A/T gap tolerance in the core sequence and flanking sequence requirements of non-canonical p53 response elements.

The canonical core sequence of the p53 response element, CATG, has a two-base A/T gap. Previously, we found that p53 can also activate a non-canonical four-base A/T gap CATATG core sequence. In this study, we investigated the possible number of A/T bases used by p53 and showed that a six-base A/T gap CATATATG core sequence was the maximum A/T gap in the p53 response element that could be upregulated by p53 and p63. Canonical and non-canonical p53 response elements also have three-base flanking sequences. A/T bases could be substituted by G/C bases, including CACACG and CGTGTG, but not CGCGCG. We found that the SV40 promoter with functional six- and two-base A/T gap core sequences could be activated by TAp63γ and that TAp63γ could upregulate SV40 small and large T antigens expression in COS7 cells. We also found that the distal region of PUMA promoter with functional two six-base A/T gap core sequences could be activated by TAp63γ in 293T cells. These new findings could provide novel rules for the non-canonical p53 family response element and could extend the entire p53 family regulation network.

Irinotecan-involved regimens for advanced gastric cancer: a pooled-analysis of clinical trials.

AIM: To assess the efficiency and toxicities of irinotecan (CPT-11)-involved regimens in patients with advanced gastric cancer. METHODS: Randomized phases II and III clinical trials on chemotherapy for advanced gastric cancer were searched from MEDLINE, EMbase, Cochrane Controlled Trials Register, and EBSCO. Relevant abstracts were manually searched. A total of 657 patients were analyzed for their overall response rate (ORR), time to treatment failure (TTF), overall survival (OS) rate, and toxicities. Overall survival rate, reported as hazard ratio (HR) with 95% CI, was used as the primary outcome measure. RESULTS: Four randomized controlled trials on chemotherapy for advanced gastric cancer were detected. The CPT-11-containing combination chemotherapy was not significantly advantageous over the non CPT-11-containing combination chemotherapy for OS rate (HR = 1.12, 95% CI: 0.92-1.36, P = 0.266) and ORR [risk ratio (RR) = 1.23, 95% CI: 0.71-2.14, P = 0.458]. However, the CPT-11-containing combination chemotherapy was significantly advantageous over the non CPT-11-containing combination chemotherapy for TTF (HR = 1.35, 95% CI: 1.12-1.64, P = 0.002). Grade 3/4 haematological toxicity (thrombocytopenia: RR = 0.20, 95% CI: 0.09-0.48; P < 0.001) and gastrointestinal toxicity (diarrhea: RR = 4.09, 95% CI: 2.42-6.93, P < 0.001) were lower in patients with advanced gastric cancer after CPT-11-containing combination chemotherapy than after non CPT-11 -containing combination chemotherapy. CONCLUSION: CPT-11-containing combination chemotherapy is advantageous over non CPT-11 -containing combination chemotherapy for TTF with no significant toxicity. CPT-11-containing combination chemotherapy can be used in treatment of advanced gastric cancer.