Regulation of de novo and salvage pathways in chemotherapy

George Weber, Masami Nagai, Yutaka Natsumeda, Seiichi Ichikawa, Hiroyuki Nakamura, John Eble, Hiremagalur N. Jayaram, Weining Zhen, Edith Paulik, Ronald Hoffman, Guido Tricot

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Abstract

An overview was presented of our approach of inhibition of de novo and salvage pathways in pyrimidine and purine metabolism. 1. 1. Combination of acivicin, an inhibitor of de novo biosynthesis, and dipyridamole, a transport inhibitor, provided synergistic cytotoxicity in hepatoma and colon carcinoma cells. 2. 2. AZT, a competitive inhibitor of the salvage enzyme, thymidine kinase, and 5-FU or MTX provided synergistic cytotoxicity in hepatoma 3924A. In human colon carcinoma HT-29 cells AZT and methotrexate yielded synergistic cytotoxicity and thymidine and hypoxanthine together provided protection from the action of these drugs. 3. 3. These observations are significant because in rat hepatoma 3924A and in human cell lines HT-29, HL-60 and K562 thymidine kinase activity was 16- to 67-fold higher than that of dTMP synthase. Therefore, inhibition of dTMP synthase activity alone may provide poor responses because the salvage pathways can circumvent this block. 4. 4. In leukemic patients treated with tiazofurin, an inhibitor of IMP dehydrogenase, the rate-limiting enzyme of GTP biosynthesis, and with allopurinol, which inhibits GPRT activity through raising plasma hypoxanthine levels, synergistic therapeutic results were obtained. The responses in sensitive patients entailed a decrease in IMP dehydrogenase activity and GTP concentration in leukemic cells and down-regulation of the ras and myc oncogenes. The down-regulation of the ras oncogene by tiazofurin through the decrease of GTP concentration has now been shown in K562, HL-60 and hepatoma cells and in patients with chronic granulocytic leukemia in blast crisis. Tiazofurin may be useful in studies on selective depression of the expression of the ras oncogene. 5. 5. In 27 consecutive patients 50% responded positively to tiazofurin treatment. From this group, 10 out of 12 patients (83%) with chronic granulocytic leukemia in blast crisis responded to tiazofurin treatment.

Original languageEnglish
Pages (from-to)45-67
Number of pages23
JournalAdvances in Enzyme Regulation
Volume31
Issue numberC
DOIs
StatePublished - 1991

Fingerprint

tiazofurin
Salvaging
Chemotherapy
ras Genes
Hepatocellular Carcinoma
Drug Therapy
Cytotoxicity
IMP Dehydrogenase
Guanosine Triphosphate
Blast Crisis
Hypoxanthine
Thymidine Kinase
Biosynthesis
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
acivicin
Colon
Down-Regulation
Cells
Carcinoma
Galectin 3

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Weber, G., Nagai, M., Natsumeda, Y., Ichikawa, S., Nakamura, H., Eble, J., ... Tricot, G. (1991). Regulation of de novo and salvage pathways in chemotherapy. Advances in Enzyme Regulation, 31(C), 45-67. https://doi.org/10.1016/0065-2571(91)90008-A

Regulation of de novo and salvage pathways in chemotherapy. / Weber, George; Nagai, Masami; Natsumeda, Yutaka; Ichikawa, Seiichi; Nakamura, Hiroyuki; Eble, John; Jayaram, Hiremagalur N.; Zhen, Weining; Paulik, Edith; Hoffman, Ronald; Tricot, Guido.

In: Advances in Enzyme Regulation, Vol. 31, No. C, 1991, p. 45-67.

Research output: Contribution to journalArticle

Weber, G, Nagai, M, Natsumeda, Y, Ichikawa, S, Nakamura, H, Eble, J, Jayaram, HN, Zhen, W, Paulik, E, Hoffman, R & Tricot, G 1991, 'Regulation of de novo and salvage pathways in chemotherapy', Advances in Enzyme Regulation, vol. 31, no. C, pp. 45-67. https://doi.org/10.1016/0065-2571(91)90008-A
Weber, George ; Nagai, Masami ; Natsumeda, Yutaka ; Ichikawa, Seiichi ; Nakamura, Hiroyuki ; Eble, John ; Jayaram, Hiremagalur N. ; Zhen, Weining ; Paulik, Edith ; Hoffman, Ronald ; Tricot, Guido. / Regulation of de novo and salvage pathways in chemotherapy. In: Advances in Enzyme Regulation. 1991 ; Vol. 31, No. C. pp. 45-67.
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