825 Cell cycle effects of taxol in a murine tumour and its implications in radiosensitization

The new chemotherapeutic agent taxol (TX) was tested as single agent and combined with an X-ray treatment in a murine mammary carcinoma. Furthermore we performed DNA flow cytometric analysis of tumour cells after in vivo TX treatment, to assess the proliferative perturbation of cell cycle. Female hybrid (C3H/RixDBA/2J) mice were used. TX (Paclitaxel, Bristol Myers Squibb P. R. I.) was administered i. p. in single doses of 30,45,60,75 mg/kg b.w. Irradiation was delivered with an X-ray machine (operating at 15 mA, 250kV, 0.5 mm Cu filter). TGT4 (the time needed to reach 4 times the initial treatment volume) was evaluated as end-point. In the tested range there was a linear dose- response between tumour growth delay and TX dose. In the combined protocol TX was administered 30 min before a 10 Gy X-ray treatment. Our results in the combined treatments show a linear regression line almost parallel to that resulting in TX alone, with a growth delay of about 6 days. The effect seems to be additive. Flow cytometric analysis demonstrated a G2/M block of tumour cell, induced by both the tested TX concentrations (30 and 45 mg/kg). An increase of G2/M fraction was evident 8 h after treatment, and about 60% of cells were in G2/M within 24 h. After that, cells began again to divide, and after 48 h the percentage of G2/M cells decreased; furthermore, a depletion of cells in S phase was obtained suggesting that TX also avoids the starting of DNA synthesis. Considering these results, combined treatment with an interval of 24 h between TX administration (45 mg/kg) and X-ray treatment (10 Gy) was performed. Although the result obtained with the last schedule was better than the previous one, no significant difference between the two protocols was observed.