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Correlation of Therapeutic Outcome in Non-Small Cell Lung Cancer and DNA Damage Assayed by Polymerase Chain Reaction in Leukocytes Damaged in Vitro¹

Department of Medical Oncology, National Cancer Center Hospital [F. O., N. Y., M. F., Y. O., T. T., K. E., T. S.], and Pharmacology Division, National Cancer Center Research Institute [N. S.], Tsukiji 5-1-1, Chuo-ku, Tokyo 104, Japan

A pilot study was conducted in patients with advanced non-small cell lung cancer to examine whether the gene-specific damage in mononuclear cells (MNCs) incubated with cisplatin in vitro correlates with chemotherapeutic outcome in cisplatin-based chemotherapy. Twenty-one patients received cisplatin-based chemotherapy, consisting of cisplatin (80 mg/m² i.v. on day 1), vindesine (3 mg/m² i.v. on days 1 and 8), with or without mitomycin (8 mg/m² i.v. on day 1). MNCs from peripheral blood were obtained from each patient before chemotherapy. The cells were incubated with cisplatin for 3 h in vitro and the 2.7-kb fragment of the hypoxanthine phosphoribosyltransferase gene was amplified by PCR for quantitation of DNA damage.

There was a 4-fold interpatient variation in DNA damage in MNCs. Seven of 21 patients had a partial response to chemotherapy. When the dose of cisplatin required to reduce amplification of the hypoxanthine phosphoribosyltransferase sequence by 63% (D63 value) of MNCs was compared in each patient (defined by a Poisson distribution as the dose that produced an average of one lesion per single strand of the 2.7-kb fragment), the mean D63 value in patients showing a partial response (n = 7; 52 ± 11 µg/ml) was significantly lower than that in patients showing no change (n = 10; 81 ± 20 µg/ml; P = 0.0045) and in patients with disease progression (n = 4; 115 ± 34 µg/ml; P = 0.0012). The mean D63 in patients with no change was also significantly lower than that in the patients with disease progression (P = 0.0386). Seven (70%) of 10 patients with a D63 value <70 µg/ml were responders. No relationship was observed between the D63 values and hematological and nonhematological toxicities.

It is suggested that DNA damage in MNCs incubated by cisplatin treatment in vitro in responders was greater than that in nonresponders. Gene-specific damage in MNCs from peripheral blood incubated with cisplatin in vitro assayed by PCR may predict the chemotherapeutic response in cisplatin-based chemotherapy for non-small cell lung cancer.

¹ This work was supported in part by a Grant-in-Aid from the Ministry of Health and Welfare for the Comprehensive 10-year Strategy for Cancer Control.

² To whom requests for reprints should be addressed.

Received 12/ 6/94. Accepted 3/30/95.

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