Chemotherapeutic agents, metabolism

When sulfanilamide was introdnced as a chemotherapeutic agent, metabolic acidosis was recognized as a side effect. This observation led to the demonstration that snl-fanilamide is an inhibitor of carbonic anhydrase. Snbse-quently, an enormous number of sulfonamides were synthesized and tested for the ability to inhibit carbonic anhydrase of these componnds, acetazolamide has been studied most extensively. Three carbonic anhydrase inhibitors currently are available in the United States—acetazolamide, dichlorphenamide (Daranide), and methazolamide (GlaucTabs). The common molecnlar motif of available carbonic anhydrase inhibitors is an nnsnbstitnted sulfonamide moiety. 

Bacteria are vulnerable to the selective attack of chemotherapeutic agents because of the many metabolic and molecular differences between them and animal cells. The biology of vims replication, with its considerable dependence on host-cell energy-producing, protein-synthesizing and biosynthetic enzyme systems, severely limits the opportunities for selective attack. Another problem is that many vims diseases only become apparent after extensive viral multiplication and tissue damage has been done. 

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 anti metabolites that block intermediary metabolism to inhibit cell proliferation. Tamoxifen is an antiestrogen compound. Doxorubicin is classified as an antibiotic chemotherapeutic agent. 

A particular toxicity associated with the administration of interferon to humans and experimental animals has been depression of the cytochrome P-450 monooxygenase (MFO) metabolizing enzymes. As a consequence of MFO inhibition following treatment with IFN, the sleep-time of mice treated with hexabarbital is increased, as is the toxicity of acetaminophen (Stebbing and Week, 1984). Possible effects on the metabolism of chemotherapeutic agents or other drugs processed by the P-450 MFOs should be anticipated. 

Bioprecursors provide relevant examples of chemotherapeutic agents whose activation occurs by reduction in oxygen-deprived cells. Bioprecursors certainly appear as a viable class of prodrugs, since they avoid potential toxicity problems caused by the carrier moiety (see below). In contrast, attention must be given here to metabolic intermediates. 

Vinflumine (Javlor ) is a second-generation Vinca alkaloid. It is more active than the nonfluorinated parent compound (vinorelbine) in several cancers (Figure 8.7). Vinflumine is currently in Phase III clinical trials as a chemotherapeutic agent against a variety of cancers (metastasic breast cancer, small cell lung cancer, and bladder cancer). This drug inhibits mitotic assembly, via inhibition of tubulin polymerization in microtubules, a major element of the cytoskeleton. Effects of fluorine substimtion on tubulin affinity or on metabolism are not responsible for the increased efficiency and decreased toxicity. The synthesis of vinflumine is reported in Chapter 4. ... 

Pharmacogenetics and Altered Drug Metabolism of Chemotherapeutic Agents for Cancer... 

H FIGURE 22-49 Thymidylate synthesis and folate metabolism as targets of chemotherapy, (a) During thymidylate synthesis, /V5,N10-methylenetetrahydrofolate is converted to 7,8-dihydrofolate the N5,N10-methylenetetrahydrofolate is regenerated in two steps (see Fig. 22-44). This cycle is a major target of several chemotherapeutic agents, (b) Fluorouracil and methotrexate are important chemotherapeutic agents. In cells, fluorouracil is converted to FdUMP, which... 

Chemotherapeutic agents are grouped by cytotoxic mechanism. The alkylating agents, such as cyclophosphamide [50-18-0] and melphalan [148-82-5], interfere with normal cellular activity by alkylation deoxyribonucleic acid (DNA). Antimetabolites, interfering with complex metabolic pathways in the cell, include methotrexate [59-05-2], 5-fluorouracil [51-21-8], and cytosine arabinoside hydrochloride [69-74-9]. Antibiotics such as bleomycin [11056-06-7] and doxorubicin [23214-92-8] have been used, as have the plant alkaloids vincristine [57-22-7] and vinblastine [865-21-4]. 

In recent years, it has been found that the barrier function of the intestinal epithelium cannot be adequately described by a combination of metabolic and physical barriers alone. Apically polarized efflux systems are known to be present in cancer cells and represent a major barrier to the uptake of a wide variety of chemotherapeutic agents (i.e. in multi-drag resistance). Efflux systems have also now been identified in normal intestinal and colonic cells, and also at other epithelial sites. 

The most widely known chemotherapeutic agent directed against TS is 5-fluorour-acil (5-FU). 5-FU was first used clinically almost 50 years ago, yet still remains a mainstay for the treatment of carcinoma of the breast and gastrointestinal tract. In cells, 5-FU is metabolized to 5-FdUMP, which forms a stable inhibitory ternary complex with the co-substrate N5N10-methylene-5,6,7,8-tetrahydrofolate (CH2H4-folate) and TS. In this complex, a covalent bond links the thiol of cysteine 195 of human TS to C6 of deoxyuracil monophosphate (dUMP) and the methylene carbon of the co-substrate is joined to C5 of the nucleotide [55]. The fluorine at C5, unlike the proton, cannot... 

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