Hypoxia-inducible factor-1 (HIF-1) is a pivotal factor that regulates cellular responses to hypoxia and is presumably linked to regulation of angiogenesis and tumor growth. We assessed the difference in transcription activity of two HIF-1alpha polymorphic variants (P582S and A588T), along with molecular epidemiological study among head and neck squamous cell carcinoma (HNSCC) patients. Both HIF-1alpha variants revealed significantly higher transcription activity than wild-type (WT) did, under normoxic and hypoxic conditions (P < 0.02). Furthermore, tumors from HNSCC patients with heterozygous alleles having P582S or A588T had significantly increased numbers of microvessels compared with those with homozygous WT (P = 0.02). In addition, all patients with tumors of T1 (below 2 cm diameter) were WT, while 14 of 47 patients with tumors of > or =T2 were heterozygous. The elevated transactivation capacity of variant forms of HIF-1alpha implies a role of HIF-1alpha polymorphisms in generating individually different tumor progression.

In the present study, we found that hypoxia or CoCl 2 enhanced the mRNA expression of DEC2, as well as DEC1, within 24 h in chondrogenic ATDC5, 293T, and HeLa cells. In luciferase assays, the regions between ؊524 and ؊401 in the DEC1 promoter, and between ؊863 and ؊258 in the DEC2 promoter, were responsible for the hypoxia-or hypoxiainducible factor-1␣ (HIF-1␣)-induced transcription. In these regions, we identified functional hypoxia response elements (HREs) that bound to HIF-1␣ and HIF-1␤. In addition to an HIF-1 binding site consensus sequence, the DEC1 HRE had cAMP response element-like and CACAG sequences, which were also involved in the transcription activation in response to HIF-1␣. Although the DEC2 HRE did not have a cAMP response element-like or CACAG sequence, it showed a higher affinity for HIF-1 than did the DEC1 HRE. Because DEC1 and DEC2 are directly inducible by HIF-1, these transcription factors may be crucial for the adaptation to hypoxia.Recently we cloned the cDNA for the novel basic helix-loophelix (bHLH) 1 transcription factor DEC1 (BHLHB2), which was expressed at a higher level in human primary chondrocytes than in fibroblastic cells (1). A mouse ortholog (Stra13) and a rat ortholog (SHARP-2) of DEC1 were identified independently by others in the P19 embryonal carcinoma cells and rat brain, respectively (2, 3), and the mRNA of DEC1 was found in a variety of embryonic and adult tissues (1-3). In addition, we cloned a member of the DEC subfamily of bHLH proteins, DEC2 (BHLHB3), by searching the expressed sequence tags data bank (4). DEC2 is similar to SHARP-1 (3), which is a truncated molecule of DEC2 produced by a sequencing error or a minor frameshift mutant (4). The bHLH regions of DEC1 and DEC2 exhibit the highest similarities to those of Drosophila Hairy, Enhancer of split and mammal HES, which are known as transcriptional repressors with the WRPW motif, which interacts with the Groucho family members of corepressors. Although the Stra13/DEC1 and DEC2/SHARP-1 lack the WRPW motif, they also act as transcriptional repressors by a discrete mechanism (5, 6). Stra13/DEC1 interacts physically with the components of the basal transcription machineries, such as TATA-binding protein and TFIIB, and can recruit the histone deacetylase 1-Sin3A-NcoR corepressor complex through their carboxyl-terminal repression domain (5).DEC1/Stra13/SHARP-2 may be involved in the control of the proliferation and/or differentiation of chondrocytes, nerve cells, fibroblasts, and T cells (1-3, 7). The overexpression of DEC1/ Stra13 promoted a chondrogenic differentiation of the mesenchymal stem cells, 2 and a neural differentiation of the P19 cells (2). Recently, Stra13-deficient mice were generated, and it was shown that Stra13/DEC1 is a key regulator of lymphocyte activation that is vital for the maintenance of self-tolerance and constraint of autoimmunity. Other phenotypic differences between Stra13 Ϫ/Ϫ mutants and the wild-type littermates have not been reported (7). On the other hand, DEC2/SHARP-1 worked as a tran...

Purpose: To evaluate the efficacy and toxicity of docetaxel in combination with a novel oral 5-fluorouracil analogue S-1for patients with advanced or recurrent gastric cancer. Experimental Design: Patients with advanced or recurrent adenocarcinoma of the stomach and up to one previous chemotherapy regimen were treated with i.v. docetaxel 40 mg/m 2 on day 1and oral S-1 80 mg/m 2 /d on days 1to 14 every 3 weeks. Results: Forty-eight patients (median age, 65 years; range, 25-75 years) received a total of 272 treatment cycles (median, 4; range, 1-17). No complete responses and 27 partial responses were observed for an overall response rate of 56.3% [95% confidence interval (95% CI), 38-66%]. Eighteen patients (37.5%) had stable disease and three patients (6.3%) had progressive disease as best response. The tumor control rate (complete response + partial response + stable disease) was 93.8% (95% CI, 83-98%). Median overall survival was 14.3 months (95% CI, 10.7-20.3 months) and median time to tumor progression was 7.3 months (95% CI, 4.3-10.0 months). The most common grade 3 to 4 hematologic toxicities were neutropenia (58.3 %), leukopenia (41.7%), febrile neutropenia (8.3%), and anemia (8.3%). The most common grade 3 nonhematologic toxicities included anorexia (14.6%), stomatitis (8.3%), and nausea (6.3%). No grade 4 nonhematologic toxicities were reported and all treatment-related toxicities were resolved. Conclusion: Docetaxel/S-1combination is highly active and well tolerated in advanced or recurrent gastric cancer. Further investigation in randomized studies is warranted.The prognosis for patients with unresectable advanced or recurrent gastric cancer is extremely poor; indeed, gastric cancer is the second most frequent cause of cancer-related mortality worldwide, accounting for f700,000 deaths annually (1). Several novel chemotherapeutic agents, including the taxanes (paclitaxel and docetaxel), irinotecan, and, more recently, oxaliplatin, S-1, and capecitabine, have shown activity in gastric cancer and offer hope for improving patient outcomes in this setting (2, 3). Response rates of up to 65% were reported in phase II studies of regimens, including taxanes, irinotecan, or oxaliplatin, and, consequently, several combinations have been investigated in randomized phase II/III studies (3).Docetaxel has shown promising activity in gastric cancer, both as monotherapy (4, 5) and in combination with other agents (6 -8). In the phase III TAX 325 study, triple-agent therapy with docetaxel-cisplatin-5-fluorouracil (5-FU; TCF) was superior to cisplatin-5-FU in terms of response rate (37% versus 25%; m 2 , P = 0.0106), time to progression (TTP; 5.6 months versus 3.7 months; risk reduction 32%; log-rank P = 0.0004), and survival (risk reduction 23% after a median follow-up of 23 months; log-rank P = 0.0201) in patients with metastatic gastric cancer (7). However, grade 3 to 4 treatment-emergent adverse events (regardless of relationship to study medication) occurred in 81% and 75% of patients receiving TCF and cis...

Metabolic response by F-FDG was effective in predicting efficacy and survival at 1 month after nivolumab treatment.