Efficacy of ifosfamide, dacarbazine, doxorubicin and cisplatin in human sarcoma xenografts.
The primary chemosensitivity of 16 highly malignant xenografted human soft-tissue sarcomas to ifosfamide, dacarbazine, adriamycin and cisplatin and the development of secondary drug resistance in two chemosensitive sarcoma cell lines was tested in the xenograft system. Single-dose, single-agent treatments with 350 mg kg-1 ifosfamide, 200 mg kg-1 dacarbazine, 10 mg kg-1 doxorubicin and 6.6 mg kg-1 cisplatin were administered and response measured as specific growth delay. Since ifosfamide induced unexpectedly higher toxicity, response was corrected based on the shape of the dose-response curve for ifosfamide. Taking a specific growth delay > 3 as the cut-off point for chemosensitivity, ifosfamide, dacarbazine, doxorubicin and cisplatin were effective in 10/16, 4/16, 2/16 and 1/16 sarcoma cell lines respectively. Five out of 16 sarcoma cell lines were resistant to all tested drugs. Ifosfamide-resistant sarcoma lines were also resistant to doxorubicin and cisplatin, indicating a high degree of cross-resistance. Dacarbazine was still effective in 1/6 ifosfamide-resistant sarcoma cell lines. Secondary drug resistance developed slowly after doxorubicin and ifosfamide pretreatments at moderate selection pressure and developed rapidly after dacarbazine pretreatment at high selection pressure.
Department of Radiation Oncology, West German Tumour Centre, University of Essen, Medical School.
W
W
Budach
V
V
Budach
M
M
Stuschke
B
B
Schmauder
P
P
Reipke
M E
ME
Scheulen
D000818:Animals; D002945:Cisplatin / Q000494:pharmacology*; D003606:Dacarbazine / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007069:Ifosfamide / Q000494:pharmacology*; D007928:Lethal Dose 50; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012513:Sarcoma, Experimental / Q000188:drug therapy*; D016019:Survival Analysis; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000637:transplantation
D003606:Dacarbazine; D004317:Doxorubicin; D002945:Cisplatin; D007069:Ifosfamide