The effect of fluorodeoxyuridine on sublethal damage repair in human colon cancer cells.

Although 5-fluoro-2'-deoxyuridine (FdUrd) has been combined with hyperfractionated radiation therapy in clinical trials, the optimal method of delivering radiation therapy is not yet known. To determine the importance of the time interval between fractions on the survival of tumor cells exposed to FdUrd, we studied the effect of FdUrd on sublethal damage repair in HT29 human colon cancer cells in culture. Cells were exposed to clinically achievable concentrations of FdUrd (10-100 nM) for 14 hr followed by either single dose (8-12 Gy) or split dose (4-6 Gy x 2) external cobalt irradiation. The interval between radiation fractions was varied from 0.5 to 6 hr. FdUrd impaired sublethal damage repair in a dose dependent fashion. FdUrd had no effect on the induction of DNA double strand breaks (DSB's), but significantly reduced the rate of the repair of DNA DSB's. Exposure to 100 nM FdUrd decreased intracellular TTP pools but elevated dATP pools. These findings suggest that FdUrd may decrease sublethal damage repair by perturbing nucleotide triphosphate pools, which leads to a decrease in the ability of the cell to repair DNA DSB's. Furthermore, they suggest that hyperfractionated irradiation will be superior to once daily treatment when combined with regional delivery of FdUrd.

Treatment planning issues related to prostate movement in response to differential filling of the rectum and bladder.

Conventional stimulation for patients with localized prostatic carcinoma often includes opacification of the dose limiting adjacent normal tissues. However, CT-based treatment planning is performed with the bladder and the rectum naturally filled or emptied. These latter conditions more closely approximate those in place at treatment Comparison of these CT-based treatment plans to simulator films taken with the rectum and bladder opacified yielded indirect evidence of movement of the prostate gland by 0.5 cm or more in 31 of 50 consecutive patients. The range of motion was 0 to 2 cm with an average of 0.5 cm (1.0 cm in the 31 patients). Six additional patients (five with local recurrence following I-125 seed implantation) were analyzed separately using CT scans. Registered CT images (3 mm slices) taken with the rectum and bladder full and/or empty provided direct evidence of prostate movement in 3 of the 6 patients. The dosimetric consequences of this movement are demonstrated using 3-dimensional dose distributions.

The effects of leucovorin and dipyridamole on fluoropyrimidine-induced radiosensitization.

The biomodulators leucovorin and dipyridamole potentiate the cytotoxicity of 5-fluorodeoxyuridine (FdUrd) and 5-fluorouracil (5-FU), respectively. It was hypothesized that these biomodulators would increase fluoropyrimidine-mediated radiosensitization. This hypothesis was tested using cultured HT29 human colon cancer cells. As was predicted, leucovorin increased both FdUrd-mediated cytotoxicity and radiosensitization. The increase in radiation sensitivity was associated with a decrease in the repair of radiation-induced DNA double strand breaks (DSB's). Dipyridamole potentiated the cytotoxicity produced by 5-FU. However, dipyridamole appeared to confer slight protection from irradiation, thus decreasing 5-FU-mediated radiosensitization. This demonstrates that the simple fact that a biomodulator can increase fluoropyrimidine-induced cytotoxicity does not guarantee a corresponding increase in radiation sensitivity. Clinical trials combining fluoropyrimidines and their biomodulators will need to take these potentially complex interactions into account.