The colony formation in
agar of human
tumor xenografts, of murine
tumors and of human bone marrow was used as a test system to determine the in vitro activity of the two novel
cytostatic agents, mitozolamide and
sparsomycin.
Mitozolomide was additionally studied in vivo in nine human
tumor xenografts. The comparison of in vitro/in vivo activity allows an assessment of the relevant in vitro dose based on in vivo pharmacological behavior of a compound. Both compounds showed clear dose/response effects in vitro. A dose of 3 micrograms/ml
mitozolomide, given by continuous exposure, was active (colony number of test less than 30% of the control group) in 12/42 (29%) human
tumor xenografts as well as in the four murine
tumors, P388, L1210,
B16 melanoma and colon
carcinoma 38, whereas the two human bone marrows showed no significant suppression of the ability to form colonies in culture. The comparison of in vitro with in vivo activity suggests that the in vitro dose of 3 micrograms/ml corresponds best to the activity observed in animal experiments. The highest activity was observed in
small-cell cancer of the lung (4/5), followed by
melanomas (2/7) and non-
small-cell cancer of the lung (2/9). Furthermore, activity was found in a
cancer of the large bowel, stomach, breast and in one
sarcoma. In the treatment of nine human
tumor xenografts growing subcutaneously in nude mice,
mitozolomide effected a complete or partial remission in 6 out of 9
tumors. In comparison to standard drugs
mitozolomide is one of the most effective compounds in these
tumors. These data indicate that
mitozolomide possesses potent broad-spectrum activity in human
tumor xenografts.
Sparsomycin (0.1 micrograms/ml, continuous exposure) was active in 11/46 (24%) human
tumor xenografts and in 4/5 of the murine
tumors, whereas the colony-forming capacity of four human bone-marrows showed no inhibition, suggesting that this dose level may be the relevant in vitro dose. However, the high in vitro activity in murine
tumors is incompatible with the in vivo activity. In mice the only responsive
tumor was
leukemia P388, whereas the L1210,
B16 melanoma and colon
carcinoma 38 were resistant. At the dose level of 0.03 microgram/ml only 3/30 (10%) of the human
tumor xenografts were sensitive. In an earlier clinical phase I study the dose-limiting adverse effect was eye toxicity and not bone-marrow suppression.(ABSTRACT TRUNCATED AT 400 WORDS)