Metabolic Basis for the Actions of Analogs of Purines and Pyrimidines

Elion, Gertrude B.; Hitchings, George H.

doi:10.1016/b978-1-4831-9930-6.50008-3

Cited by 92 publications

(26 citation statements)

References 387 publications

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“…This immune tolerance induction of cyclophosphamide correlates well in the present experiments with profound suppression of DNA synthesis in the remaining lymphoid cells of the spleen (those not destroyed by cyclophosphamide). Thus, the nucleic acid evidence favors a mechanism for cyclophosphamide tolerance in which tolerance results from immunological stimulation in the presence of profound inhibition of DNA synthesis and mitosis (21)(22)(23)(24). Further, it appears plausible that the immunological stimulation of such DNA-damaged cells leads to their death, with consequent elimination of the specific clone (25,26).…”

Section: Discussionmentioning

confidence: 99%

Studies on Cyclophosphamide-Induced Tolerance to Sheep Erythrocytes

Aisenberg

1967

The Journal of Experimental Medicine

112

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Immunological tolerance remains a fundamental but incompletely understood problem in immunology (1, 2). Of the several varieties of such tolerance, that induced by immunosuppressive drugs (3) affords several advantages in the study of the general problem. Immunosuppressive drugs produce tolerance to a variety of antigens in adult animals under conditions that can be controlled and varied (4). Further, these drugs produce metabolic alterations which, though multiple, are well-known, and can therefore be correlated with the resulting immune suppression.The present study concerns immunological tolerance to sheep erythrocytes produced in CBA mice with the immunosuppressive drug cyclophosphamide (Cytoxan). This cytotoxic alkylating agent is effective in the mouse, producing complete tolerance at dosage well below that which causes any fatal toxicity (5, 6). Employing sheep erythrocytes and the Jerne plaque technique (7,8), it is possible to obtain information about the cellular kinetics of developing tolerance and recovery there-from which is unavailable from antibody methods. With isotopic methods, deoxyribonucleic acid and ribonucleic acid synthesis can be measured and correlated with the induction of tolerance. Finally, because both the clearing of foreign erythrocytes from the blood (9, 10) and the cytoxic effect of cyclophosphamide (11) are prompt, the chronology of events can be established with precision. This paper deals with tolerance induction in this system, and a subsequent one will consider recovery from tolerance and the effect of the thymus. MethodsAnimals and Mater*:a2s.--Female CBA mice 10-14 wk of age obtained from the Jackson Laboratory, Bar Harbor, Mdme, were used. Cyclophosphamide (Cytoxan, Mead Johnson Laboratories, Evansville, Ind.) was injected intraperitoneally as a freshly made saline solution containing 5 mg per ml. The usual tolerance-inducing drug dose was 330 mg per kg given either as a single dose or as four daily divided doses. Unless otherwise stated, the tolerance-inducing

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Section: Discussionmentioning

confidence: 99%

Studies on Cyclophosphamide-Induced Tolerance to Sheep Erythrocytes

Aisenberg

1967

The Journal of Experimental Medicine

112

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“…The purine analogue 6-mercaptopurine and some of its substituted thioether derivatives, such as azathioprine, are potent inhibitors of purine synthesis in bacterial cells, in mammalian tumor cells, and in human fibroblasts (23)(24)(25)(26).3 The ribonucleotide of 6-mercaptopurine is a very effective inhibitor of phosphoribosylpyrophosphate amidotransferase (27). However, the precise mechanism of inhibition of uric acid synthesis produced by these agents is not fully established.…”

Section: Discussionmentioning

confidence: 99%

The Effects of Azathioprine (Imuran) on Purine Synthesis in Clinical Disorders of Purine Metabolism*

Kelley

Rosenbloom²,

Seegmiller³

1967

J. Clin. Invest.

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Abstract. Azathioprine, a purine analogue, significantly suppressed the purine synthesis de novo of two gouty patients manifesting overproduction of uric acid, as well as three of four gouty patients who showed normal uric acid production. This suppression is taken as evidence that phosphoribosylpyrophosphate amidotransferase, the rate-controlling step in purine synthesis de novo, has a normal sensitivity to feedback inhibitors in the patients who responded to the drug.Two children afflicted with the familial disorder of hyperuricemia, choreoathetosis, and self-mutilation described by Lesch and Nyhan showed no reduction in the activity of the biosynthetic pathway in response to azathioprine. This inability to respond to azathioprine can be directly related to the absence in these patients of the enzyme hypoxanthine-guanine phosphoribosyltransferase which is required for conversion of the drug or its metabolites to the biochemically active ribonucleotide form.

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“…coli tRNAs, while 6-thioinosine and 6-thioguanosine are effective as enzyme inhibitors and antitumor agents (Elion & Hitchings, 1965). The function of the thio analogues of the pyrimidine and purine systems in tRNAs is not clear.…”

Section: Introductionmentioning

confidence: 99%