Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Paclitaxel (Taxol) is a promising anti-tumor agent with poor water solubility. It is effective for various cancers especially ovarian and breast cancer. Intravenous administration of a current formulation in a non-aqueous vehicle containing Cremophor EL may cause allergic reactions and precipitation on aqueous dilution. Moreover, the extensive clinical use of this drug is somewhat delayed due to the lack of appropriate delivery vehicles. Due to this there is a need for the development of alternate formulation of paclitaxel having good aqueous solubility and at the same time free of any side effects. Various approaches employed so far include cosolvents, emulsions, micelles, liposomes, microspheres nanoparticles, cyclodextrins, pastes, and implants etc. which are discussed in this paper.
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PMID:Paclitaxel and its formulations. 1187 53

Recombinant rIL-2 was reported to be able to decrease P-glycoprotein (P-gp) expression in cultured cells from human colon carcinoma. P-gp is considered an important factor in the control of Taxol efflux from tumor cells. Based on the premise that Taxol pharmacokinetic parameters could be modified as a result of diminished P-gp expression induced by recombinant interleukin (rIL)-2 and that this might elicit an interaction between the two drugs, we evaluated the pharmacokinetics of a novel strategy combining i.p. immunotherapy with rIL-2 and a cytotoxic agent, Taxol. Mice were allocated to two groups treated with rIL-2 (15 microg x 2/day from day 1 to 4) then Taxol (10 mg/kg i.p. day 5) or Taxol (10 mg/kg i.p.) alone (control group). The Taxol + rIL-2 combination provoked the development of ascites, presumably due to the presence of Cremophor EL in the Taxol preparation. Paclitaxel was measured in plasma and ascites by HPLC with UV detection. Paclitaxel pharmacokinetics were strongly modified by rIL-2 pretreatment. Compared to that observed in control mice, the apparent volume of distribution increased dramatically (Vd/F = 18.2 versus 4.1 l/kg) and the apparent plasma clearance decreased (Cl/F = 1.12 versus 1.66 l/h/kg). P-gp expression was determined in the liver, lung, intestine, brain and kidney in the two groups by immunodetection with the C219 anti-P-gp monoclonal antibody. A significant decrease in P-gp expression was observed in the intestine and in the brain in the rIL-2-pretreated mice as compared to controls. To study the functionality of P-gp, we compared digoxin (a model P-gp substrate) pharmacokinetics before and after pretreatment with rIL-2 (10 microg x 2/day from day 1 to 4), after a single 1 microg oral dose of digoxin used to quantify P-gp activity. Results showed a decrease in oral digoxin clearance after rIL-2 pretreatment indicating modified P-gp activity. We conclude that rIL-2 pretreatment is able to decrease P-gp activity and paclitaxel metabolism in vivo. This is the first study to demonstrate a decrease in P-gp activity and expression in organs such as the brain in vivo. A novel strategy combining immunotherapy with rIL-2 and a cytotoxic agent could potentially improve clinical results, particularly in brain cancer.
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PMID:Recombinant interleukin-2 treatment decreases P-glycoprotein activity and paclitaxel metabolism in mice. 1191 41

Different pH-sensitive, randomly- and terminally-alkylated N-isopropylacrylamide (NIPAM) copolymers were synthesized and used to prepare pH-responsive polymeric micelles (PM). These copolymers were modified from previously-studied copolymers by incorporating an additional hydrophilic monomer, N-vinyl-2-pyrrolidone (VP) to decrease uptake by the mononuclear phagocyte system (MPS) and improve localization in tumors. VP lowered the phase transition pH of the copolymers but did not affect the onset of micellization. The in vitro cytotoxicity of the copolymers was evaluated on EMT-6 mouse mammary tumor cells in comparison to Cremophor EL (CRM). The anticancer photosensitizer aluminum chloride phthalocyanine (AlClPc) was loaded into the PM with a standard dialysis procedure. Biodistribution and in vivo photodynamic activity were then evaluated in Balb/c mice bearing intradermal EMT-6 tumors. All NIPAM copolymers demonstrated substantially lower cell cytotoxicity than the control surfactant CRM. In vivo, similar AlClPc tumor uptake was observed for the PM and CRM formulations. However, the PM appeared to exhibit greater activity in vivo than CRM formulation at an AlClPc subtherapeutic dose. Therefore, NIPAM-based copolymers containing VP units represent promising alternatives for the formulation of poorly water-soluble phthalocyanines.
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PMID:Optimizing pH-responsive polymeric micelles for drug delivery in a cancer photodynamic therapy model. 1244 14

