Effect of docetaxel on the therapeutic ratio of fractionated radiotherapy in vivo.

The aim of this investigation was to determine whether docetaxel increases the therapeutic ratio of fractionated radiotherapy in vivo. Two tumor types were chosen based on their sensitivity to docetaxel as a single agent: (a) docetaxel-sensitive MCa-4 mammary adenocarcinoma, which responds to docetaxel by G2-M-phase cell cycle arrest, apoptosis, and subsequent reoxygenation of surviving tumor cells; and (b) docetaxel-resistant SCC-VII squamous cell carcinoma, which responds to docetaxel treatment only by G2-M-phase arrest. Response of the normal jejunal mucosa in mice was compared to the response of both tumor types to confirm therapeutic gain. We conducted micromorphometric analysis of tumor cell mitosis, assayed apoptosis by its histological appearance in tissue sections, and determined tumor response by tumor growth delay. Normal tissue response of the jejunum was assayed by micromorphometric analysis of mitotic and apoptotic indices, and clonal crypt stem cell survival was measured using the microcolony assay. Two clinically relevant treatment schedules were tested for both antitumor efficacy and normal tissue toxicity: (a) a single bolus of docetaxel (33 mg/kg i.v.) 24 h before five daily fractions of radiation; and (b) daily administration of docetaxel (8 mg/kg i.v.) with radiation delivered at the peak of mitotic arrest (9 h for MCa-4 and 6 h for SCC-VII tumors). The best therapeutic gain for docetaxel-sensitive MCa-4 was achieved with a single bolus of drug 24 h before the start of fractionated radiotherapy (therapeutic gain = 2.04). This schedule takes advantage of reoxygenation of hypoxic tumor cells during the interval between drug treatment and radiation delivery. The best therapeutic gain for docetaxel-resistant SCC-VII was achieved with intermittent multiple doses of docetaxel given during the course of fractionated radiotherapy. This schedule maximized the exposure of cells to radiation while they were arrested by docetaxel in the radiosensitive G2-M phases of the cell cycle (enhancement factor = 2.0). Final therapeutic gain was reduced to 1.59 because of increased normal tissue toxicity in mice treated with multiple intermittent doses of docetaxel in combination with fractionated radiotherapy. Thus, docetaxel greatly enhanced tumor response to fractionated radiotherapy, but the magnitude of therapeutic efficacy depended on drug-radiation scheduling. The greatest therapeutic gain in the treatment of docetaxel-sensitive tumors was achieved by a single large dose of docetaxel administered 1 day before the initiation of fractionated radiotherapy and in the treatment of docetaxel-resistant tumors by daily concomitant docetaxel-radiation treatments.