Abstract
In response to anticancer therapeutics, human colon cancer cells growing in vitro either enter into a stable arrest or die, depending on the integrity of their cell-cycle checkpoints1. To test whether altered checkpoints can modulate sensitivity to treatment in vivo, xenografts were established from isogenic lines differing only in their p21 checkpoint status. Although all tumors with intact checkpoint function underwent regrowth after treatment with γ-radiation, a significant fraction of checkpoint-deficient tumors were completely cured. This difference in sensitivity was not detected by the clonogenic survival assay, because both arrest and death preclude outgrowth of colonies. These results demonstrate that checkpoint status affects sensitivity to anticancer treatments in vivo, and these findings have important implications for identifying and testing new therapeutic compounds.
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References
Waldman, T., Lengauer, C., Kinzler, K.W. & Vogelstein, B. Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature 381, 713–716 (1996).
Kastan, M.B., Onyekwere, O., Sidransky, D., Vogelstein, B. & Craig, R.W. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 51, 6304–6311 (1991).
Cross, S.M. et al. A p53-dependent mouse spindle checkpoint. Science 267, 1353–1356 (1995).
Tishler, R.B., Lamppu, D.B., Park, S. & Price, B.D. Microtubule active drugs Taxol, vinblastine, and nocodazole increase the levels of transcriptionally active p53. Cancer Res. 55, 6021–6025 (1995).
Linke, S.P., Clarkin, K.C., Di Leonardo, A., Tsou, A. & Wahl, G.M. A reversible, p53-dependent G0/G1 cell cycle arrest induced by ribonucleotide depletion in the absence of detectable DNA damage. Genes Dev. 10, 934–947 (1996).
Lowe, S.W., Ruley, H.E., Jacks, T. & Housman, D.E. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74, 957–967 (1993).
Hartwell, L.H. & Kastan, M.B. Cell cycle control and cancer. Science 266, 1821–1828 (1994).
EI-Deiry, W. et al. WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817–825 (1993).
Xiong, Y. et al. p21 is a universal inhibitor of cyclin kinases. Nature 366, 701–704 (1993).
Harper, J.W., Adami, C.R., Wei, N., Keyomarsi, K. & Elledge, S.J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75, 805–816 (1993).
Waldman, T., Kinzler, K. & Vogelstein, B. p21 is necessary for the p53-mediated C1 arrest in human cancer cells. Cancer Res. 55, 5187–5190 (1995).
Deng, C., Zhang, P., Harper, J.W., Elledge, S.J. & Leder, P. Mice lacking P21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 82, 675–684 (1995).
Brugarolas, J. et al. Radiation-inducede cell cycle arrest compromised by p21 deficiency. Nature 377, 552–557 (1995).
Di Leonardo, A., Linke, S.P., Clarkin, K. & Wahl, G.M. DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev. 8, 2540–2551 (1994).
Li, C., Nagasawa, H., Tsang, N. & Little, J.B. Radiation-induced irreversible G0/G1, block is abolished in human diploid fibroblasts transfected with human papilloma virus E6 gene: Implications of the p53-Cip1/WAF1 pathway. Int. J. Oncol. 6, 233–236 (1995).
Revesz, L. Effect of tumour cells killed by x-rays upon the growth of admixed viable cells. Nature 178, 1391–1392 (1956).
Revesz, L. Effect of lethally damaged tumor cells upon the development of admixed viable cells. J. Natl. Cancer Inst. 20, 1157–1186 (1958).
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Waldman, T., Zhang, Y., Dillehay, L. et al. Cell-cycle arrest versus cell death in cancer therapy. Nat Med 3, 1034–1036 (1997). https://doi.org/10.1038/nm0997-1034
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DOI: https://doi.org/10.1038/nm0997-1034
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