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 ill vivo, Two tumor type s were chosen based on their sensitivity to docetaxel as a single agent: (a ) docetaxel-sensitive MCa-4 mammary adenocarcinoma, which responds to docet axel by G(2)-M-phase cell cycle arrest, apoptosis, and subsequent reoxygena tion of surviving tumor cells; and (b) docetaxel-resistant SCC-VII squamous cell carcinoma, which responds to docetaxel treatment only by G(2)-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 micr omorphometric analysis of tumor cell mitosis, assayed apoptosis by its hist ological appearance in tissue sections, and determined tumor response by tu mor growth delay. Normal tissue response of the jejunum was assayed by micr omorphometric analysis of mitotic and apoptotic indices, and clonal crypt s tem cell survival was measured using the microcolony assay, Two clinically relevant treatment schedules were tested for both antitumor efficacy and no rmal 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 d ocetaxel (8 mg/kg i,v,) with radiation delivered at the peak of mitotic arr est (9 h for MCa-4 and 6 h for SCC-VII tumors), The best therapeutic gain f or docetaxel-sensitive MCa-4 was achieved with a single bolus of drug 24 h before the start of fractionated radiotherapy (therapeutic gain = 2.04). Th is schedule takes advantage of reoxygenation of hypoxic tumor cells during the interval between drug treatment and radiation delivery. The best therap eutic gain for docetaxel-resistant SCC-VII was achieved with intermittent m ultiple doses of docetaxel given during the course of fractionated radiothe rapy, This schedule maximized the exposure of cells to radiation while they were arrested by docetaxel in the radiosensitive G(2)-M phases of the cell cycle (enhancement factor = 2.0). Find therapeutic gain was reduced to 1.5 9 because of increased normal tissue toxicity in mice treated with multiple intermittent doses of docetaxel in combination with fractionated radiother apy. Thus, docetaxel greatly enhanced tumor response to fractionated radiot herapy, but the magnitude of therapeutic efficacy depended on drug-radiatio n scheduling. The greatest therapeutic gain in the treatment of docetaxel-s ensitive tumors was achieved by a single large dose of docetaxel administer ed I day before the initiation of fractionated radiotherapy and in the trea tment of docetaxel-resistant tumors by daily concomitant docetaxel-radiatio n treatments.