In Vivo Experiments.
In vivo, BVDU enhanced anticarcinogenic effects on AH13r sarcomas in rats. Three cytostatic drugs of different mode of action (DOX, glufosfamide, and cisplatin) were tested in two independent experiments (Fig. 4A, panels 1 and 3). On the basis of previous results with rats (17), we used a daily dose of 15 mg/kg to gain peak plasma levels of 25 µg/ml 20 min after application. After cotreatment, BVDU was additionally administered in the recovery phase for 4 days (Fig. 4)

  Fig. 4. SD-rats treated with DOX, glufosfamide, and cisplatin. A, rats with AH13r sarcomas. A1 and A3, comparison of control animals, BVDU-control animals, cytostatic drug-treated animals, and cytostatic drug+BVDU-treated animals (calculation of the mean of all individual tumor areas). A2, tumor areas of single tumors 10–17 days after treatment start (—mean). B, rats with DMBA-induced fibrosarcomas and mammary adenocarcinomas. B1, top, SD-rats with DMBA-induced fibrosarcomas, calculation of the mean tumor area. Three control animals, three DOX-treated animals, and five DOX+BVDU-treated animals with fibrosarcomas. Bottom, DMBA-induced mammary adenocarcinomas, calculation of the mean of all individual tumor areas. Within the control animals, 8 tumors, within the DOX-treated animals, 6 tumors, and within the DOX+BVDU-treated animals, 9 tumors could be observed. B2, area of the individual tumors 39 days after treatment start (—mean). B3, Mdr1 gene amplification and expression patterns of DMBA-induced fibrosarcomas and mammary adenocarcinomas in SD-rats. Representative tumor of 1) rat treated with solvent, 2) rat treated with DOX, and 3) rat treated with DOX+BVDU. Amplification of the Mdr1 gene was detected by Southern blot analysis and expression of the MDR1 protein by Western blot analysis using the murine anti-P-glycoprotein monoclonal antibody JSB-1. The densitometrically determined Mdr1 gene dosages (amplification levels) were subdivided into two categories. , indicate normal copy number, , amplification. , indicate that no analysis was performed because the whole tumor probe was used for histological analysis. Western blot analysis gave a yes () or no () result in respect to Mdr11 = male, 2 = female/animal number, position of mammary adenocarcinomas). gene express patterns. The numbers indicate different tumors examined (1  male, 2  female/animal number, position of mammary adenocarcinomas).