Gemcitabine (Gem) is a dFdC analogue with activity against several solid tumors. Gem is intracellularly phosphorylated by dCK, leading to the production of the metabolite dFdCDP. dFdCDP exhibits the cytotoxic effect by inactivating ribonucleotide reductase larger subunit 1 (RRM1), which is a rate limiting enzyme for de novo DNA synthesis. To date, RRM1 expression is believed to determine sensitivity to Gem in pancreatic and non-small cell lung cancer. In the present study, we found that an anti-allergic drug, tranilast strongly enhanced the sensitivity of pancreatic cancer cell line KP4 to Gem. In growth inhibition assay, 100 microM of tranilast plus 1 microM of Gem more strongly suppressed the growth of KP4 at 12.7-fold in IC50 than single Gem treatment, while this compound no longer affected the sensitivity to other drugs such as 5-fluorouracil, irinotecan or paclitaxel. FACS and TUNEL analysis demonstrated the increased apoptotic population in KP4 cells under tranilast plus Gem, compared with single Gem treatment. In Western blot analysis, tranilast treatment decreased RRM1 expression at protein level with dose-dependency in KP4 cells. Proteasome inhibitor MG132 disturbed the reduction of RRM1 expression in tranilast treated KP4 cells, indicating protein degradation by the activated proteasome. Transfection using siRNA against RRM1 increased the sensitivity of KP4 to Gem, suggesting that RRM1 suppression is an important step in increasing Gem efficacy. Finally, we demonstrated that tranilast reduced RRM1 protein and increased Gem efficacy in 4 other pancreatic cell lines. In a future, a novel chemotherapeutic strategy by Gem along with tranilast might improve Gem efficacy against pancreatic cancer. less...

Telomelysin (OBP-301) is a telomerase-specific replication-component adenovirus. Telomelysin has a human telomerase reverse transcriptase (hTERT) promoter element which efficiently kills human cancer cells, but not normal cells. The present study investigated the correlation between the antitumor effect of telomelysin and mRNA expression of hTERT and coxsackievirus and adenovirus receptor (CAR) in head and neck squamous cell carcinoma (HNSCC) in vitro and whether telomelysin enhances the antitumor effect of paclitaxel or cisplatin, in vivo using a HNSCC xenograft model. We also determined the optimal order for combining telomelysin treatment and chemotherapy as concurrent treatment, telomelysin treatment first and chemotherapy later, chemotherapy first and telomelysin treatment later for achieving the best anticancer effect. The mRNA expression of hTERT and CAR genes was examined by quantitative RT-PCR in 17 HNSCC cell lines. There was no significant correlation between the growth inhibition of telomelysin (ID50 for day 3, 5 and 7) in vitro and mRNA expression levels of hTERT and CAR. Regarding the correlation between CAR expression and telomelysin ID50 for day 3, all cell lines that showed a relative amount of CAR/beta-actin mRNA >0.4 had a low telomelysin ID50. This may indicate that CAR expression contributes to the efficacy of adenovirus infection and the antitumor activity of telomelysin in early stages of treatment. In our in vivo study, combining telomelysin and paclitaxel had an additive effect regardless of treatment order. On the other hand, combining telomelysin and cisplatin had additive effect only when cisplatin treatment preceded telomelysin treatment. These results suggest that paclitaxel is considered innocuous for replication of telomelysin, however cisplatin may influence replication of telomelysin. less...

Extramammary Paget's disease (EMPD) is a rare intraepithelial neoplasm occurring less frequently in men and even more rarely in the axilla. A 59-year-old man with severe Parkinson's disease presented with axillary EMPD. The neurological comorbidity made treatment of the EMPD problematical and prompted us to propose locoregional intra-arterial chemotherapy in single short sessions. Two innovative chemotherapeutic macrocomplexes were used: doxorubicin incorporated in large liposomes and the taxane paclitaxel incorporated in albumin nanoparticles. A therapeutic response was seen right from the first treatment and was macroscopically close to complete after four cycles. Five months after the end of treatment the patient had minimal visible disease and had enjoyed a distinct improvement in quality of life, with no noteworthy complications related to the intra-arterial chemotherapy with percutaneous transfemoral catheterization. less...

Platinum-based doublet chemotherapy remains the cornerstone of therapy in the first-line setting in advanced non-small-cell lung cancer (NSCLC) for patients with good performance status. However, this paradigm has recently been challenged by the results of a study that showed a survival benefit with the addition of bevacizumab to carboplatin and paclitaxel in bevacizumab-eligible patients and by the superior efficacy of gefitinib and erlotinib compared to chemotherapy in epidermal growth factor receptor (EGFR) gene mutation-positive tumors (mainly adenocarcinomas). In addition, histology has been recently recognized as a potential predictive factor in advanced NSCLC patients treated with chemotherapy. Prospective data from a preplanned subgroup analysis of a phase III study and retrospective reviews consistently reported a significant interaction between treatment by histology and response/survival in nonsquamous NSCLCs treated with pemetrexed, compared to squamous cell carcinoma (SCC). Thymidylate synthase, the main target of pemetrexed, was found to be differentially expressed among the histotypes of lung cancer, being lower in adenocarcinoma and higher in SCC and small-cell lung cancer. Thus, the availability of adequate amounts of tissue from biopsies to allow accurate pathologic subclassifications at diagnosis will be critical to help the oncologist select the most appropriate chemotherapy regimen as we move toward an individualized molecularly based approach. less...

