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Potent Inhibition of Tumor Survival in vivo by β -Lapachone Plus Taxol: Combining Drugs Imposes Different Artificial Checkpoints
Chiang J. Li, You-Zhi Li, Antonio Ventura Pinto and Arthur B. Pardee
Proceedings of the National Academy of Sciences of the United States of America
Vol. 96, No. 23 (Nov. 9, 1999), pp. 13369-13374
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/49172
Page Count: 6
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Ablation of tumor colonies was seen in a wide spectrum of human carcinoma cells in culture after treatment with the combination of β -lapachone and taxol, two low molecular mass compounds. They synergistically induced death of cultured ovarian, breast, prostate, melanoma, lung, colon, and pancreatic cancer cells. This synergism is schedule dependent; namely, taxol must be added either simultaneously or after β -lapachone. This combination therapy has unusually potent antitumor activity against human ovarian and prostate tumor prexenografted in mice. There is little host toxicity. Cells can commit to apoptosis at cell-cycle checkpoints, a mechanism that eliminates defective cells to ensure the integrity of the genome. We hypothesize that when cells are treated simultaneously with drugs activating more than one different cell-cycle checkpoint, the production of conflicting regulatory signaling molecules induces apoptosis in cancer cells. β -Lapachone causes cell-cycle delays in late G1 and S phase, and taxol arrests cells at G2/M. Cells treated with both drugs were delayed at multiple checkpoints before committing to apoptosis. Our findings suggest an avenue for developing anticancer therapy by exploiting apoptosis-prone "collisions" at cell-cycle checkpoints.
Proceedings of the National Academy of Sciences of the United States of America © 1999 National Academy of Sciences