Chemopreventive effects of Xiang Sha Liu Jun Zi Tang on paclitaxel-induced leucopenia and neuropathy in animals.

Paclitaxel frequently induces peripheral neuropathy and myelosuppression during cancer treatment. According to the National Health Insurance Research Database of Taiwan, traditional Chinese medicine doctors widely use Xiang Sha Liu Jun Zi Tang (XSLJZT) to treat breast cancer patients who have received paclitaxel. We explored the combined therapeutic effects of XSLZJT with paclitaxel. XSLJZT did not exhibit significant cytotoxic effects on P388-D1 cells; however, the combination of XSLJZT (100 and 500 mg/kg) with paclitaxel prolonged the survival rate in P388-D1 tumor-bearing mice compared to paclitaxel-only. In addition, XSLJZT was found to enhance white blood cells (WBC) counts and promote leukocyte rebound in paclitaxel-induced leukopenia in mice. XSLJZT also reduced paclitaxel-induced mechanical pain and inhibited c-Fos protein expression in the L4-6 spinal cords of Wistar rats. Moreover, paclitaxel-induced shortening of the nerve fibers of dorsal root ganglion cells was ameliorated by pre-treatment with XSLJZT. Therefore, we suggest that XSLJZT could be used as an adjunct for cancer patients, as the formula could decrease paclitaxel-induced neuropathy and myelosuppression.

A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma.

LESSONS LEARNED: A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies. This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC. BACKGROUND: This study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical-grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV). METHODS: This study was an open-label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m2 capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1-4 and days 8-11 every 21-day cycle. The primary endpoint was 6-month survival rate, and secondary endpoints were progression-free survival, overall survival, disease control rate, and safety. RESULTS: Thirty-nine subjects completed the study with a 46.2% stable disease rate. The median progression-free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6-month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha-fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome. CONCLUSION: Our data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.

Effects of Dang-Gui-Bu-Xue-Tang, an herbal decoction, on iron uptake in iron-deficient anemia.

Dang-Gui-Bu-Xue-Tang (DBT), a combination of Angelicae Sinensis Radix and Astragali Radix, is a widely used herbal decoction in traditional Chinese medicine primarily to promote or invigorate the "blood". In this study, we explored this ancient formulation and provide evidence of its blood-toning properties. We used the improvement iron uptake as promote or invigorate the "blood" indicator. Ferritin formation of Caco-2 cells in vitro assay and diet-induced anemia (DIA) in rat model were used to prove its improvement iron uptake and ameliorating effects. Finally, the iron-DBT interactions were measured by iron-binding assay. We first demonstrated DBT increased uptake of ferrous iron through the biosynthesis of ferritin by Caco-2 cells and determined which complementary treatment would provide optimum results. Thereafter, effects of the treatment on improving the bioavailability of absorbed iron in the form of hemoglobin (Hb) were established using a DIA-animal model. The results showed that DBT slightly improved Hb levels compared with the baseline Hb and pretreatment with DBT for 2 hours prior to supplementation with ferrous sulfate provided the greatest gain in Hb levels in DIA rats. However, DBT and ferrous sulfate were co-treated with Caco-2 cell or DIA rats, the ferritin formation and Hb levels both were decreased. In iron-binding assay, the DBT extract influenced the free Fe(II) type in the FeSO4 solution. Therefore, we suggest that complementary treatment with DBT and iron supplementation can have a strong ameliorating effect on iron-deficiency anemia in clinical settings, but needs a 2-hour interval of DBT administration prior to ferrous sulfate treatment.

Novel feedback inhibition of surface antigen synthesis by mammalian target of rapamycin (mTOR) signal and its implication for hepatitis B virus tumorigenesis and therapy.

UNLABELLED: Ground glass hepatocytes (GGHs) harboring hepatitis B virus (HBV) pre-S mutants have been recognized as precursor lesions of hepatocellular carcinoma (HCC). Previously, we observed the activation of mammalian target of rapamycin (mTOR) in GGHs and HCCs, together with a decreased expression of HBV surface antigen (HBsAg) in HCC tissues. It is, therefore, hypothesized that the activation of mTOR during HBV tumorigenesis may potentially down-regulate HBsAg expression. In this study, we verified an inverse relationship between the expression of HBsAg and phosphorylated mTOR (p-mTOR) in 13 of 20 paired nontumorous liver and HCC tissues. In vitro, wild-type or mutant pre-S proteins could activate mTOR in the HuH-7 cell line. Interestingly, the up-regulated mTOR, in turn, suppressed HBsAg synthesis at the transcriptional level via the transcription factor, Yin Yang 1 (YY1), which bound to nucleotide 2812-2816 of the pre-S1 promoter. This inhibitory effect by the mTOR signal could be abolished by the knockdown of histone deacetylase 1 (HDAC1). Furthermore, YY1 was physically associated with HDAC1 in a manner dependent on mTOR activation. Collectively, pre-S protein-induced mTOR activation may recruit the YY1-HDAC1 complex to feedback suppress transcription from the pre-S1 promoter. CONCLUSION: The activation of mTOR signal in GGHs may feedback suppress HBsAg synthesis during HBV tumorigenesis and explain the observed decrease or absence of HBsAg in HCC tissues. Therapy using mTOR inhibitors for HCCs may potentially activate HBV replication in patients with chronic HBV infection.

Phase I-II trial of weekly gemcitabine plus high-dose 5-fluorouracil and leucovorin in advanced pancreatic cancer.

