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Elevated DT-diaphorase Activity and Messenger RNA Content in Human Non-Small Cell Lung Carcinoma: Relationship to the Response of Lung Tumor Xenografts to Mitomycin C¹

Molecular Toxicology and Environmental Health Sciences Program and School of Pharmacy, University of Colorado, Boulder, Colorado 80309 [A. M. M., D. S., D. R.]; Beckman Research Institute, City of Hope, Duarte, California 91010 [G. L. F.]; Navy Medical Oncology Branch, National Cancer Institute, Bethesda, Maryland 20814 [A. F. G., H. K. O.]; Division of Medical Oncology and Cancer Center, University of Colorado School of Medicine, Denver, Colorado 80262 [D. C. C., P. A. B.]; The Oncology Center, The Johns Hopkins School of Medicine, Baltimore, Maryland 21205 [M. M.]; Southern Research Institute, Birmingham, Alabama 35255 [D. J. D., S. D. H.]

The enzyme DT-diaphorase (DTD; NAD(P)H:quinone oxidoreductase, EC 1.6.99.2), is an obligate two electron reductase which catalyzes reduction of a broad range of substrates, including quinones. We report here variations in DTD concentrations among different classes of lung tumors known also to vary in their responsiveness to cytotoxic agents. Small cell lung carcinomas (SCLCs) and cell lines derived from them have the low DTD activities and mRNA content characteristic of normal human lung, whereas non-small cell lung carcinomas (NSCLCs) have greatly elevated levels. DTD activity was increased up to 80-fold in NSCLC tumors relative to normal lung and 20–35-fold in NSCLC relative to SCLC cell lines. Increased DTD activity appeared to be a function of the NSCLC phenotype rather than a result of derivation from a cell type rich in DTD, since all histological classes of NSCLC showed this phenotype. In addition, where transfection of SCLC cell lines with the v-Ha-ras protooncogene caused a transition to a NSCLC phenotype, DTD activity was also elevated. Neuroendocrine-positive cells (SCLC, carcinoids, and a few NSCLC lines) typically had far lower DTD activities than did cell lines which lacked neuroendocrine markers (most NSCLC cells and mesotheliomas). High DTD activity may be exploited in the design of drugs which undergo bioreductive activation by this enzyme. Consistent with this, xenografts derived from NSCLC cell lines with high DTD that were grown in athymic nude mice were more susceptible to the antitumor quinone, mitomycin C, than were xenografts derived from SCLC cells containing low DTD. These data provide a mechanistic basis for the rational design of more effective bioreductive antitumor agents for use against NSCLC.

¹ Supported by USPHS Grants RO1 CA 51210, RO1 ES 02370, and Contract N01-CM-97553.

² To whom requests for reprints should be addressed.

Received 3/10/92. Accepted 6/16/92.

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