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Departments of Medical Oncology [R. G., J. A., W. P] and Hematology [H. K., M. J. K.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and Lilly Research Laboratories [P. T.], Indianapolis, Indiana 46285
The objective of this study was to determine the dose rate of 2',2'-difluorodeoxycytidine (dFdC) that maximizes the accumulation of the active 5'-triphosphate (dFdCTP) in circulating leukemia cells during therapy. The investigational approach was to evaluate the relationship between plasma dFdC and the accumulation of dFdCTP by circulating leukemia cells during infusion of different dFdC dose rates in the same individuals. Four patients with relapsed leukemia were treated weekly with two or three consecutive infusions of 800 mg/m2, the first administered over 1 h, the second over 2 h, and the third over 3 h. Two patients, one with acute myelogenous leukemia and one with acute lymphocytic leukemia, received all three infusions, but thrombocytopenia prohibited infusion of the third dose to two patients with chronic lymphocytic leukemia. The average steady-state plasma dFdC levels, achieved within 15 min after the infusion began, were 43.8 µM during infusion of 800 mg/m2/h, 9.4 µM during infusion of 400 mg/m2/h, and 5.6 µM at 267 mg/m2/h. The median area under the concentration times time curve of dFdCTP in leukemia cells during infusion was increased 2.3- and 5.1-fold for the 2- and 3-h infusions, respectively. In vitro incubations of leukemia cells from the four patients with 2.5–100 µM dFdC for 1 h showed that the maximum cellular accumulation of dFdCTP was produced by 15–20 µM dFdC. We conclude that a dose rate of >400 mg/m2/h was required to achieve plasma dFdC levels that supported the maximum rate of dFdCTP accumulation in leukemia cells.
1 This work was supported in part by grant CA32839 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, Box 52, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030.
Received 4/18/90. Accepted 7/30/90.
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