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The effect of vinblastine on the incorporation of C14-formate into the acid-soluble fraction of thymus cell suspensions. Jones, Richard Gareth Wyn

Abstract

In earlier studies by Beer¹ the alkadloid vinblastine, VLB, has been shown to cause an almost complete inhibition in the incorporation of C¹⁴-formate into the deoxyribonucleic acid (DNA) of rat bone marrow in vivo. Also the incorporation of the same isotope into the DNA of suspensions of rat bone marrow and thymus cells in vitro was substantially depressed within one hour by the presence of the alkaloid² . In this work, the effect of VLB on the incorporation of C¹⁴-formate into the purine and pynmidine bases isolated from the hydrolysed acid-soluble fraction of thymus cell preparations was studied. A method for the separation of the constituents of this fraction was standardized and some of the major ultraviolet absorbing and radio-active compounds were identified. In general, VLB did not cause a marked depression in the incorporation of C¹⁴ -formate into the bases isolated from the hydrolysed acid-soluble fraction of either washed or unwashed cell suspensions. It was therefore considered probable that vinblastine did not inhibit the activation of 1-carbon units by tetrahydrofolic acid or their transfer. Also the results indicated that the de novo synthesis of the purine and pyrimidine compounds was not inhibited by the alkaloid. It is tentatively suggested that VLB inhibits a step in the incorporation of the mononucleotides into the nucleic acids. Comparison of the compounds isolated from the hydrolysed acid-soluble fractions of washed and unwashed cell preparations showed that considerably less hypoxanthine and xanthine were recovered from the former. VLB was found to markedly increase the total radio-activity of serine in washed cell preparations in the third hour of incubation but this effect was not pronounced in unwashed cell preparations. The total count of adenine decreased in the third hour of washed cell incubations in the presence of VLB. Neither the effect on serine nor on adenine is considered to be directly related to the inhibition of DNA synthesis as the latter is apparent within only 1 hour's incubation. Washing appears to increase the sensitivity of certain biochemical changes in the cell. It is tentatively suggested that the appearances of changes in the total radio-activity of adenine may be related to the loss of a substrate on washing. 1 Beer, C.T., Canadian Cancer Conference 4, 355 (1961) Academic Press, Inc., New York. 2 Richards, J.F., and Beer, C.T., personal communication.

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