Cancer Chemotherapy and Immunology

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106, The answer is b, (Hardman.. pp 1296-1299J Cyclosporins is the preferred agent because it is a specific T cell inhibitor, and its success rate in protecting a gain si rejection is considerably better than that of any other agent. All of the other agents listed in the question are cytotoxic, because of the severe adverse reactions with cyclosporin^ it is used in conjunction with azathioprine, which reduces the required dose. Prednisone is also used in conjunction with cyclosporine.

107, The answer is d, (Katzung, pp 925-926. llardman, pp 1231-1232.) There are various phases described for the cell cycle. The M phase is the period of cell division (mitosis). Following the M phase, a cell may enter either the G) phase or Gn phase. The G! phase of the cell cycle is associated with cell growth, ribonucleic acid (RNA) synthesis, and protein synthesis. The Gq phase is the resting or dormant stage. No cell division takes place, although the cells are still capable of undergoing mitosis. This phase of the cell cycle is the most resistant to chemotherapeutic agents and may require a high dosage of the chemotherapeutic agent because most cancer drugs produce their lethal effect on cells that are actively involved in division. The S phase of the cell cycle involves DNA synthesis, and cells that are in the C2 phase show the synthesis of specialized proteins in preparation for cell replication.

108, The answer is a, (llardman.. p 1302J Cyclophosphamide, an alkylating agent, reacts with purine and pyrimidine bases of DNA to form bridges and dinners. These products interfere with DNA replication. 5-FU: methotrexate, and 6-thioguanine are antimetabolites, and the steroid prednisone has some tumor-suppressive effects.

109, The answer is b, (Hardman, p 1241.) Busulfan is an alkylating agent that, in contrast to other alky la tors, is an alky] sulfonate. Thio guanine is a purine antimetabolite. Bleomycin is classified as a chemotherapeutic antibiotic, and vincristine is a vine a alkaloid. Tamoxifen is an a nti estrogen hormone.

I 10. The answer is a. (Hardman, p 1302J Cyclophosphamide is classified as a poly functional alkylating drug that transfers its alkyl groups to cellular components. The cytotoxic effect of this agent is directly associated with the alkylation of components of DNA. Methotrexate and 5-FU are classified as antimetabolites that block intermediary metabolism to inhibit cell proliferation. Tamoxifen is an antiestrogen compound. Doxorubicin is classified as an antibiotic chemotherapeutic agent.

ML The answer is d. (Hardman, pp 1247, 1335.) Leucovorin prevents methotrexate from inhibiting dihydrofolate reductase and reverses all of its adverse effects except neurotoxicity

I 12. The answer is b. (Hardman, pp 1264-1265,) Dactinomycins major toxicities include stomatitis, alopecia, and bone marrow depression. Bleomycin's toxicities include edema of the hands, alopecia, and. stomatitis. Mitomycin causes marked bone marrow depression, renal toxicity and interstitial pneumonitis. Plicamycin causes thrombocytopenia, leukopenia, liver toxicity, and hypocalcemia. The latter may be of use in the treatment of hypercalcemia Doxorubicin causes cardiotoxicity, as well as alopecia and bone marrow depression. The cardiotoxicity has been linked to a lipid peroxidation within cardiac cells.

113. The answer is c, (Hardman7 pp 1243-1247.) Antimetabolites of folic acid such as methotrexate, which is an important cancer chemotherapeutic agent, exert their effect by inhibiting the catalytic activity of the enzyme dihydro folate reductase. The enzyme functions to keep folic acid in a reduced state. The first step in the reaction is the reduction of folic acid to 7,8-dihydrofolic acid (FH2)> which requires the cofactor nicotinamide adenine dinucleotide phosphate (NADPH). The second step is the conversion of FH2 to 5,6,7,8-tetrahydrofolic acid (FH4), This part of the reduction reaction requires nicotinamide adenine dinucleotide (NADU) or NADP11. The reduced forms of folic acid are involved in one-carbon transfer reactions that are required during the synthesis of purines and pyrimidine thym idyl ate. The affinity of methotrexate for dihydro folate reductase is much greater than for the substrates of folic acid and Fib. The action of methotrexate can be blocked or reduced by the administration of leucoyo rin (lY'-formyl FH4), which can substitute for the reduced forms of folic acid in the cell. Methotrexate affects the S phase of the cell cycle. The drug is actively transported into the cell, and at very large doses the drug can enter the cell by simple diffusion. Although cladribine is an antimetabolite, it does not inhibit d i hydro folate reductase. Procarbazine, paclitaxel, and i fosiamide exert their anticancer effects through other mechanisms of action that are not associated with d i hydro folate reductase.

