| In vitro: |
| Drug Metab Dispos. 2008 Apr;36(4):753-8. | | Identification of a novel glucosylsulfate conjugate as a metabolite of 3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione (ARQ 501, beta-lapachone) in mammals.[Pubmed: 18227145] |
METHODS AND RESULTS:
3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione (ARQ 501) is a fully synthetic version of the natural product beta-lapachone, which has been isolated from the lapacho tree (Tabebuia impetiginosa or Tabebuia avellanedae) and has demonstrated promising anticancer activity. 3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione formulated with hydroxypropyl-beta-cyclodextrin has successfully completed phase I clinical trials and is currently in several phase II human clinical trials for the treatment of pancreatic cancer, head and neck cancer, and leiomyosarcoma. The metabolites of 3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione were investigated by low-resolution and high-resolution mass spectrometry in plasma from (nu/nu) mice, rats, and humans treated with the compound. The data for one of the metabolites identified are consistent with conjugation of 3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione with a glucosylsulfate moiety (m/z 241; fragment ion).
CONCLUSIONS:
Although other glucosylsulfate conjugates have been identified as metabolites of pesticides in cotton plants and in crustaceans as phase II metabolites of pyrenes, none have been previously identified in mammals. Data reported here identify a novel metabolic pathway for humans. | | Cancer Res. 1987 Oct 15;47(20):5361-6. | | Potentiation of halogenated pyrimidine radiosensitizers in human carcinoma cells by beta-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran- 5,6-dione), a novel DNA repair inhibitor.[Pubmed: 3652040] | 3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione (beta-lapachone) is a novel DNA repair inhibitor. 3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione was tested for synergistic X-ray-induced lethality in combination with several halogenated pyrimidine radiosensitizers.
METHODS AND RESULTS:
3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione synergistically increased the dose enhancement ratios (DERs) of all analogues screened, with the exception of the 2'-chloro derivative of 5-bromodeoxyuridine. 3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione 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. 3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione 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.
CONCLUSIONS:
3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dioneenhanced 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 3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione treatment. |
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