Accelerated repopulation during fractionated irradiation of a murine ovarian carcinoma: downregulation of apoptosis as a possible mechanism.

OBJECTIVE

To test whether accelerated tumor clonogen repopulation occurs during continuous fractionated radiotherapy of a slow-growing mouse ovarian tumor, and if so whether the accelerated rate of repopulation is predicted by the pretreatment potential doubling time, and whether changes in apoptotic response are a possible mechanism for this change.

METHODS

The rate of clonogen production during fractionated radiotherapy was followed using the tumor-control assay, with an independent determination of the sensitivity to repeated dose fractions in vivo in the absence of repopulation. The pretreatment potential doubling time was measured by bromodeoxyuridine (BrdUrd) labeling and fluorescence measurements. The apoptotic and mitotic indices at various times during treatment were scored histologically.

RESULTS

The slow-growing (pretreatment volume doubling time 6 days) ovarian tumor OCA responds to daily irradiation with 6 Gy under hypoxia by negligible tumor clonogen production in the first few days, followed by a change at about 9 days to accelerated repopulation, after which the effective clonogen doubling time Tclon was about 2 days, near the pretreatment Tpot of 1.7 days. Alternative interpretations of the data, such as a change in radiosensitivity vs. a change in the repopulation rate or acceleration at 3 days as opposed to 9 days, were shown to be unlikely. This change was accompanied by a reduced apoptotic response (measured morphometrically).

CONCLUSIONS

When sensitivity to fractionated doses has been corrected for in vivo, this slow-growing mouse tumor exhibits a change to accelerated clonogen production during a continuous radiotherapy regimen that is accompanied or preceded by a reduced histologic apoptotic response. Tclon during accelerated repopulation was slightly longer than the pretreatment Tpot.