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PubMedDate not supplied

Interaction between vinblastine and ionizing radiation in the mouse MO4 fibrosarcoma in vivo.

The effect of combining vinblastine (VLB) and ionizing radiation (IR) on tumor response was investigated in CDF1 mice bearing the MO4 mouse fibrosarcoma. Favorable interactions were assumed to occur if VLB treatment caused accumulation of cells in metaphase (M-)phase at the time of IR. High pressure liquid chromatography (HPLC) measurements showed that VLB administered at 2.0 mg/kg (0.4 maximal tolerated dose, MTD) was taken up rapidly by the tumor in vivo, and that sufficient concentrations of VLB were achieved to cause blocking of tumor cells in M-phase. However, different treatment schedules of the combination of 2.5 mg/kg VLB (0.5 MTD) and 10 Gy IR resulted in additive tumor responses. The best therapeutic response was observed when IR was given 6 hours after intravenous injection of VLB. In order to increase the therapeutic response, we attempted to enhance the accumulation of cells in M-phase by treating mice with VLB at the MTD. The maximum percentage of tumor cells that could be accumulated in mitosis by a single intravenous bolus of VLB at the MTD was around 13%. The results show that this will probably be insufficient for significant IR enhancement.

Animals↗

PubMedDate not supplied

DNA breakage, cytotoxicity, drug accumulation and retention in two human ovarian tumor cell lines AZ224 and AZ364 treated with adriamycin, modulated by verapamil.

We investigated the cytotoxicity of adriamycin in two human ovarian tumor cell lines, AZ224 and AZ364, by the MTT-test and we analysed the formation of DNA single-strand (SSB) and double-strand breaks (DSB) by means of the alkaline and neutral elution technique. The AZ364 cell line was 15 times more resistant to ADR (ID50 = 10.0 micrograms/ml) than the AZ224 cell line (ID50 = 0.66 microgram/ml) after 1hr of drug exposure. Immediately after exposure, we observed a biphasic dose response for SSB in the AZ224 cells over a concentration range of 0.1 to 32.0 micrograms/ml, while practically no DSB were found. Upon drug removal and incubation in drug-free medium, full repair of SSB was observed for an ADR concentration of 1 microgram/ml. On the contrary, the DSB became significantly increased for all tested concentrations and persisted as observed after 3hr and 7hr in drug-free medium. The resistant cell line AZ 364 showed consistently less DNA breakage than the AZ 224 cell line. This inherent difference in sensitivity to ADR could, however, not be explained on the basis of the cellular pharmacokinetics of the drug. Verapamil induced a 3 to 4 fold potentiation of the ADR cytotoxicity in both cell lines after continuous exposure and was associated with an increase in DNA-breakage. The results of our study confirm that there is a lack of correlation between cytotoxicity of ADR and DNA strand breakage immediately after 1 hr of drug exposure. Instead, we emphasize the importance of the formation, extent and persistence of protein-associated DSB upon drug removal to the cytotoxic action of ADR in vitro.

DNA Damage↗