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Potentiation of Halogenated Pyrimidine Radiosensitizers in Human Carcinoma Cells by ß-Lapachone (3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione), a Novel DNA Repair Inhibitor¹

Division of Cell Growth and Regulation [D. A. B.] and Department of Pharmacology [A. B. P.], Harvard Medical School, Dana Farber Cancer Institute (D-810A), Boston, Massachusetts 02115, and Department of Microbiology and Immunology (R-138), School of Medicine, University of Miami, Miami, Florida 33101 [S. G.]

3,4-Dihydro-2,2-dimethyl-2H-naptho[1,2,-b]pyran-5,6-dione (ß-lapachone) is a novel DNA repair inhibitor. It was tested for synergistic X-ray-induced lethality in combination with several halogenated pyrimidine radiosensitizers. Logarithmic-phase growing human epidermoid laryngeal carcinoma (HEp-2) cells were allowed to incorporate pyrimidine analogues for 48 h (approximately two cell doublings) and then were X-irradiated and subjected to various posttreatments. ß-Lapachone synergistically increased the dose enhancement ratios (DERs) of all analogues screened, with the exception of the 2'-chloro derivative of 5-bromodeoxyuridine. For example, following 5-bromodeoxycytidine sensitization an X-ray DER value of 1.87 ± 0.04 at 1% survival was increased to 3.51 ± 0.42 due to a 4-h post-X-irradiation exposure to 4 µM ß-lapachone. D_o and D_q values for halogenated pyrimidine-sensitized human epidermoid laryngeal carcinoma cells were decreased 1.4- to 5.4-fold and 1.4- to 4.0-fold, respectively. ß-Lapachone had little effect upon the cytotoxicities of unirradiated human epidermoid laryngeal carcinoma cells whether or not they were previously exposed to any of the halogenated pyrimidine radiosensitizers. ß-Lapachone treatment following X-irradiation of cells that had not incorporated a pyrimidine analogue exhibited DER values of 1.38 ± 0.05 and 1.40 ± 0.01 at 10 and 1% survival levels, respectively.

ß-Lapachone enhanced the radiosensitization of deoxycytidine analogues to a greater extent than the structurally related deoxyuridine analogues. Greater DERs and lower D_o and D_q values were found for deoxycytidine than for deoxyuridine analogue radiosensitizers following ß-lapachone treatment. This agent may improve presently used radiation therapies and enhance proposed strategies which utilize deoxycytidine analogue radiosensitization together with protection of normal tissues by tetrahydrouridine to achieve tumor-selective radiotherapy.

¹ Supported by Grant CA22427 to A. B. P. from the National Cancer Institute and, in part, by Grant CA33219 to S. G. from the National Cancer Institute.

² To whom requests for reprints should be addressed.

Received 3/31/87. Revised 7/ 6/87. Accepted 7/14/87.

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