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

Abstract

3,4-Dihydro-2,2-dimethyl-2H-naptho[1,2,-b]pyran-5,6-dione (β-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. β-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 β-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. β-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. β-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.

β-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 β-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.