KINETICS OF BROMODEOXYURIDINE ELIMINATION FROM HUMAN COLON-CANCER CELLS IN-VITRO AND IN-VIVO

We have previously shown that the thymidine analogue radiation sensitizer bromodeoxyuridine (BrdUrd) is incorporated into human tumors to a greater extent than into the livers of athymic mice bearing these tumors as xenografts. However, incorporation into the intestine and bone marrow exceeds that of the tumor (T. S. Lawrence, M. A. Davis, J. Maybaum, S. K. Mukhopadhyay, P. L. Stetson, D. P. Normolle, P. E. McKeever, and W. D. Ensminger, Cancer Res., 52:3698-3704, 1992). We hypothesized that the ratio of tumor incorporation to intestinal or bone marrow incorporation might increase during a period of drug elimination following the termination of an infusion. To test this hypothesis, we infused athymic mice bearing HT29 human colon cancer xenografts with BrdUrd and measured incorporation in the tumor and normal tissues up to 7 days after the infusion was discontinued. In addition, me assessed the effect of exposure to BrdUrd on subsequent incorporation in vitro and in vivo through the use of a stable isotope of BrdUrd (''isotopic BrdUrd''), which could be differentiated from normotopic BrdUrd using the gas chromatographic-mass spectrometric assay. We found a significant increase in the ratio of BrdUrd in the tumor compared to bone marrow and intestine during the drug elimination period. We also found that BrdUrd incorporation slowed the kinetics of subsequent BrdUrd incorporation and elimination. These findings suggest that when the radiation dose-limiting organ is rapidly proliferative, such as the intestine or bone marrow, delivering radiation during a drug elimination period may improve the therapeutic index.