The expression level of the telomerase catalytic subunit (telomerase reverse transcriptase, TERT) positively correlates with cell survival after exposure to several lethal stresses. However, whether the protective role of TERT is independent of telomerase activity has not yet been clearly explored. Here, we genetically evaluated the protective roles of both TERT and telomerase activity against cell death induced by staurosporine (STS) and N-methyl-Daspartic acid (NMDA). First generation (G1) TERTdeficient mouse embryonic fibroblasts (MEFs) displayed an increased sensitivity to STS, while TERT transgenic MEFs were more resistant to STS-induced apoptosis than wildtype. Deletion of the telomerase RNA component (TERC) failed to alter the sensitivity of TERT transgenic MEFs to STS treatment. Similarly, NMDA-induced excitotoxic cell death of primary neurons was suppressed by TERT, but not by TERC both in vitro and in vivo. Specifically, NMDA accelerated death of TERT-deficient mice, while TERT transgenic mice showed enhanced survival when compared with wild-type littermates after administration of NMDA. In addition, the transgenic expression of TERT protected motor neurons from apoptosis induced by sciatic nerve axotomy. These results indicate that telomerase activity is not essential for the protective function of TERT. This telomerase activity-independent TERT function may contribute to cancer development and aging independently of telomere lengthening.

13121 Purpose: To determine whether UGT1A1, UGT1A7, and UGT1A9 polymorphisms affect pharmacokinetics (PK) of irinotecan and treatment outcome of Korean patients with advanced non-small cell lung cancer (NSCLC). Methods: Eighty-one patients with advanced NSCLC were treated with irinotecan and cisplatin chemotherapy. Genomic DNA was extracted from peripheral blood and genotyped using direct sequencing. We analyzed the association of UGT1A genotypes with irinotecan PK and clinical outcomes. Results: In genotype-PK association analysis, UGT1A1*6/*6 (n = 6), UGT1A7*3/*3 (n = 6) and UGT1A9–118(dT)9/9 (n = 11) were associated with significantly lower AUCSN-38G/AUCSN-38 ratio (P = 0.002, 0.009and 0.001, respectively). In linkage disequilibrium (LD) analysis, the UGT1A7 variants were highly linked with UGT1A1*6 (D` = 0.85, r2 = 0.63) and UGT1A9*22 (D` = 0.95, r2 = 0.88), which was substantiated in haplotype analysis. Patients with UGT1A1*6/*6 had lower tumor response and higher incidence of severe neutropenia. UGT1A9–118(dT)9/9 also showed a trend for high incidence of severe diarrhea, but not tumor response. In survival analysis, patients with UGT1A1*6/*6 had significantly shorter progression-free survival (P = 0.001) and overall survival (P = 0.017). Conclusions: These findings suggest that UGT1A1*6 and UGT1A9*22 genotypes may be important for SN-38 glucuronidation and associated with irinotecan-related severe toxicity. Specifically, UGT1A1*6 might be useful for predicting tumor response and survival outcome of Korean patients with NSCLC treated with irinotecan-based chemotherapy. (Supported in part by NCC Grant 0210130 and 0510080 from National Cancer Center, Korea). No significant financial relationships to disclose.

4537 Background: Although the adjuvant chemoradiation therapy has gained popularity and has become the standard of care in patients with resected gastric cancer in U.S., the role of chemoradiation therapy after extended D2 dissection has been questioned. We conducted a phase III trial to compare capecitabine/cisplatin (XP) vs XP + radiotherapy (RT) in curatively D2 resected gastric cancer patients in terms of disease free survival and overall survival. Methods: Eligibility criteria were as follows: stage Ib (T1N1, T2bN0) - IV (M1 excluded), curatively ≥ D2 resected gastric adenocarcinoma. XP only: X 2,000 mg/m2/d D1∼14, CDDP 60 mg/m2 D1 repeated every 3 weeks, 6 cycles; XP + RT: X 2,000 mg/m2/d D1∼14, CDDP 60 mg/m2 D1 x 2 cycles ⋄ RT 45 Gy (25 fractions) + X 1,650 mg/m2/d during RT ⋄ X 2,000 mg/m2/d D1∼14, CDDP 60 mg/m2 D1 x 2 cycles. The primary endpoint is 3-year disease-free survival. Results: From October 2004 to April 2008, 458 patients (XP arm: 228 patients; XP/RT arm: 230 patients) were enrolled. In XP arm, 172 (75%) of 228 enrolled patients completed 6 cycles of chemotherapy. In XP + RT arm, 188 (82%) of 230 patients completed the full course of XP 2 cycles - X + RT - XP 2 cycles. Conclusions: Safety and feasibility analysis of the two arms will be reported at the meeting. No significant financial relationships to disclose.

4030 Background: The perioperative treatment strategy for locally advanced gastric cancer (LAGC) has not been clearly established. We conducted a randomized phase II study of neoadjuvant vs. adjuvant docetaxel/cisplatin (DC) chemotherapy in LAGC. Methods: LAGC was radiographically defined by CT and PET. Pts were randomized to receive neoadjuvant or adjuvant DC (docetaxel 36 mg/m2 + cisplatin 40 mg/m2 on D1, D8, q 3 wks X 3 cycles) according Japanese staging system (IIIa, IIIb, IV M-, and IV with a single M+ node). Results: All planned 88 pts in 44 per each arm were enrolled between Jan 2003 and Nov 2005. One pt was not eligible. The median age was 57 yrs vs. 58 yrs, PS 1 90.7% vs. 84.1%, and stage III/IV 72.1%/27.9% vs. 70.5%/29.5% in the neoadjuvant and adjuvant arm, respectively. Clinical response rate of 42 evaluable pts in neoadjuvant arm according to WHO criteria was 64.3% (95% CI 49.8–78.8%) with CR 2.4%, PR 61.9%, SD 31.0%, and PD 4.7%. There was no treatment related death. Comparison of G3/4 adverse events in neoadjuvant vs. adjuvant arm were; leukopenia 14.0% vs. 32.4% (p=0.04), neutropenia 37.2% vs. 62.2% (p=0.02), febrile neutropenia 0% vs. 2.7%, diarrhea 2.3% vs. 10.8%, stomatitis 2.3% vs. 8.1% (p=NS). There were no difference in the postoperative morbidity and the duration of hospital stay between both arms, but surgery was delayed in one pt who developed tuberculosis during neoadjuvant chemotherapy. Downstaging of the T stage could be obtained in 6 (14.3%) among 42 evaluable pts in neoadjuvant arm, according to EUS. Conclusions: Both neoadjuvant and adjuvant DC chemotherapy were relatively well tolerated in LAGC, with the lower incidence of G3/4 toxicities in neoadjuvant arm. Neoadjuvant DC showed a high response rate and a modest downstaging effect. (Supported by National Cancer Center Grant; Docetaxel was provided by Sanofi Aventis Korea) [Table: see text] No significant financial relationships to disclose.

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