I 14, The answer is a. (Hardman, pp 1259, 1260J The vinca alkaloids, vineristine and vinblastine, have proved valuable because they work on a different principle from most cancer chemotherapeutic agents. They (like colchicine) inhibit mitosis in meta phase by their ability to bind to tubulin. This prevents the formation of tubules and, consequently, the orderly arrangement of chromosomes, which apparently causes cell death.

115, The answer is d* (Katzung, pp 925—926., 953J Cell-cycle-specific cytotoxic agents are most effective in malignancies in which a large portion of the population of malignant cells is undergoing mitosis. In leukemia, lymphoma, choriocarcinoma, and other rapidly growing tumors, these agents may induce a high-percentage cell kill of the entire tumor and at least of those cells that are actively dividing. In slowly growing, solid tumors, such as carcinomas of the colon, the frequency of actively dividing cells is low, and perhaps the resting cells survive the cycle-specific agents and then can be recruited back into the proliferative cycle.

1 16. The answer is d. (Katzung, p 940. Hardman, p 1267.) The potential serious adverse effect of bleomycin is pneumonitis and pulmonary fibrosis. This adverse effect appears to be both age- and dose-related. The clinical onset is characterized by decreasing pulmonary function, fine rales, cough, and diffuse basilar infiltrates. This complication develops in approximately 5% to 10% of patients treated with bleomycin. Thus, extreme caution must be used in patients with a preexisting history of pulmonary disease. All of the other drugs listed in the question are effective against carcinomas and have not been associated with significant lung toxicity

117. The answer is d. (Hardman, p 1236.) Cell-cycle-specific agents such as 6-MP, 5-FU, bleomycin, and vincristine have proved to be the most effective against proliferating cells. Busulfan is an alkylating agent that binds to DNA and causes damage to these macromolecules. It is useful against low-growth, as well as high-growth, tumors and is classified as a cell-cycle-nonspecific (CCN5) agent.

118. The answer is e. (Hardman, p 1302J Muromonab-CD3 is a monoclonal antibody that interferes with T cell function. It is classified as an immunosuppressive drug. This drug is given intravenously and is indicated in the treatment of acute allograft rejection. Generally, azathioprine and prednisone are used along with muromonab-CD3. Interferon a and aldesleukin (interleukin 2) are cytokines that are classified as immuno-stimulants. Sargramostim and filgrastim are also immunostimulants. These drugs are produced by recombinant DNA technology. Sargramostim is a human granulocyte-macrophage colony stimulating factor (GM-CSF), and filgrastim is a human granulocyte colony stimulating factor (G-GSF).

119. The answer is c. (Katzung, pp 603-609, 932-933.) Methotrexate is classified as an antimetabolite with therapeutic uses in cancer chemotherapy and as an immunosuppressive agent indicated in the treatment of severe active classical rheumatoid arthritis. Leucovorin is related to methotrexate in that it is an antagonist of its actions. It can supply a source of reduced folate for the methylation reactions that are prevented by methotrexate.

120, The answer is f. (Katzung, p 972J Azathioprine is a derivative thai is closely related to 6-MP, which is used as a cancer chemotherapeutic agent, while azathioprine is used as an immunosuppressive agent because it is more effective than 6-MP in this regard. Azathioprine is used in organ transplantation, particularly kidney allografts. Like 6-MP azathioprine is biotransformed to an inactive product by xanthine oxidase. Allopurinol, which inhibits this enzyme, can increase the therapeutic action of azathioprine and. possibly its adverse reactions. The dosage of azathioprine should be decreased in the presence of allopurinol.

121, The answer is d. (Hardman, p 1258. Katzung, pp 935-936.) Vinblastine binds to tubulin and blocks the protein from polymerizing to microtubules. The drug-tubulin complex binds to the developing microtubule, resulting in inhibition of microtubule assembly and subsequent depoly-merization.

122, The answer is i, (Katzung, p 984.) Bacille Calmette-Gu£rin vaccine is a nonspecific stimulant of the reticuloendothelial system. It is an attenuated strain of Mycobacterium tois that appears most effective in small, localized bladder tumors. This agent is approved for intravesicular use in bladder cancer Adverse reactions are associated with the renal system, such as problems with urination, infection, and cystitis.

I 23, The answer is d. (Katzmg p 969.) Cyclosporine is a peptide antibiotic that both inhibits early stages of differentiation of T cells and blocks their activation This most likely occurs in activated T lymphocytes by inhibition of gene transcription of immune-enhancing substances such as interferon y and interleukins. Cyclophosphamide, an alkylating agent, destroys proliferating lymphoid cells. Sirolimus amarolide ab blocks the response of T cells to cytokines. Methotrexate is an inhibitor of folic acid synthesis. Azathioprine inhibits enzymes that are related to the biosynthesis of purines.

