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Basic Sciences

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

David A. Boothman, Sheldon Greer and Arthur B. Pardee
David A. Boothman
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Sheldon Greer
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Arthur B. Pardee
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DOI:  Published October 1987
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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. Do and Dq 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 Do and Dq 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.

Footnotes

  • ↵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 March 31, 1987.
  • Revision received July 6, 1987.
  • Accepted July 14, 1987.
  • ©1987 American Association for Cancer Research.
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October 1987
Volume 47, Issue 20
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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
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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
David A. Boothman, Sheldon Greer and Arthur B. Pardee
Cancer Res October 15 1987 (47) (20) 5361-5366;

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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
David A. Boothman, Sheldon Greer and Arthur B. Pardee
Cancer Res October 15 1987 (47) (20) 5361-5366;
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