Phase I/II Study of PHY906/Capecitabine in Advanced Hepatocellular Carcinoma
Medical Oncology, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010-3000, USA. Anticancer research
(Impact Factor: 1.83).
PHY906 is a Chinese medicine formula with claims for the treatment of severe gastrointestinal distress. PHY906 enhanced the therapeutic index of various chemotherapeutic agents in human hepatocellular carcinoma xenografts. Accordingly, here a phase I/II clinical study was conducted with the combination of capecitabine in patients with advanced, unresectable hepatocellular carcinoma. More than 60% of patients had either stable disease or better after two treatment cycles. Median overall survival was 9.2 months. Asian patients had a higher median overall survival (16.5 months) than non-Asian patients (6.2 months, p=0.03). Patients' quality of life did not deteriorate significantly during treatment. This finding supported further investigation of PHY906 as an adjuvant therapy of capecitabine in a larger hepatocellular cancer population.
Available from: PubMed Central
- "The clinical trials of PHY906 not only demonstrated reduced chemotherapy-induced gastrointestinal toxicity but also reported an overall stronger protective effect of global toxicity . Two open-labeled clinical studies of PHY906 with capecitabine were conducted in patients with unresectable HCC . The first study was a phase I/II study with 93% of patients being enrolled in the US, whereas the second study was a phase II study in Taiwan. "
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ABSTRACT: This paper is a systematic review of evidence-based studies of the effectiveness of Chinese herbal medicine (CHM) in the treatment of liver cancer. After a detailed analysis of the literature, five animal studies and four human clinical trials met the criteria for inclusion. Analysis revealed that results of the clinical trials, whilst encouraging, need to be interpreted with caution as problems with study designs may lead to apparent benefits being attributable to various forms of bias. However, as each of the CHM agents used in these studies appeared to be potentially beneficial, further well-designed and controlled randomized clinical trials are warranted. The second part of this review focused on the lessons learned from the relationships between Traditional Chinese Medicine (TCM) theory, TCM Syndrome Differentiation, and modern scientific understanding of mechanisms of action of CHM agents. The understanding of TCM Syndrome Differentiation may allow identification of different patterns of disharmony and may provide important guidance to the prescription of CHM. Furthermore, quality control using both biological and chemical fingerprinting of CHM is important to ensure batch-to-batch consistency to deliver sustained therapeutic benefit. Also, careful assessment of herb-drug interactions is paramount for safety and integrative use of western chemotherapeutic and CHM agents.
Available from: Weidong Lu
- "Therefore, botanical medicines are increasingly combined with chemical medicines in anticancer drug cocktails, especially in countries where botanical medicines are well-accepted [9,10]. Some studies have suggested that for cancer treatment, drug cocktails combining botanical and chemical medicines may exhibit enhanced efficacies with diminished side effects and complications [11-13]. "
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ABSTRACT: Botanical medicines are increasingly combined with chemotherapeutics as anticancer drug cocktails. This study aimed to assess the chemotherapeutic potential of an extract of Taxus cuspidata (TC) needles and twigs produced by artificial cuttage and its co-effects as a cocktail with 5-fluorouracil (5-FU).
Components of TC extract were identified by HPLC fingerprinting. Cytotoxicity analysis was performed by MTT assay or ATP assay. Apoptosis studies were analyzed by H & E, PI, TUNEL staining, as well as Annexin V/PI assay. Cell cycle analysis was performed by flow cytometry. 5-FU concentrations in rat plasma were determined by HPLC and the pharmacokinetic parameters were estimated using 3p87 software. Synergistic efficacy was subjected to median effect analysis with the mutually nonexclusive model using Calcusyn1 software. The significance of differences between values was estimated by using a one-way ANOVA.
TC extract reached inhibition rates of 70-90% in different human cancer cell lines (HL-60, BGC-823, KB, Bel-7402, and HeLa) but only 5-7% in normal mouse T/B lymphocytes, demonstrating the broad-spectrum anticancer activity and low toxicity to normal cells of TC extract in vitro. TC extract inhibited cancer cell growth by inducing apoptosis and G(2)/M cell cycle arrest. Most interestingly, TC extract and 5-FU, combined as a cocktail, synergistically inhibited the growth of cancer cells in vitro, with Combination Index values (CI) ranging from 0.90 to 0.26 at different effect levels from IC50 to IC90 in MCF-7 cells, CI ranging from 0.93 to 0.13 for IC40 to IC90 in PC-3M-1E8 cells, and CI < 1 in A549 cells. In addition, the cocktail had lower cytotoxicity in normal human cell (HEL) than 5-FU used alone. Furthermore, TC extract did not affect the pharmacokinetics of 5-FU in rats.
The combinational use of the TC extract with 5-FU displays strong cytotoxic synergy in cancer cells and low cytotoxicity in normal cells. These findings suggest that this cocktail may have a potential role in cancer treatment.
Available from: Zaoli Jiang
- "Tumors were measured 72 hours after treatment (Figure 1a) and then removed. As expected , PHY906 enhanced the anti-tumor activity of CPT-11 although alone it had no effect on tumor growth. These early effects resulted in better long term reduction of tumor growth compared to CPT-11 treatment alone up to the 14th day from the beginning of treatment . "
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ABSTRACT: Traditional Chinese Medicine (TCM) has been used for thousands of years to treat or prevent diseases, including cancer. Good manufacturing practices (GMP) and sophisticated product analysis (PhytomicsQC) to ensure consistency are now available allowing the assessment of its utility. Polychemical Medicines, like TCM, include chemicals with distinct tissue-dependent pharmacodynamic properties that result in tissue-specific bioactivity. Determining the mode of action of these mixtures was previously unsatisfactory; however, information rich RNA microarray technologies now allow for thorough mechanistic studies of the effects complex mixtures. PHY906 is a long used four herb TCM formula employed as an adjuvant to relieve the side effects associated with chemotherapy. Animal studies documented a decrease in global toxicity and an increase in therapeutic effectiveness of chemotherapy when combined with PHY906.
Using a systems biology approach, we studied tumor tissue to identify reasons for the enhancement of the antitumor effect of CPT-11 (CPT-11) by PHY906 in a well-characterized pre-clinical model; the administration of PHY906 and CPT-11 to female BDF-1 mice bearing subcutaneous Colon 38 tumors.
We observed that 1) individually PHY906 and CPT-11 induce distinct alterations in tumor, liver and spleen; 2) PHY906 alone predominantly induces repression of transcription and immune-suppression in tumors; 3) these effects are reverted in the presence of CPT-11, with prevalent induction of pro-apoptotic and pro-inflammatory pathways that may favor tumor rejection.
PHY906 together with CPT-11 triggers unique changes not activated by each one alone suggesting that the combination creates a unique tissue-specific response.
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