Cytotoxic effects of MGI 114 are independent of tumor p53 or p21 expression.
MGI 114, an analog of illudin S, shows potent activity against a broad range of human tumors in vitro and in vivo, including drug resistant tumors. In this study we examined cytotoxicity of MGI 114 against human tumor cell lines (MCF7, MDA.MB.468, EJ1, J82, SCaBER, KG-1, HL60, and IMR-90) with differing expression of p53 and/or p21 (WAF1) tumor suppressor genes. Only MCF7 and IMR-90 express the wild type p53, WAF1 is present in high levels in MCF7 and SCaBER. WAF1 expression can be induced in KG-1, HL60, and IMR-90. The cells were treated with MGI 114 at 0.1, 1.0 and 10 micrograms/ml in 1 h exposure and with 0.01, 0.1 and 1.0 microgram/ml MGI 114 in a continuous exposure. Cell numbers were measured at days 2, 4, and 7. MGI 114 suppressed growth in all cell lines at day 2 after 1 h exposure at the two highest concentrations and at all concentrations in a continuous exposure. Some cells partly recovered from the inhibition by day 4. Expression of WAF1 had no apparent effect on growth suppression by MGI 114, however, cells with inducible WAF1 showed slower recovery from MGI 114 inhibition in comparison with the cells under non-permissive conditions. Overall, MGI 114 effectively inhibited growth of human cancer cells regardless of their p53 and WAF1 status.
Izbicka
E
E
Institute for Drug Development, CTRC Research Foundation, San Antonio, TX 78245, USA.
Davidson
K
K
Lawrence
R
R
Cote
R
R
MacDonald
J R
JR
Von Hoff
D D
DD
D000970:Antineoplastic Agents / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis / Q000502:physiology*; D005260:Female; D006801:Humans; D012717:Sesquiterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000502:physiology*
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D012717:Sesquiterpenes; D016159:Tumor Suppressor Protein p53; C102714:irofulven