PURPOSE: Gastric cancer is one of the leading cancerous diseases worldwide. It is diagnosed often at the advanced stage for which chemotherapy is the main treatment option. The prognosis remains poor for metastatic, especially the diffuse type, gastric cancers. We investigated the efficacy of intravenously administered paclitaxel treating metastases of locally disseminated gastric tumors of diffuse type. METHODS: Transfection of green fluorescent proteins (GFP)-expressing plasmid into human gastric cancer MKN45 cells of diffuse type was performed, and MKN45-GFP cells constitutively expressing GFP were isolated. The MKN45-GFP cells were orthotopically inoculated into the mouse peritoneal cavity, and tumor growth and organ metastases were monitored. Liver metastases were harvested, re-inoculated, monitored for liver metastases again, and harvested for further inoculation. This in vivo selection procedure was repeated to isolate a subline with high metastatic abilities demonstrated by in vitro invasion abilities using Transwell((R)) system. By visualizing the GFP-expressing tumors, the effects of intravenously administered paclitaxel against the growing peritoneally disseminated and metastasized tumors in nude mice without laparotomy were measured. RESULTS: An in vivo selected gastric cancer cell line MKN45-GFP-ip4 with high metastatic ability was established. Its invasion ability was inhibited by paclitaxel treatments in vitro. The growths of metastatic and intraperitoneally disseminated MKN45-GFP-ip4 tumors were significantly suppressed by intravenous paclitaxel treatments in nude mice. CONCLUSIONS: We found that intravenous paclitaxel is active against the metastases of human gastric cancer of peritoneal diffuse type, which warrants further investigations on optimizing the perioperative regimens with intravenous paclitaxel therapy for gastric cancer in patients. less...

BACKGROUND: Although triweekly administration of paclitaxel is approved for gastric cancer in Japan, currently, the drug is often delivered with a weekly schedule because of the equivalent efficacy and lesser toxicity of this dosing schedule as compared with the triweekly administration schedule. Weekly administration of paclitaxel as second-line or first-line chemotherapy for gastric cancer has been reported to yield a response rate of about 20%. Because there has been no report of the efficacy of weekly paclitaxel in the third-line setting, this retrospective study investigated the efficacy and toxicities of weekly paclitaxel used in the third-line setting for the treatment of gastric cancer refractory to all three key drugs, fluorouracil, irinotecan, and cisplatin, used in clinical practice. METHODS: In 85 patients with advanced or recurrent histologically confirmed gastric adenocarcinoma who had failed to respond to prior chemotherapy regimens containing fluorouracil, irinotecan, and cisplatin, paclitaxel (80 mg/m(2)) was administered weekly, three times, for 3 weeks out of 4. RESULTS: The median number of courses was 3 (range, 1-38). The overall response rate was 23.2% (19/82) in the patients with measurable lesions, and ascites disappeared in 15 of 48 patients (31.3%). Progression-free survival was 105 days and the median survival time was 201 days from the initiation of paclitaxel administration. Grade 3 or 4 leukopenia, neutropenia, anemia, and thrombocytopenia were observed in 25 (29%), 25 (29%), 37 (44%), and 3 (4%) patients. Other, nonhematological, toxicities were nausea, vomiting, anorexia, sensory neuropathy, fatigue, and febrile neutropenia. CONCLUSION: Weekly paclitaxel administration shows activity against advanced gastric cancer also in the third-line setting. less...

Takayasu's arteritis can involve the ostia of coronary arteries. We report a patient with Takayasu's arteritis involving the ostia of three large coronary arteries who was successfully treated by percutaneous coronary intervention (PCI) with a drug-eluting stent (DES) and had a good clinical outcome after 12 months. A 37-year-old male with unstable angina was admitted to our cardiovascular center. The patient had Takayasu's arteritis and an aortic valve replacement with a metallic valve due to severe aortic regurgitation 7 years previously. Coronary angiography (CAG) showed a 95% discrete eccentric luminal narrowing at the ostia of the large left anterior descending (LAD) and left circumflex (LCX) arteries, and a 99% discrete eccentric luminal narrowing at the ostium of the large right coronary artery (RCA). The patient was treated with prednisolone for 14 days. Two large paclitaxel-eluting stents (PES) were then implanted in the distal left main coronary artery using the kissing stent technique. After 6 months, a CAG did not reveal restenosis or recurrent coronary artery disease. Thus, PCI with a DES for patients with significant coronary involvement secondary to Takayasu's arteritis is an effective and an alternative treatment when coronary bypass grafting is not option. less...

