Abstracts
1999 Digestive Disease Week

# 4671 TARGETING MOLECULAR PATHWAYS AS NOVEL THERAPY FOR GASTRIC CANCER
D A Litvak, H T Papaconstantinou, C M Townsend Jr., B M Evers, Univ of Texas Med Branch, Galveston, TX

The prognosis for gastric cancer remains dismal. Camptothecin (CPT), an inhibitor of topoisomerase I, is effective in the treatment of certain solid tumors; the effect of CPT on gastric cancers in vivo has not been well described. The purpose of our study was: (1) to characterize the effects of CPT on the growth of human gastric cancers in vivo, and (2) to assess potential cellular mechanisms responsible for CPT-mediated inhibition. METHODS. Two human gastric cancers (WIL and TOR), established in our laboratory, were transplanted s.c. into athymic nude mice. After tumors reached ~50-100 mm2, mice were randomized to receive either low dose CPT (5 mg/kg), high dose CPT (10mg/kg) or vehicle (Control) i.p. 3 days/wk for 3 wks; tumor size and body weight were measured biweekly. Mice were sacrificed on treatment day 21 and tumors removed, weighed and protein analyzed for expression of the cell cycle inhibitor protein p21Waf1/Cip1 and the anti-apoptotic protein Bcl-2 by Western blot. RESULTS. (Mean ± SEM; *=p<0.05 vs. Control; †=p<0.05 vs. baseline; ‡=p<0.05 vs. CPT 5 mg/kg). CPT significantly inhibited tumor size and weight of both WIL (Fig.) and TOR (not shown) tumors compared with Control. In addition, CPT (10 mg/kg) significantly decreased tumor size of both cancers compared to baseline, indicating a tumoricidal effect. Treatment with CPT resulted in a significant increase in expression of p21Waf1/Cip1 and a decrease in the expression of Bcl-2. CONCLUSIONS. CPT effectively inhibits the growth of human gastric cancers in vivo; potential cellular mechanisms of CPT-mediated inhibition may be upregulation of p21Waf1/Cip1 and/or downregulation of Bcl-2. Novel agents, like CPT, which selectively target specific molecular pathways, may prove clinically useful in the treatment of gastric cancers.

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