In vitro and in vivo anticancer activity of mitozolomide and sparsomycin in human tumor xenografts,murine tumors and human bone marrow |
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Authors: | Heinz H. Fiebig Dietmar P. Berger Karin Köpping Harry C. J. Ottenheijm Zbigniew Zylicz |
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Affiliation: | (1) Department of Internal Medicine, Division of Hematology-Oncology, University of Freiburg, D-7800 Freiburg, Federal Republic of Germany;(2) Department of Organic Chemistry, University of Nijmegen, NL-6525 ED Nijmegen, The Netherlands;(3) Department of Internal Medicine, Division of Medical Oncology, St. Radboud University Hospital, Federal Republic of Germany |
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Abstract: | Summary 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, mitozolomide 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 g/ml mitozolomide, given by continuous exposure, was active (colony number of test <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 g/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 g/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 g/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. This example illustrates that comparing in vitro with in vivo activity in the same tumor results in a more reliable estimation of the relevant in vitro dose than does comparing in vitro activity with in vitro effects on human bone marrow.Abbreviations Mitozolomide 8-carbamoyl-3-(2-chloroethyl)imidazo(5,1-d)-1,2,3,5-tetrazin-4(3H)-one - NSC 353451 formerly known as azolastone - sparsomycin NSC 59 729 - DTIC 5-(3,3-dimethyltriazen-1-yl)-imidazole-4-carboxamide - MTIC 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide - DMSO dimethylsulfoxideDedicated to Professor Dr. D. Schmähl, Heidelberg, on the occasion of his 65th birthday |
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Keywords: | Clonogenic assay Xenografts Murine tumors Bone marrow Mitozolomide Sparsomycin |
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