Optimal Time Interval for Surgery After Neoadjuvant Chemoradiotherapy in Patients With Locally Advanced Rectal Cancer: Analysis of Health Insurance Review and Assessment Service Data.

PURPOSE: Pathologic downstaging of rectal cancer has been suggested to be associated with the time interval from chemoradiotherapy (CRT) completion to surgery. We aimed to evaluate the effect of this time interval for patients with rectal cancer on the pathologic response. METHODS: All patients with rectal cancer undergoing neoadjuvant CRT with evaluable data were selected from among the Health Insurance Review and Assessment Service data. Patients were divided into groups according to the time between CRT and surgery. CRT responses were analyzed. RESULTS: Two hundred forty-nine patients were included, of whom 86 (34.5%) were in the 5- to 7-week interval, 113 (45.4%) in the 7- to 9-week interval, 38 (15.3%) in the 9- to 11-week interval, and 12 (4.8%) in the >11-week interval. The median time interval between CRT completion and surgery was 7.4 weeks (range: 5-22.7 weeks; interquartile range, 6.7-8.7 weeks). Surgery 9-11 weeks after CRT completion resulted in the highest, but not statistically significant, pathologic complete response (pCR) rate (3 patients, 8.6%; P = 0.886), no pCR was noted in the >11-week interval group. Results for downstaging in the 9- to 11-week interval group were as follows: T downstaging, 38.2% (P = 0.735); N downstaging, 50.0% (P = 0.439); and TN downstaging, 52.9% (P = 0.087). The 3-year overall survival rates for the 5- to 7-week, 7- to 9-week, 9- to 11-week, and >11-week interval groups were 93.0%, 85.0%, 81.6%, and 91.7%, respectively (P = 0.326). CONCLUSION: Delaying surgery by 9 to 11 weeks may increase TN downstaging, but delaying for over 11 weeks may not increase additional tumor downstaging from long-course CRT.

Combination of ginsenoside Rg3 with docetaxel enhances the susceptibility of prostate cancer cells via inhibition of NF-kappaB.

Ginsenoside Rg3 has been a subject of interest for use as a cancer preventive or therapeutic agent. Nuclear factor-kappa (NF-kappaB) is constitutively activated in prostate cancer, and gives cancer cells resistance to chemotherapeutic agents. To investigate whether Rg3 can suppress the activation of NF-kappaB, and thus increase susceptibility of prostate (LNCaP and PC-3, DU145) cells against chemotherapeutics, prostate cancer cell growth as well as activation of NF-kappaB was examined. We found that a combination treatment of Rg3 (50 microM) with a conventional agent docetaxel (5 nM) was more effective in the inhibition of prostate cancer cell growth and induction of apoptosis as well as G(0)/G(1) arrest accompanied with the significant inhibition of NF-kappaB activity than those by treatment of Rg3 or docetaxel alone. It was also found that NF-kappaB target gene expression of Bax, caspase-3, and caspase-9 was much more significantly enhanced, but the expression of Bcl-2, inhibitor of apoptosis protein (IAP-1) and X chromosome IAP (XIAP), and the expression of cell cycle regulatory proteins cyclin B, D1 and E, and cyclin dependent kinases 2 and 4 was also much more significantly inhibited by the combination treatment. The combination of Rg3 (50 microM) with cisplatin (10 microM) and doxorubicin (2 microM) was also more effective in the inhibition of prostate cancer cell growth and NF-kappaB activity than those by the treatment of Rg3 or chemotherapeutics alone. These results indicate that ginsenoside Rg3 inhibits NF-kappaB, and enhances the susceptibility of prostate cancer cells to docetaxel and other chemotherapeutics. Thus, ginsenoside Rg3 could be useful as an anti-cancer agent.

Obovatol enhances docetaxel-induced prostate and colon cancer cell death through inactivation of nuclear transcription factor-kappaB.

Nuclear transcription factor-kappaB (NF-kappaB) is constitutively activated in prostate and colon cancers and is related with the resistance of cancer cells against chemotherapeutics. Previously, we found that obovatol, an active compound isolated from Magnolia obovata, inhibited cancer cell growth through inhibition of NF-kappaB activity. We investigated here whether obovatol could sensitize cancer cells against docetaxel through inhibition of NF-kappaB activity in prostate cancer (LNCaP and PC-3) and colon cancer (SW620 and HCT116) cells. The combination treatment with each drug at one half the respective IC(50) dose (5 microM obovatol + 5 nM docetaxel) was more effective and significant (60%-70%) in the inhibition of cancer cell growth than single treatment by each drug (20%-40%); inhibition was exerted through a significant increase of apoptosis induction (60%-80%) by the combination treatment compared to the single treatment (10%-30%). Correlating well with the synergistic inhibition (combination indices are less than 1 in all cell types), the combination significantly inhibited NF-kappaB activities as well as expression of NF-kappaB target apoptotic cell death proteins, but decreased anti-apoptotic cell death proteins. Similar combination effects of obovatol with other chemotherapeutic agents (paclitaxel, cisplatin, and doxorubicin) on the inhibition of cell growth and NF-kappaB activity were also found. These results indicate that obovatol augments cell growth inhibition by chemotherapeutics through inactivation of NF-kappaB and suggest that obovatol may have therapeutic advantages in the combination treatment with other chemotherapeutics. [Supplementary Figure: available only at http://dx.doi.org/10.1254/jphs.09048FP].

Evaluation of paclitaxel rearrangement involving opening of the oxetane ring and migration of acetyl and benzoyl groups.

The stability of drug is a critical factor in quality control, drug efficacy, safety, storage, and production conditions. The rearrangement of paclitaxel, which involves opening of the oxetane ring and migration of acetyl group occurred on heating a powder of purified paclitaxel. Subsequently, the unusual migration of benzoyl groups progressed rapidly in organic solvents. These rearrangement derivatives were isolated carefully. The structures of the intermediate derivative A and the product derivative B were confirmed using (1)H NMR, high performance liquid chromatography (HPLC), and mass spectrometry. We proposed the rearrangement pathway here for the first time. Neither derivative exhibited bioactivity in SKOV3 (ovarian cancer) or MDA-MB-435 (breast cancer) cell culture assays.