Cell-cycle arrest versus cell death in cancer therapy.
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 checkpoints. 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 gamma-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.
Waldman
T
T
Johns Hopkins Oncology Center, Program in Human Genetics, Baltimore, Maryland 21231, USA.
Zhang
Y
Y
Dillehay
L
L
Yu
J
J
Kinzler
K
K
Vogelstein
B
B
Williams
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D005720:Gamma Rays; D016158:Genes, p53; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D011836:Radiation Tolerance / Q000235:genetics; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins