[37 Transgenic Shuttle Vector Assays for Determining Genetic Differences in Oxidative B Cell Mutagenesis in Vivo

By Klaus Felix, Lynne D. Rockwood, and Siegfried Janz

Because tumorigenesis is an in vivo phenomenon that can be evaluated optimally only in in vivo studies, it has been postulated that attempts to link tumor development with mutagenesis may be most informative when mutagenesis can also be assessed in vivo. We have chosen two transgenic shuttle vector assays, A LIZ (Big Blue) and pUR288 (placZ), to explore in mice the role of oxidative B cell mutagenesis in the development of the malignant plasma cell tumor, plasmacytoma (PCT). Here we provide a brief introduction to the putative role of oxidative stress during mouse plasmacytomagenesis (PCTG) and describe the utility of the XLIZ and pUR288 assays for determining oxidative B cell mutagenesis in vivo. In addition, we introduce a genetic system that employs congenic mouse strains to associate the susceptibility to PCT development with the genetic control of oxidative mutagenesis in the B cell compartment.

BALB/c Plasmacytomas

Our interest in oxidative mutagenesis in B lymphocytes stems from our efforts to learn about the pathogenesis of inflammation-induced PCTs in mice. PCTs are immunoglobulin-producing neoplasms of terminally differentiated

Concluding Remarks

We have devised alternative approaches for inhibiting NADPH oxidase activity in human monocytes, using antisense ODNs. Although several pharmacologic inhibitors have been suggested to inhibit the activity of this enzyme complex, antisense ODN-mediated inhibition offers greater specificity and related lower toxicity. We recommend that none of these approaches, outlined in this chapter, be used in isolation. The use of multiple complementary approaches to modulate NADPH oxidase activity, or for that matter any enzyme activity, affords the investigator confidence that the experimental observations are sound.

Acknowledgments

This work was supported by NIH Grants HL-51068 and HL-61971 (M.K.C.). Additional support was provided by Minority Research Supplement HL-51068 (E.A.B.).

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