Studies on the mechanism of action of 2-β-d-ribofuranosylthiazole-4-carboxamide-V. Factors governing the response of murine tumors to tiazofurin

Gurpreet S. Ahluwalia, Hiremagalur N. Jayaram, Jacqueline P. Plowman, David A. Cooney, David G. Johns

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Abstract

The pharmacological effects and metabolism of tiazofurin have been compared in the six transplantable tumors comprising the NCI rodent tumor panel, viz. the P388 leukemia (S); the L1210 leukemia (S); the Lewis lung carcinoma (S); the B16 melanoma (R); the colon 38 carcinoma (R); and the M5076 sarcoma (R), where (S) denotes sensitivity and (R) resistance to tiazofurin. In addition, a variant of the P388 leukemia rendered resistant to the drug in vitro, and maintaining stable resistance in vivo, P388/TR, was also studied. Intraperitoneal administration of tiazofurin (100 mg/kg) resulted in a 3- to 30-fold greater accumulation of thiazole-4-carboxamide adenine dinucleotide (TAD), the proposed active metabolite of the drug in S versus R lines. In general, levels of TAD, percent inhibition of IMP dehydrogenase (mean 40% in S versus 10% in R), depression in the concentration of guanosine nucleotides, (50% in S versus 20% in R) and percent elevation of levels of IMP (500% in S versus 60% in R) correlated well with sensitivity or resistance. However, the B16 melanoma, although resistant to tiazofurin treatment, showed certain biochemical features characteristic of an S line. The sensitive and resistant tumors displayed comparable abilities to phosphorylate tiazofurin, but there was significant depression only in the R lines of the pyrophosphorylase which converts tiazofurin-5'-monophosphate to TAD (mean 78 nmoles/mg protein/hr in S versus 22 nmoles/mg protein/hr in R). The naturally resistant tumors were also found to exhibit a greater ability to degrade synthetic TAD than the sensitive lines (mean 102 nmoles/mg protein/hr in R versus 29 nmoles/mg protein/hr in S lines). The state of sensitivity or resistance could not be attributed to the basal levels of IMP dehydrogenase, to the specific activities of the enzymes of purine salvage, or to the basal concentration of purine and pyrimidine nucleotides. Moreover, treatment with tiazofurin did not influence the enzymes of TAD synthesis or of purine salvage.

Original languageEnglish (US)
Pages (from-to)1195-1203
Number of pages9
JournalBiochemical Pharmacology
Volume33
Issue number8
DOIs
StatePublished - Apr 15 1984
Externally publishedYes

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tiazofurin
Tumors
IMP Dehydrogenase
Leukemia P388
Neoplasms
Experimental Melanomas
Salvaging
Proteins
Pyrimidine Nucleotides
Lewis Lung Carcinoma
Purine Nucleotides
Leukemia L1210
Inosine Monophosphate
Guanosine
Enzymes
Sarcoma
Pharmaceutical Preparations
Metabolites
Rodentia
Metabolism

ASJC Scopus subject areas

  • Pharmacology

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Studies on the mechanism of action of 2-β-d-ribofuranosylthiazole-4-carboxamide-V. Factors governing the response of murine tumors to tiazofurin. / Ahluwalia, Gurpreet S.; Jayaram, Hiremagalur N.; Plowman, Jacqueline P.; Cooney, David A.; Johns, David G.

In: Biochemical Pharmacology, Vol. 33, No. 8, 15.04.1984, p. 1195-1203.

Research output: Contribution to journalArticle

Ahluwalia, Gurpreet S. ; Jayaram, Hiremagalur N. ; Plowman, Jacqueline P. ; Cooney, David A. ; Johns, David G. / Studies on the mechanism of action of 2-β-d-ribofuranosylthiazole-4-carboxamide-V. Factors governing the response of murine tumors to tiazofurin. In: Biochemical Pharmacology. 1984 ; Vol. 33, No. 8. pp. 1195-1203.
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