ANTITUMOR-ACTIVITY AND RETINOTOXICITY OF ETHYLDESHYDROXY-SPARSOMYCIN IN MICE

The colony formation in agar of human tumour xenografts was used as a test system to study the cytostatic activity of ethyldeshydroxy-spatso mycin (EdSm) at the cellular level. EdSm was additionally studied in v ivo in human tumour xenografts and murine tumour models. EdSm showed a clear dose-response effect in vitro. At continuous exposure with 0.01 mu g/ml, 2 out of 11 of the tumours responded (a gastric and a small cell lung carcinoma). At 0.1 mu/ml EdSm, the tumour response was 5/11 tumours and at 1 mu g/ml the compound was active in all tumours. The m aximal tolerable doses of EdSm in vivo have been determined in non-tum our bearing CDF1 mice. In the intraperitoneally (i.p.) given multiple dose schedules the respective LD(10) doses indicated that the tolerabl e cumulative dose increases when lower doses are given more frequently . This also enhances the antitumonr activity in L1210 leukaemia to 172 % T/C. On the other hand, continuous infusion strongly diminished the tolerable dose as well as the antitumour activity. EdSm was also activ e against i.p. inoculated P388 leukaemia (150% T/C), B16 melanoma (156 % T/C), and RC carcinoma (197% T/C), and the subcutaneously (s.c.) ino culated L1210 (139% T/C) and RC (138% T/C). Absence of tumour response s was found in the following s.c. implanted murine tumours: M5076 sarc oma, osteosarcomas C22LR and CP369, and the LL carcinoma, as well as i n the human tumour xenografts: LXFG 529, a non-small cell lung carcino ma; GXF 251, a gastric carcinoma; and FMa, an ovary carcinoma. Possibl e long-range retinotoxic effects of EdSm were investigated in tumour-b earing mice, cured after surviving treatment with LD(50) doses of EdSm , by assaying the protein biosynthetic capacity of the retina by assay ing the ocular rhodopsin and opsin levels as parameters. In none of th ese cases could a significant reduction in either opsin or rhodopsin l evels be measured and no changes were seen histologically.