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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

In vitro and in vivo anticancer activity of mitozolomide and sparsomycin in human tumor xenografts, murine tumors and human bone marrow.

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)[1]

References

  1. In vitro and in vivo anticancer activity of mitozolomide and sparsomycin in human tumor xenografts, murine tumors and human bone marrow. Fiebig, H.H., Berger, D.P., Köpping, K., Ottenheijm, H.C., Zylicz, Z. J. Cancer Res. Clin. Oncol. (1990) [Pubmed]
 
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