CONCENTRATION AND SEQUENCE-DEPENDENT SYNERGISM OF ETHYLDESHYDROXY-SPARSOMYCIN IN COMBINATION WITH ANTITUMOR AGENTS

The modulating effect of ethyldeshydroxy-sparsonycin (EDSM), an inhibi tor of ribosomal protein synthesis, on cytostatic agents was studied o n cultured B16 melanoma cells using the microculture tetrazolium test (MTT). The data were analyzed for true synergism using the combination index and the median effect principle The extent of cytotoxic drug in teraction was influenced by the duration of drug exposure, the dose ra tio, as well as the treatment schedule. When drug ratios were used, sy nergism was observed upon pre- and post-treatment in combination with cisplatin, cytosine arabinoside (Ara-C), methotrexate (MTX) and 5-fluo rouracil (5-FU). The combination of a fixed dose of EDSM was synergist ic with cisplatin, Ara-C, vincristine (VCR) and MTX, in the order MTX > Ara-C > VCR > cisplatin, while the combinations with doxorubicin, 5- FU and etoposide (VP-16) were shown to be antagonistic. These results suggest that only certain drugs and treatment schedules might be worth while for combination studies with EDSM in vivo and indicate a role fo r EDSM as modifier of antitumor responses in cancer chemotherapy.