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[Cancer Research 48, 4024-4031, July 15, 1988]
© 1988 American Association for Cancer Research
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Comparison of the Cellular Pharmacokinetics and Toxicity of 2',2'-Difluorodeoxycytidine and 1-ß-D-Arabinofuranosylcytosine1

Volker Heinemann, Larry W. Hertel, Gerald B. Grindey and William Plunkett2

Department of Medical Oncology, The University of Texas, M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas 77030 [V. H., W. P.], and Lilly Research Laboratories, Indianapolis, Indiana 46285 [L. W. H., G. B. G.]

2',2'-Difluorodeoxycytidine (dFdC) is a new deoxycytidine analogue with good activity against human leukemic cell lines and murine solid tumors, while the activity of 1-ß-D -arabinofuranosylcytosine (ara-C) is established in experimental systems and for the treatment of human adult leukemia. This study compared the cellular metabolism and cytotoxic properties of dFdC and ara-C in Chinese hamster ovary cells. In wild-type cells, dFdC was significantly more cytotoxic than ara-C after both 4- and 18-h incubations. The 5'-triphosphate of dFdC (dFdCTP) was the major cellular metabolite (85–90%), reaching cellular concentrations up to 20-fold greater than those observed for ara-C 5'-triphosphate at equimolar concentrations of the parent drug. A deoxycytidine kinase-deficient mutant neither accumulated dFdCTP nor showed any cytotoxic response up to drug concentrations of 100 µM. The cytotoxicity of dFdC could be competitively reversed by deoxycytidine further suggesting that dFdC, like ara-C, required phosphorylation by deoxycytidine kinase for biological activity. Several explanations for the different cellular accumulation of the drug triphosphates were established: (a) nucleoside transport studies demonstrated that the membrane permeation of dFdC was 65% more rapid than that of ara-C; (b) deoxycytidine kinase had a higher affinity for dFdC (Km = 3.6 µM) than for ara-C (Km = 8.8 µM), while the Km for deoxycytidine was 1.4 µM; (c) the elimination of intracellular dFdCTP was biphasic with tv2{alpha} = 3.9 and tv2ß > 16 h while the degradation of ara-CTP was monophasic and significantly faster (tv2 = 0.7 h). The comparatively long half-life of dFdCTP was related to the prolonged inhibition of DNA synthesis after removal of exogenous nucleoside. Together these factors contribute to the more potent cytotoxicity of dFdC compared with ara-C.

1 Supported by Grant CA28596 from the National Cancer Institute, Department of Health and Human Services, and Grant CH-130 from the American Cancer Society.

2 To whom requests for reprints should be addressed, at Department of Medical Oncology, The University of Texas, M. D. Anderson Hospital and Tumor Institute at Houston, 1515 Holcombe Blvd., Box 52, Houston, TX 77030.

Received 10/ 7/87. Revised 1/26/88. Revised 4/11/88. Accepted 4/14/88.




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