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Basic Biochemical Effects and Mechanism of Action of 6-Thioguanine

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

The correlation between the carcinostasis produced by thioguanine (TG) and incorporation of the drug into cellular DNA reported earlier for ascites tumors in mice was extended to studies in early transplant generations of C3H mammary tumors and to spontaneous mammary tumors in C3H females. The incorporation appeared to be "geared" to DNA synthesis. Use was made of this finding to reduce toxicity to the host bone marrow and enhance tumor response by suitable spacing of treatments. The transplanted and spontaneous tumors were equally responsive. Complete regressions were noted in some of the latter.

Of four TG-resistant lines of mouse tumor cells, one achieved resistance because of loss of the activating (nucleotide-forming) enzyme. The other three lines do not lack this enzyme, and must achieve resistance through some other (as yet unexplained) mechanism, but respond to therapy with azaserine and TG.

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