We focus on unique roles of miR-200c in breast, ovarian, and endometrial cancers. Members of the miR-200 family target ZEB1, a transcription factor which represses E-cadherin and other genes involved in polarity. We demonstrate that the double negative feedback loop between miR-200c and ZEB1 is functional in some, but not all cell lines. Restoration of miR-200c to aggressive cancer cells causes a decrease in migration and invasion. These effects are independent of E-cadherin status. Additionally, we observe that restoration of miR-200c to ovarian cancer cells causes a decrease in adhesion to laminin. We have previously reported that reintroduction of miR-200c to aggressive cells that lack miR-200c expression restores sensitivity to paclitaxel. We now prove that this ability is a result of direct targeting of class III beta-tubulin (TUBB3). Introduction of a TUBB3 expression construct lacking the miR-200c target site into cells transfected with miR-200c mimic results in no change in sensitivity to paclitaxel. Lastly, we observe a decrease in proliferation in cells transfected with miR-200c mimic, and cells where ZEB1 is knocked down stably, demonstrating that the ability of miR-200c to enhance sensitivity to paclitaxel is not due to an increased proliferation rate. less...

BACKGROUND:: Little information is available regarding the effects of new adjuvant treatment regimens on menstrual functioning in premenopausal women with early breast cancer. METHODS:: The authors conducted a retrospective review of data from premenopausal women who received treatment for early breast cancer to evaluate the rates of amenorrhea in follow-up. The women who were included received treatment with either doxorubicin and cyclophosphamide (AC) or combined AC and paclitaxel (T) (AC-T) given either every 3 weeks, or as a dose-dense (DD) regimen, or as AC followed by weekly T with trastuzumab or followed by trastuzumab (AC-T+trastuzumab). A multivariate logistic regression analysis was conducted to evaluate amenorrhea during follow-up. RESULTS:: Of 431 patients who were eligible for analysis, the average age at diagnosis was 13 years (range, 25-55 years), 61% of women received AC only, and 39% received AC-T. Of the 39% who received AC-T, 49% of women received DD therapy, 14% received AC-T+trastuzumab, and 71% of all patients received tamoxifen (TAM). The median follow-up was 33 months (range, 6-114 months). After adjusting for age, weight, gravidity, parity, age at menarche, smoking, alcohol use, TAM use, type and regimen of chemotherapy, and use of trastuzumab, the likelihood of remaining amenorrheic was not statistically different in patients who received AC-T versus AC (odds ratio [OR], 1.59; 95% confidence interval [CI], 0.8-3.2), DD treatment versus treatment every 3 weeks (OR, 0.56; 95% CI, 0.25-1.3), or AC-T + trastuzumab (OR, 0.6; 95% CI, 0.22-1.61). Amenorrhea was associated significantly with TAM use and age at diagnosis. CONCLUSIONS:: Recent advances in the adjuvant treatment of early breast cancer do not appear to have increased the risk of amenorrhea in premenopausal women. Cancer 2010. (c) 2010 American Cancer Society. less...

BACKGROUND:: This study was performed to compare efficacy and toxicity profiles of paclitaxel using 3-hour versus 96-hour infusion schedules. METHODS:: Patients with metastatic breast cancer (MBC) were randomly assigned to receive paclitaxel starting at a dose of 250 mg/m(2) intravenously (iv) over 3 hours every 21 days or paclitaxel starting at a dose of 140 mg/m(2) iv over 96 hours every 21 days. Stratification variables included number of prior chemotherapy regimens and previous response to anthracyclines. Response was assessed every 2 cycles using bidimensional measurements. Patients were allowed to cross over at disease progression or therapy intolerance. RESULTS:: A total of 214 patients received therapy (107 patients per arm). Response rates were similar: 23.4% in the 3-hour arm and 29.9% in the 96-hour arm (P = .28). The median duration of response (8.9 months vs 5.7 months; P = .75) and progression-free survival (5.0 months vs 3.8 months; P = .17) slightly favored the 96-hour arm. Overall survival was slightly longer in the 3-hour arm (14.2 months vs 12.7 months; P = .57). One patient who crossed over to the 96-hour arm (N = 18) developed a partial response; no response was noted with crossover to the 3-hour arm (N = 10). Myalgia/arthralgia and neuropathy were more frequent in the 3-hour arm, whereas mucositis, neutropenic fever/infection, and diarrhea were more common in the 96-hour arm. CONCLUSIONS:: Paclitaxel given by 3-hour or 96-hour infusion was active in MBC. The 96-hour paclitaxel regimen did not significantly improve response or time to disease progression, was more cumbersome to administer, and was associated with greater myelosuppression (but less neuropathy and myalgia) compared with the 3-hour schedule. Cancer 2010. (c) 2010 American Cancer Society. less...