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Detection of Sequence-Specific Antitumor Alkylating Agent DNA Damage from Cells Treated in Culture and from a Patient¹

Division of Hematology/Oncology, Beth Israel Hospital, Harvard Medical School 02215 [G. J. B., G. K. O.], and Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [N. P. D., B. A. T.]

Detection of sequence-specific DNA damage induced by antitumor alkylating agents might provide a mechanism for detecting and discriminating damage specific to one or more of these drugs. Using repetitive primer-extension and human alphoid DNA as a substrate, lesions specific for an activated form of cyclophosphamide, 4-hydroperoxycyclophosphamide, were detected at 32 of 33 guanines within a 200-base pair region in DNA from cells treated in culture. There was a marked variation in lesion site intensity among affected guanines. For instance, guanines flanked by cytosine were weak sites of 4-hydroperoxycyclophosphamide-induced damage. Damage at bases other than guanine induced by cisplatin, UV irradiation, and adozelesin were compared to drug-DNA lesions induced by 4-hydroperoxycyclophosphamide. Using this method it was possible to detect, and at some sites distinguish, between cyclophosphamide- and cisplatin-induced DNA damage within WBC DNA from a patient treated with both agents. There was a different damage pattern for DNA derived from cells treated in culture compared to DNA derived from the patient sample.

¹ Supported by Grants R-29 CA51438 [G. J. B.] and PO-1-38493 [B. A. T.] from the National Cancer Institute.

² To whom requests for reprints should be addressed, Division of Hematology/Oncology, Beth Israel Hospital, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215.

Received 9/ 2/94. Accepted 11/ 2/94.

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