BACKGROUND: Pancreatic cancer is a dismal disease. Few drugs, including gemcitabine and 5-fluorouracil (5-FU), have notable antitumor effects against advanced pancreatic cancer. The purpose of the present study was to determine the maximum tolerated dose (MTD) of 5-FU and the efficacy and toxicity profile of weekly gemcitabine plus infusional 5-FU/leucovorin in advanced pancreatic cancer. METHODS: Patients with histo-/cytologically confirmed, advanced pancreatic cancer were eligible. Treatment consisted of a 30-min infusion of gemcitabine (800 mg/m2), followed by a 24-h infusion of 5-FU and leucovorin (300 mg/m2) at day 1, day 8 and day 15 every 28 days, and was termed the GemFL24 regimen. The dose of 5-FU was escalated from 1600, 2000, to 2600 mg/m2 in the phase I study, and fixed MTD for subsequent enrolled patients. RESULTS: Eighteen patients were enrolled in the phase I study, and 24 in phase II. The MTD of 5-FU was 2000 mg/m2, with major dose-limiting toxicities being febrile neutropenia and delayed recovery from neutropenia. The dose intensity of gemcitabine of the 35 patients with 5-FU dosage set at MTD was 593 mg/m2 per week. In the entire series of 42 patients, myelosuppression was the main toxicity, with grade 3 neutropenia in eight patients, and grade 3/4 thrombocytopenia in six. On an intention-to-treat analysis, the overall and clinical benefit response rates were 22% and 46%, respectively; with median progression-free and overall survival of 4.1 and 6.9 months, respectively. CONCLUSIONS: The GemFL24 regimen is a feasible and moderately active treatment with manageable toxicities for advanced pancreatic cancer, and could be a basis for further combination with other anticancer drugs.

Prognostic implications of the expression of erbB2, topoisomerase II alpha and thymidylate synthase in metastatic gastric cancer after fluorouracil-based therapy.

OBJECTIVE: This retrospective study aimed to ascertain the expression of erbB2 in relation to topoisomerase II alpha (T2 alpha) and thymidylate synthase (TS) markers in 30 consecutive metastatic gastric cancer patients with a specimen available for study. METHODS: All patients had been entered on consecutive chemotherapeutic clinical trials that were all 5-fluorouracil based. The specimens were evaluated by fluorescence in situ hybridization to ascertain erbB2 and T2 alpha gene amplification, and by immunohistochemical staining for T2 alpha and TS protein expression. RESULTS: erbB2 amplification was detected in 16.7% of specimens, with co-amplification of the T2 alpha gene in 40%, and 44% had undetectable TS protein expression. Kaplan-Meier survival curves showed significantly prolonged overall survival in patients with erbB2 and T2 alpha gene amplification, T2 alpha protein overexpression and absence of TS protein expression (P = 0.0011, P = 0.0048, P = 0.0061 and P = 0.0267, respectively, by log rank test). There was a positive correlation between erbB2 amplification and T2 alpha amplification, T2 alpha protein overexpression, and a trend towards absence of TS expression (P = 0.0001, P = 0.003 and P = 0.066 by Fisher's exact test). CONCLUSION: High dose fluorouracil/leucovorin-based chemotherapy may have the potential to reverse the adverse effects resulting from erbB2 gene amplification in gastric cancer.

A phase I study of weekly docetaxel, 24-hour infusion of high-dose fluorouracil/leucovorin and cisplatin in patients with advanced gastric cancer.

OBJECTIVES: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of both docetaxel and 5-fluorouracil (5-FU) when administered weekly in a regimen of docetaxel, 5-FU/leucovorin and cisplatin (DFLP) for 2 consecutive weeks every 3 weeks. PATIENTS AND METHODS: A total of 31 patients with chemo-naive, advanced adenocarcinoma of the stomach were enrolled in the study. Cisplatin and leucovorin dosages were fixed throughout the study at 30 and 300 mg/m2, respectively. 5-FU dosage was fixed at 1,600 mg/m2 while docetaxel was evaluated at weekly 1-hour infusion dosages of 30, 40 and 50 mg/m2 to determine the MTD. Cisplatin, 5-FU and leucovorin were administered together as a 24-hour continuous infusion following docetaxel. Weekly 5-FU dosages of 1,600, 2,000 and 2,400 mg/m2 were then evaluated after setting the docetaxel dosage at the MTD. RESULTS: A total of 95 chemotherapy cycles were administered, with a median of three cycles per patient. The MTD of docetaxel was defined at 40 mg/m2. At a docetaxel dosage of 50 mg/m2 per week, the dose-limiting events of grade 4 febrile neutropenia and grade 3 hypomagnesemia occurred. With fixation of docetaxel to 40 mg/m2, the DLT for 5-FU was found at 2,400 mg/m2 per week. This incurred grade 4 neutropenia such that the MTD of 5-FU was defined at 2,000 mg/m2. Grade 3/4 neutropenia occurred in 14 patients (45%), with 2 patients developing febrile neutropenia. Grade 2 and 3 hypomagnesemia and hypokalemia occurred in 9 (41%) and 4 (18%) patients, respectively, of the first 22 patients treated with a 24-hour infusion of cisplatin and 5-FU/leucovorin immediately following docetaxel. Following a change in the cisplatin administration schedule to a 3-hour infusion after 5-FU/leucovorin infusion, no such complications were observed in 9 subsequently treated patients. Grade 2 diarrhea was recorded in 11 patients (35%). Grade 2/3 asthenia occurred in 9 patients (30%), which resolved after correction of electrolyte disorders. Twenty-six patients were assessable for response analysis. There were 2 (7.8%) complete and 14 (53.8%) partial responses, with the overall response rate being 61.5% (95% confidence interval, 41.5-81.6%). Responses were observed at all dose levels. CONCLUSION: Two consecutive weeks of DFLP infusions every 3 weeks appear to be an active regimen with a tolerable toxicity profile in advanced gastric cancer. For further phase II studies, the recommended dose for this combination is 40 mg/m2 of docetaxel and 2,000 mg/m2 of 5-FU per week.