124, The answer is c, (Katzung, p 933J Resistance to thioguanine occurs because of an increase in alkaline phosphatase and a decrease in hypoxanthine-guanine phosphoribosyl transferase These enzymes are responsible, respectively for the increase in dephosphorylation of thiopurine nucleotide and the conversion of thioguanine to its active form, 6-thioinosinic acid.

125, The answer is d, (Hardmant pp 1242-1243J Streptozocin is an alkylating agent with the capacity to cross-link DNA, thereby inhibiting its synthesis. It is a nitrosourea Tike antibiotic that contains a glucosamine moiety that allows it to be selectively taken up by the p cells of the islets of Langerhans. Consequently it can be useful in treating metastatic islet cell carcinoma.

126, The answer is c, (Hardman, pp 1260-1262.) Paclitaxel is a large structural molecule that contains a 15-membered taxane ring system. This anticancer agent is an alkaloid derived from the bark of the Pacific yew tree. Its chemotherapeuric action is related to the microtubules in the cell. Paclitaxel promotes microtubule assembly from dinters and causes microtubule stabilization by preventing depolymerization. As a consequence of these actions, the microtubules form disorganized bundles, which decreases interphase and mitotic function. Furthermore, paclitaxel also causes premature cell division. The drug is administered intravenously and is useful in such diseases as cisplatin-resistant ovarian cancer, metastatic breast cancer, malignant melanoma, and acute myelogenous leukemia.

127, The answer is e, (Katzung, pp 941-942.) Tamoxifen is a partial antagonist of the estrogen receptor. It blocks the binding of estrogen to estrogen-sensitive cancer cells, particularly in breast cancer. It also acts effectively in proges tin-re si statu endometrial cancer.

128, The answer is a, (Katzung, pp 931—932.) Cisplatin is an inorganic metal complex that is thought to act in an analogous fashion as an alkylating agent. It inhibits DNA synthesis primarily through cross-linking of DNA and acts throughout the cell cycle. Binding of cisplatin occurs in DNA primarily with guanine residues, but interactions also can occur with adenosine and cytosine residues. It is used in bladder, testicular, and ovarian cancers.

129, The answer is h. (Hardman, pp 1268-1269.) Asparaginase is an enzyme that catalyzes the hydrolysis of serum asparagine to a spar tic acid and ammonia. Major toxicities are related to antigenicity and pancreatitis. In addition, more than 50% of those treated present biochemical evidence of hepatic dysfunction.

130, The answer is a, (Hardman, pp 1247-1251.) 5-Huorouracil is a pyrimidine antagonist that has a low neurotoxicity when compared with other fluorinated derivatives; however, its major toxicities are myelosup-pression and oral or gastrointestinal ulceration. Leukopenia is the most frequent clinical manifestation of the myelosuppression

131, The answer is c. (Hardman, pp 1238-1239.) Remission maintenance can be carried out by combination therapy, which includes cyclophosphamide. Cyclophosphamide causes hemorrhagic cystitis. Doxorubicin and car must ine are useful in the treatment of acute lymphatic leukemia, but neither is known to cause hemorrhagic cystitis.

132, The answer is e. (Hardman, pp 1269—1271.) Cisplatin causes acoustic nerve damage. Paclitaxel causes peripheral neuritis Dose-

dependent pneumonitis and fibrosis are caused by bleomycin. Doxorubicin causes cardiac toxicity which may lead to congestive heart failure. VFluorouracil causes myelosuppression, stomal it is. and oral and gastrointestinal ulcerations.

1331—135. The answers are 133-b, 134-d, 135-a. (Hardman, pp 12301232.) Specific cell cycle events are pre sen 1 in both normal and cancerous cells. These phases of the cell cycle are shown in the diagram with the questions. Although general statements can be made regarding the cell cycle phases in which certain classes of chemotherapeutic agents act, some drugs listed m a particular category of antineoplastic agents may exhibit their effects on a different phase of the cell cycle. Alkylating agents are considered to be nonspecific in regard to the phase at which they have their effects. 1 lowever, the alkylating agent busulfan is mostly active in the G0 phase. S-phase-specific agents are cytosine arabinoside and hydroxyurea, while S-phase-specific agents that are self-limiting are 6-MP and methotrexate. M-phase-specific agents are vincristine, vinblastine, and paclitaxel. Antibiotic chemotherapeutic agents are considered to have effect in the G2 phase of the cell cycle, with the exception of dactinomycin, which is most active in the 5 phase.

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