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Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255
Previous cell line comparisons indicated that neither S-phase fraction nor topoisomerase I (top1) levels are sufficient to predict camptothecin (CPT) cytotoxicity (F. Goldwasser et al., Cancer Res., 55: 2116–2121, 1995.). To identify new determinants for CPT activity, two mutant p53 human colon cancer cell lines, SW620 and KM12, that were previously reported to have similar top1 levels and differential sensitivity to CPT were studied. No difference in the kinetics of top1-mediated DNA single-strand breaks or DNA synthesis inhibition were observed after 1 h exposure to 1 µM CPT. Pulse-labeling alkaline elution showed deficiency of damaged replicon elongation in the more sensitive SW620 cells. Consistently, flow cytometry analyses showed that KM12 was arrested in G2, whereas SW620 cells were irreversibly blocked in S phase. Aphidicolin protection was minimal in KM12 and more pronounced in the more sensitive SW620 cells. Thus, CPT appears to have two cytotoxic mechanisms, one protectable by aphidicolin and present in SW620 and the other not protectable by aphidicolin and common to both cell lines. SW620 exhibited also a greater capacity to break through the G2 checkpoint after DNA damage. Consistently, SW620 cells failed to down-regulate cyclin B-cdc2 kinase activity, whereas KM12 cells down-regulated cyclin B/cdc2 kinase activity within 30 min to 20% of control level after CPT treatment. Analysis of the 7 human colon carcinoma cell lines of the NCI Anticancer Drug Screen showed that defects in replicon elongation and G2 break-through capability correlate with sensitivity to CPT. Our results suggest that misrepair of damaged replicons and/or alterations in DNA damage checkpoints is critical to defining chemosensitivity to CPT-induced top1-cleavable complexes and that CPT appears to have two cytotoxic mechanisms, one protectable by aphidicolin, and the other not.
1 Supported in part by a fellowship from the French Ligue Nationale contre le Cancer and from the NCI/European Organisation for Research and Treatment of Cancer (to F. G.).
2 Present address: Hôpital Paul Brousse, 94800 Villejuif, France.
3 To whom requests for reprints should be addressed, at Laboratory of Molecular Pharmacology, Building 37, Room 5C25, National Cancer Institute, NIH, Bethesda, MD 20892-4255. Fax: (301) 402-0752.
Received 1/18/96. Accepted 7/29/96.
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