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Metabolic Effects of an Antibiotic, NSC-51954, on Susceptible and Resistant Tumor Cells¹

( Life Sciences Research, Stanford Research Institute, Menlo Park, California)

An antibiotic of unknown structure, NSC-51954, produced a very significant prolongation of survival time in mice bearing the ascites cell froms of Ca-755, Ehrlich, and S-180, but had only slight effects on mice bearing L1210. A subline of S-180 resistant to this drug was selected to aid the study of the mechanism by which it acts. The resistance of the derived cell line was confirmed by survival tests and by measurements of total packed cell volume after the treatment.

The incorporation of exogenously administered guanine-8-¹⁴C into ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) of the sensitive S-180 cells was strongly inhibited by a single i.p. injection of 50 µg/kg NSC-51954, which did not appreciably inhibit the incorporation of glycine-2-¹⁴C into nucleic acids and protein. This inhibition of guanine-8-¹⁴C utilization was maintained for more than 24 hr. Although the incorporation into nucleic acids of exogenously administered adenine-8-¹⁴C, orotic acid-6-¹⁴C and uracil-2-¹⁴C was also inhibited in the sensitive cells, these inhibitions were moderate and recovery was earlier than with guanine. The same dose of this drug inhibited the incorporation of guanine-8-¹⁴C into the nucleic acids of the resistant S-180 cells and of L1210 cells only moderately. The inhibitions found in less sensitive tumor lines were no longer evident after 12 hr, and the incorporation of the labeled precursors was greater than in controls by 24 hr after the treatment.

In vitro experiments revealed that the incorporation of guanine-8-¹⁴C into nucleic acids and the conversion of guanine-8-¹⁴C into acid soluble nucleotides of the sensitive cells were both inhibited, whereas these reactions in the resistant cells were accelerated. Guanosine-5'-phosphate was formed at the same rate by the guanylic pyrophosphorylase reaction in cell free extracts from the sensitive and resistant S-180 cells, and the reaction was not affected by treating with NSC-51954.

The observed inhibition in the utilization of guanine for nucleic acid synthesis was correlated with tumor response in sensitive and resistant tumor cell lines.

¹ This work was supported in part by contract SA-43-ph-3068 with the Cancer Chemotherapy National Service Center, National Cancer Institute, NIH.

² Visiting scientist from the Research Institute for Tuberculosis, Leprosy and Cancer, Tohoku University, Sendai, Japan.

Received 11/16/64.