Purine chemotherapeutic agents

I I 3. The answer is c. (Hardman, 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 dihydrofolate 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 (FH ). This part of the reduction reaction requires nicotinamide adenine dinucleotide (NADH) or NADPH. The reduced forms of folic acid are involved in one-carbon transfer reactions that are required during the synthesis of purines and pyrimidine thymidylate. The affinity of methotrexate for dihydrofolate reductase is much greater than for the substrates of folic acid and FH2. The action of... 

We examine here the biosynthetic pathways of purine and pyrimidine nucleotides and their regulation, the formation of the deoxynucleotides, and the degradation of purines and pyrimidines to uric acid and urea. We end with a discussion of chemotherapeutic agents that affect nucleotide synthesis. 

Chemotherapeutic agents, useful in me treatment of neoplastic diseases, exert their therapeutic effects by modifying me synthesis or functions of nucleic acids (see Chapter 51 and Chapter 58). For example, 6-mercaptopurine inhibits purine-ring biosynthesis, cytarabine inhibits DNA polymerase, alkylating agents crosslink DNA, and hydroxyurea inhibits the conversion of ribonucleotides into deoxyribonucleotides. However, other pharmacologic agents such as chlorpromazine, a... 

The chemotherapeutic agent d.v-diammincdichloroplatinum(II), cis-DDP, or cisplatin, can form covalent adducts with many cellular macromolecules, but there is convincing evidence that its cytotoxic properties are a consequence of bifunctional-DNA adduct formation [ 1 ] [2]. Platinum binds to the N(7) position of purine nucleotides, resulting predominantly in 1,2-d(GpG) and l,2-d(ApG) intrastrand cross-links, but also in l,3-d(GpNpG) intrastrand, interstrand and protein-DNA cross-links [3][4], The 1,2-intrastrand cross-links, which comprise 90% of the DNA adducts, are not formed by the clinically inactive trans-DDP because of geometric constraints, and attention has therefore focused on these adducts as the active lesions in the anticancer activity of the drug. 

Secondary gout is a result of hyperuricemia attributable to several identifiable causes. Renal retention of uric acid may occur in acute or chronic kidney disease of any type or as a consequence of administration of drugs diuretics, in particular, are implicated in the latter instance. Organic acidemia caused by increased acetoacetic acid in diabetic ketoacidosis or by lactic acidosis may interfere with tubular secretion of urate. Increased nucleic acid turnover and a consequent increase in catabolism of purines may be encountered in rapid proliferation of tumor cells and in massive destruction of tumor cells on therapy with certain chemotherapeutic agents. 

Fusion of the purine/pyrimidine rings either as intra- or interstrand cross-links can occur upon exposure to ionizing radiation, chemotherapeutic agents (e.g., cisplatin), or photosensitization reactions (psoralens), or from endogenous generation of bisfunctional enals mentioned earlier (e.g., acrolein, crotonaldehyde, and... 

AO and XO are cytosolic enzymes and are closely related. However, they differ in their substrate/inhibitor specificities. AO is involved in the metabolism of several clinically significant drugs such as famciclovir, zaleplon, zonisamide, and ziprasidone [69-72], XO has a narrower substrate specificity than AO and is mainly active toward purines and pyrimidines. XO plays a role in the oxidation of several chemotherapeutic agents and has been implicated in the bioactivation of mitomycin B [73]. 

Marr, J. J. (1991) Purine analogues as chemotherapeutic agents in leishmaniasis and American trypanosomiasis. J. hib Clin. Med. 118 111-119. 

Chemotherapeutic agents - The fate of the aminonucleoside of puromycin ( AN), (5-dimie thylamino-9- (3 -amino-3 -deoxy-3- -ribofuranosyl)purine, was studied either in vitro with rat liver slices or in vivo with the livers of rats that haH een dosed i.v. with PAN . BotBTin vrtro and in vivo,... 

The rifamycins act on the sensitive bacteria, blocking the synthesis of all cellular RNA, because they are potent inhibitors of all bacterial DNA-directed RNA polymerases. Most rifamycins are not effective on the mammalian RNA polymerase. Therefore, they possess the necessary requisite for ideal chemotherapeutic agents, that is, selective toxicity against pathogens. Detailed studies on the mechanism of action of rifamycins revealed that they inhibit the initiation of RNA synthesis by inactivating the enzyme before the incorporation of the first purine nucleotide of the RNA chain. Rifamycins form a rather stable equimolecular complex with the bacterial RNA polymerase, binding with the subunit of the enzyme [201-203]. 

Elion and Hitchings shared the 1988 Nobel Prize in Physiology or Medicine for their work in the development of chemotherapeutic agents derived from purines. 

Biosynthesis and function of RNA - Mcmy inhibitors of RNA synthesis, such as aotinomycin, act by complexing with DNA and inhibiting its template function in the biosynthesis of RNA.3 Base analogs, such as 6-mercapto-purine and 8-azaguanine, interfere with interconversions of ribonucleotide subunits and inhibit novo synthesis of RNA.3 Utilization of these biochemical pathways for the design of chemotherapeutic agents is limited by considerations similar to those discussed for inhibitors of DNA synthesis. 

R. B. Martin Hydrolytic Equilibria and N7 Versus N1 Binding in Purine Nucleosides of cis-Diamminedichloroplatinum(II) Palladium(II) as a Guide to Platinum(II) Reactions at Equilibrium (Platinum, Gold, and Other Metal Chemotherapeutic Agents, ACS Symposium Series 209, Ed. S. J. Lippard), pp. 231—244 (1983). 

Methylated xanthines have pharmacologic applications (theophylline = 1,3-di-methylxanthine, caffeine = 1,3,7-trimethylxanthine). Certain analogs of the purines (8-azaguanine, 6-mercaptopurine) have antibiotic and cytostatic properties they have been used as chemotherapeutic agents against tumors. 

The answer is b. (Hardmanr p 1241.) Busulfan is an alkylating agent that, in contrast to other alkylators, is an alkylsulfonate. Thioguanine is a purine antimetabolite. Bleomycin is classified as a chemotherapeutic... 

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