The feasibility of tumor sampling followed by ex vivo assessment of drug sensitivity, using the short-term fluorometric microculture cytotoxicty assay (FMCA), for selection of chemotherapy was investigated prospectively in patients with advanced cancer not amenable to standard treatment. Taxol (175 mg/m2 every 3 wk) was given to patients with tumor samples being low drug resistant (LDR) to Taxol ex vivo, to patients with no LDR drug, and if other drugs were unsuitable. The remaining patients received the most optimal drug(s) based on the FMCA results. Gastrointestinal cancer was dominating among the 61 eligible patients. Tumor sampling was safely performed in 75% by ultrasound-guided core biopsy. Eighty-two percent of the patients had Taxol. Five patients (8%) had a partial remission and 18 (30%) had stable disease. Tumor response was poorly predicted, probably because the Taxol excipient Cremophor EL is cytotoxic exclusively ex vivo. However, patients with tumor cells being LDR to at least one drug ex vivo lived significantly longer than those with no such drug.
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PMID:Selection of chemotherapy by ex vivo assessment of tumor sensitivity to cytotoxic drugs: results of a clinical trial. 1248 25

Paclitaxel is an alkaloid that inhibits endothelial cell proliferation, motility, and tube formation at nanomolar concentrations. Cationic liposome preparations have been shown to target blood vessels. We wished to explore the possibility that paclitaxel encapsulated in cationic liposomes carries paclitaxel to blood vessels and thereby provides an antiangiogenic effect. We used a humanized SCID mouse melanoma model, which allowed us to analyze tumor growth and tumor angiogenesis in an orthotopic tumor model. Here, human melanoma cells grow on human dermis and are in part nourished by human vessels. We show that paclitaxel encapsulated in liposomes prevents melanoma growth and invasiveness and improves survival of mice. Moreover, liposome-encapsulated paclitaxel reduces vessel density at the interface between the tumor and the human dermis and reduces endothelial cell mitosis to background levels. In contrast, equimolar concentrations of paclitaxel solubilized in Cremophor EL(R) had only insignificant effects on tumor growth and did not reduce the mitotic index of endothelium in vivo, although the antiproliferative effect of solubilized paclitaxel in Cremophor EL(R)in vitro was identical to that seen with liposome-coupled paclitaxel. In conclusion, we present a model of how to exploit cytotoxic effects of compounds to prevent tumor growth by using cationic liposomes for targeting an antiproliferative drug to blood vessels.
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PMID:Paclitaxel encapsulated in cationic liposomes diminishes tumor angiogenesis and melanoma growth in a "humanized" SCID mouse model. 1260 62

Primary malignant fibrous histiocytoma (MFH) of the heart is a rare and highly malignant soft tissue tumor, which is largely resistant to conventional chemotherapy and radiotherapy. Therefore, we analyzed growth inhibitory effects of different chemotherapeutic agents and mechanisms of drug resistance in the recently established cell line MFH-H derived from a human primary cardiac MFH. The growth inhibitory effects of etoposide, vincristine, and paclitaxel were tested using the MTT assay. The expression and function of multidrug resistance-related proteins, i.e. the P-glycoprotein, the multidrug resistance-associated protein (MRP) and the lung resistance-related protein (LRP) were determined by FACScan and functional assays of cellular drug efflux. The concentration required for a 50% inhibition of growth (IC50) was 0.001 microM for etoposide and 0.035 microM for vincristine. Paclitaxel dissolved in Cremophor EL/ethanol inhibited the cell growth of MFH-H cells more intensively (IC50: 0.27 microM) than paclitaxel dissolved in DMSO (IC50: 11.09 microM) suggesting that Cremophor EL is contributing to the inhibitory effects of paclitaxel. The response of MFH-H to etoposide, vincristine and paclitaxel/Taxol could not be predicted by the expression and function of P-glycoprotein, MRP and LRP. This study demonstrates that etoposide and to a lesser extent vincristine can effectively inhibit the growth of MFH-H cells, irrespective of the multidrug resistance phenotype. MFH-H cells are relatively insensitive to paclitaxel dissolved in DMSO, in contrast to paclitaxel dissolved in Cremophor EL/ethanol indicating that the diluent Cremophor contributes to the antiproliferative effects of the taxane paclitaxel.
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PMID:Chemotherapeutic potential of plant alkaloids and multidrug resistance mechanisms in malignant fibrous histiocytoma of the heart. 1476 15

