In the latter case, a glycosylase excises the 5-FU, damaging the DNA. 5-FU produces the anticancer effect in the S phase of the cell cycle. Pharmacology | Cancer Chemotherapy Pharmacology | Cancer Chemotherapy Pharmacokinetics Because of severe toxicity to the GI tract, 5-FU is administered IV or, in the case of skin cancer, topically. The drug penetrates well into all tissues, including the CNS. 5-FU is rapidly metabolized in the liver, lung, and kidney. It is eventually converted to fluoro-β-alanine, which is removed in the urine. Pharmacology | Cancer Chemotherapy Elevated levels of dihydropyrimidine dehydrogenase (DPD) can increase the rate of 5-FU catabolism and decrease its bioavailability. Patients with DPD deficiency may experience severe toxicity manifested by pancytopenia, mucositis, and life-threatening diarrhea. Knowledge of DPD activity in an individual should allow more appropriate dosing of 5-FU. Pharmacology | Cancer Chemotherapy 2. Capecitabine Capecitabine is a fluoropyrimidine carbamate. It is used in the treatment of colorectal and metastatic breast cancer. Capecitabine is well absorbed following oral administration. After being absorbed, capecitabine, which is itself nontoxic, undergoes a series of enzymatic reactions, the last of which is hydrolysis to 5-FU. Pharmacology | Cancer Chemotherapy This step is catalyzed by thymidine phosphorylase, an enzyme that is concentrated primarily in tumors. Thus, the cytotoxic activity of capecitabine is the same as that of 5-FU and is tumor specific. The most important enzyme inhibited by 5-FU (and, thus, capecitabine) is thymidylate synthase. Pharmacology | Cancer Chemotherapy Pharmacology | Cancer Chemotherapy Cytidine analogs These pyrimidine inhibitors are cytidine analogs with antineoplastic action include : 1. Cytarabine 2. Azacitidine 3. Gemcitabine Pharmacology | Cancer Chemotherapy Cytarabine Cytarabine : is an analog of 2′-deoxycytidine in which the natural ribose residue is replaced by Darabinose. Cytarabine acts as a pyrimidine antagonist. The major clinical use of cytarabine is in acute nonlymphocytic (myelogenous) leukemia (AML). Pharmacology | Cancer Chemotherapy Cytarabine enters the cell by a carrier-mediated process and, like the other purine and pyrimidine antagonists, must be sequentially phosphorylated by deoxycytidine kinase and other nucleotide kinases to the nucleotide form (cytosine arabinoside triphosphate or ara- CTP) to be cytotoxic. Ara-CTP is an effective inhibitor of DNA polymerase. The nucleotide is also incorporated into nuclear DNA and can terminate chain elongation. It is, therefore, S phase (and, hence, cell cycle) specific. Pharmacology | Cancer Chemotherapy Pharmacokinetics Cytarabine is not effective when given orally, because of deamination to the noncytotoxic araU by cytidine deaminase in the intestinal mucosa and liver. Given IV, it distributes throughout the body but does not penetrate the CNS in sufficient amounts. Therefore, it may also be injected intrathecally. Pharmacology | Cancer Chemotherapy Cytarabine undergoes extensive oxidative deamination in the body to ara-U, a pharmacologically inactive metabolite. Both cytarabine and ara-U are excreted in urine. Pharmacology | Cancer Chemotherapy Azacitidine Azacitidine is a pyrimidine nucleoside analog of cytidine. It is used for the treatment of myelodysplastic syndromes and AML. Azacitidine undergoes activation to the nucleotide metabolite azacitidine triphosphate and gets incorporated into RNA to inhibit RNA processing and function. It is S-phase cell cycle specific. Pharmacology | Cancer Chemotherapy Gemcitabine Gemcitabine is an analog of the nucleoside deoxycytidine. It is used most commonly for pancreatic cancer and non–small cell lung cancer. Gemcitabine is a substrate for deoxycytidine kinase, which phosphorylates the drug to 2′,2′difluorodeoxycytidine triphosphate. Pharmacology | Cancer Chemotherapy Gemcitabine is administered by IV infusion. It is deaminated to difluorodeoxyuridine, which is not cytotoxic, and is excreted in urine.