Elevated alpha1-acid glycoprotein in gastric cancer patients inhibits the anticancer effects of paclitaxel, effects restored by co-administration of erythromycin (original) (raw)
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Pharmacokinetic study of paclitaxel in malignant ascites from advanced gastric cancer patients
World Journal of …, 2006
To examine the paclitaxel concentrations in plasma and ascites after its intravenous administration in patients with ascites due to peritonitis carcinomatosa resulting from advanced gastric cancer. Figure 3 CT scanning of case 1 showing markedly decreased amount of ascites after 2 courses of the combined chemotherapy of 5-fl uorouracil and PTX. A1, A2: before chemotherapy; B1, B2: after chemotherapy.
Frontiers in Pharmacology
Paclitaxel (PTX) is a natural alkaloid isolated from the bark of a tree, Taxus brevifolia, and is currently used to treat a variety of tumors. Recently, it has been found that low-dose PTX is a promising treatment for some cancers, presenting few side effects. However, antitumor mechanisms of low-dose PTX (<1 nM) have rarely been illuminated. Here we report a new antitumor mechanism of low-dose PTX in colorectal carcinoma cells. We treated colorectal carcinoma HCT116 cells with PTX at 0.1 and 0.3 nM for 0, 1, 2, or 3 days, and found that low-dose PTX inhibits cell growth without altering cell morphology and cell cycle. There was a significant decrease of pH in culture media with 0.3 nM PTX for 3 days. Also, lactate production was significantly increased in a dose-and time-dependent manner. Furthermore, expression of glutaminolysis-related genes GLS, SLC7A11 and SLC1A5 were significantly decreased in the colorectal carcinoma cells treated with low-dose PTX. Meanwhile, protein expression levels of p53 and p21 increased significantly in colorectal carcinoma cells so treated. In summary, low-dose PTX down-regulated glutaminolysis-related genes and increased their lactate production, resulting in decreased pH of tumor microenvironments and inhibition of tumor cell growth. Up-regulation of p53 and p21 in colorectal carcinoma cells treated with low-dose PTX also contributed to inhibition of tumor cell growth.
Cancer Letters, 2008
Intraperitoneal (i.p.) administration of paclitaxel (PTX) is a hopeful therapeutic strategy for peritoneal malignancy. Intravenously (i.v.) injected nanoparticle anticancer drugs are known to be retained in the blood stream for a long time and favorably extravasated from vessels into the interstitium of tumor tissue. In this study, we evaluated the effect of i.p. injection of PTX (PTX-30W), which was prepared by solubulization with water-soluble amphiphilic polymer composed of PMB-30W, a co-polymer of 2-methacryloxyethyl phosphorylcholineand n-butyl methacrylate, for peritoneal dissemination of gastric cancer. In a peritoneal metastasis model with transfer of MKN45P in nude mice, the effct of i.p. administration of PTX-30W was compared with conventional PTX dissolved in Cremophor EL (PTX-Cre). The drug accumulation in peritoneal nodules was evaluated with intratumor PTX concentration and fluorescence microscopic observation. PTX-30W reduced the number of metastatic nodules and tumor volume significantly more than did conventional PTX dissolved in Cremophor EL (PTX-Cre), and prolonged the survival time (P < 0.05). PTX concentration in disseminated tumors measured by HPLC was higher in the PTX-30W than in the PTX-Cre group up to 24 h after i.p. injection. Oregon greenconjugated PTX-30W, i.p. administered, preferentially accumulated in relatively hypovascular areas in the peripheral part of disseminated nodules, which was significantly greater than the accumulation of PTX-Cre. I.p. administration of PTX-30W may be a promising strategy for peritoneal dissemination, due to its superior characteristics to accumulate in peritoneal lesions
PTX Treatment of Colon Cancer: Mode of Action Based on Tumor Marker and Cytokine Kinetics
Anticancer Research, 2022
Background/Aim: Cancer progression is associated with significant cachexia-induced weight loss and stomatitis. Pentoxifylline (PTX) is a drug shown to have beneficial antiinflammatory effects in cancer patients, mainly through anti-TNFα mechanisms. This study determined the PTX effects and mode of action on weight-loss, stomatitis, and survival in colon cancer patients treated with chemotherapy, examining the kinetics of tumor markers and cytokine levels. Patients and Methods: Forty patients with metastatic colon cancer receiving chemotherapy, were randomized in this study. Seventeen patients were assigned to the treatment group-8 received a full PTX dose (400 mg TID) and 9 a reduced dose (200 mg TID). Results were compared to 23 untreated, control patients. Blood analysis of tumor markers (CEA and TPS), inflammatory cytokines (IL-1β, IL-6, IL-8, TNFα, TNF-R), CRP and sIL-2R, were performed. Additionally, clinical parameters were assessed. Results: Patients treated with PTX (full/reduced doses), gained significant weight, and experienced a reduction in stomatitis, resulting in multiple beneficial effects, including improved life quality. Significant reductions in CRP, sIL-2R, and inflammatory cytokine levels, correlated to increases in weight and a reduction in stomatitis. A similar pattern was observed in tumor marker levels, where decreasing levels were correlated with weight gain and reduction in inflammatory cytokine levels. Conclusion: Colon cancer patients receiving PTX with chemotherapy, experienced weight gain and reduced stomatitis occurrence. Beneficial PTX effects were correlated to significant decreases in patient inflammatory cytokines and tumor marker levels, probably due to PTX mode of action. Cancer progression, especially in end-stage patients, is associated with cachexia-a complex metabolic syndrome characterized by a loss of muscle mass/ fat mass and reduced well-being and survival (1). While there are various treatment options for cancer cachexia, including cyproheptadine, hydrazine, and metoclopramide, none of these drugs has been found to be sufficiently effective. Pentoxifylline (PTX), anti-TNFα monoclonal antibody and selective COX-2 inhibitors, have been suggested as promising treatment options (1, 2). PTX, a xanthine derivative, has been shown to have a significant effect on the cellular mediators of inflammation and tissue injury. Cancer cachexia has been linked to elevated levels of inflammatory cytokines, mainly tumor necrosis factor-alpha (TNFα), but also IL-6 and IL-8 (3). PTX has been shown to inhibit TNFα production and therefore reduce cachexia parameters. In a randomized double-blind controlled clinical trial involving hemodialysis patients, PTX decreased TNFα, IL-6 and CRP serum levels (4). In another study, PTX was shown to decrease TLR-mediated TNFα mRNA while increasing IL-10 mRNA, an anti-inflammatory cytokine (3-5). PTX not only possesses direct anticancer activity by inducing both apoptosis and the sensitization of multi-drug resistant cells (6, 7) but also increases cancer cell susceptibility to radiation therapy, while reducing long-term radiation side effects. It has been reported that the combination of PTX and vitamin E (7) reduces the severity of radiation-induced oral mucositis and dysphagia in head and neck cancer patients (8, 9). In addition, it has been suggested that PTX reduces chemotherapy-induced stomatitis and osteonecrosis, through inflammatory cytokine reduction (8-12). We have previously reported on the significance of using tumor and cytokine markers in the clinical work-up of oncological patients, including the importance of tumor markers (TMs) in the early detection of recurrence and metastasis, such as in breast (13-16), colon (14), and head 5487
Low-dose paclitaxel modulates tumour fibrosis in gastric cancer
International journal of oncology, 2013
Various treatments have been used for peritoneal dissemination, which is the most common mode of metastasis in gastric cancer, but sufficiently good clinical outcomes have not yet been obtained because of the presence of rich fibrous components and acquired drug resistance. Epithelial-mesenchymal transition (EMT) is one of the major causes of tissue fibrosis and transforming growth factor-β (TGF-β) has a pivotal function in the progression of EMT. Smad proteins play an important role in the TGF-β signalling pathway. The TGF-β/Smad signalling pathway can be modulated by stabilising microtubules with paclitaxel (PTX). Here, we investigated whether paclitaxel can modulate TGF-β/Smad signalling in human peritoneal methothelial cells (HPMCs). To determine the cytostatic concentrations of antineoplastic agents in HPMCs, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was performed using PTX, 5-fluorouracil and cisplatin. The minimum concentration that caused si...
Proceedings of the National Academy of Sciences, 1997
In mice, the mdr1a and mdr1b genes encode drug-transporting proteins that can cause multidrug resistance in tumor cells by lowering intracellular drug levels. These P-glycoproteins are also found in various normal tissues such as the intestine. Because mdr1b P-glycoprotein is not detectable in the intestine, mice with a homozygously disrupted mdr1a gene [mdr1a(؊͞؊) mice] do not contain functional P-glycoprotein in this organ. We have used these mdr1a(؊͞؊) mice to study the effect of gut P-glycoprotein on the pharmacokinetics of paclitaxel. The area under the plasma concentration-time curves was 2-and 6-fold higher in mdr1a(؊͞؊) mice than in wild-type (wt) mice after i.v. and oral drug administration, respectively. Consequently, the oral bioavailability in mice receiving 10 mg paclitaxel per kg body weight increased from only 11% in wt mice to 35% in mdr1a(؊͞؊) mice. The cumulative fecal excretion (0-96 hr) was markedly reduced from 40% (after i.v. administration) and 87% (after oral administration) of the administered dose in wt mice to below 3% in mdr1a(؊͞؊) mice. Biliary excretion was not significantly different in wt and mdr1a(؊͞؊) mice. Interestingly, after i.v. drug administration of paclitaxel (10 mg͞kg) to mice with a cannulated gall bladder, 11% of the dose was recovered within 90 min in the intestinal contents of wt mice vs. <3% in mdr1a(؊͞؊) mice. We conclude that Pglycoprotein limits the oral uptake of paclitaxel and mediates direct excretion of the drug from the systemic circulation into the intestinal lumen. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked ''advertisement'' in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Japanese Journal of Clinical Oncology, 2011
Owing to its peculiar pharmacological characteristics, paclitaxel attains substantial intra-peritoneal concentration for a prolonged period when delivered intra-peritoneally, and is active against peritoneal metastasis of ovarian cancer. It is also considered promising against disseminated gastric cancer. However, the fact that the intra-peritoneal paclitaxel has not been approved in Japan has rendered its evaluation by a formal clinical trial impossible. The authors designed a randomized phase II trial using the Kodo Iryo Hyoka system, a new system to legally test an yet unapproved mode of treatment. It is hoped that this trial will result in a breakthrough in the treatment of peritoneal carcinomatosis from gastric cancer.