Cationic liposomes have been shown to be internalized selectively by angiogenic tumor endothelial cells after intravenous injection. Therefore, encapsulation of cytotoxic substances in cationic liposomes is a new approach to target tumor vasculature. It was the aim of our study to quantify the effects of paclitaxel encapsulated in cationic liposomes (MBT-0206) on tumor microvasculature and growth in vivo. Experiments were performed in the dorsal skinfold chamber preparation of Syrian Golden hamsters bearing syngeneic A-Mel-3 melanomas. Tumors were treated with intravenous infusion of MBT-0206 (20 mM) resulting in an effective paclitaxel dose of 5 mg/kg body weight (b.w.). Control animals received conventional paclitaxel in Cremophor EL (Taxol(R); 5 mg/kg b.w.), unloaded cationic liposomes (20 mM) or the solvent 5% glucose, respectively. Using intravital microscopy, tumor growth and effects on intratumoral microvasculature were analyzed. Tumor growth was significantly retarded after treatment with MBT-0206 compared to the treatment with paclitaxel. Analysis of intratumoral microcirculation revealed a reduced functional vessel density in tumors after application of liposomal paclitaxel. At the end of the observation time, vessel diameters were significantly smaller in animals treated with paclitaxel encapsulated in cationic liposomes while red blood cell velocity was less affected. This resulted in a significantly reduced blood flow in vessel segments and a reduced microcirculatory perfusion index in these animals. Histochemical TUNEL stain was vessel-associated after treatment with liposomal paclitaxel in contrast to few apoptotic tumor cells in the control groups. Our data demonstrate that encapsulation of paclitaxel in cationic liposomes significantly increased the antitumoral efficacy of the drug. Remarkable microcirculatory changes indicate that encapsulation of paclitaxel in cationic liposomes resulted in a mechanistic switch from tumor cell toxicity to an antivascular therapy.
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PMID:Neovascular targeting chemotherapy: encapsulation of paclitaxel in cationic liposomes impairs functional tumor microvasculature. 1505 76

Repeated, local, nonviral IL12 (interleukin-12) gene delivery decreased tumor progression and increased immunogenicity. We combined our IL12 gene delivery with systemic paclitaxel chemotherapy as a treatment for paclitaxel (PCT)-resistant 4T1 subcutaneous mouse mammary carcinomas and PCT-sensitive, immunogenic/nonimmunogenic tumors. We mixed PCT with either a biodegradable polymeric solubilizer, HySolv, or Cremophor EL for bimonthly systemic treatments and injected water-soluble lipopolymer (WSLP)/p2CMVmIL-12 (plasmid encoding IL12 gene) complexes locally every week. We compared treated subcutaneous tumor volume and lung metastasis with controls. HySolv alone performed better compared to Cremophor EL in combination with WSLP/p2CMVmIL-12. We showed inhibition of 4T1 tumor growth and lung metastases in the combined WSLP/p2CMVmIL-12/HySolv group compared to the controls and the paclitaxel-only treated groups. In parallel experiments we also demonstrated additive responses for tumor growth and number of lung metastases within other PCT-sensitive mammary tumor models using this combination strategy. Our combination therapy provides evidence for the efficacy and feasibility of improved drug delivery systems. Local cytokine gene delivery can augment local and systemic chemotherapy without placing the host at risk for further systemic toxicity.
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PMID:Combination of local, nonviral IL12 gene therapy and systemic paclitaxel treatment in a metastatic breast cancer model. 1519 49

Chemotherapy remains the preferred choice of treatment for prostate cancer but modest drug response and significant toxicity by conventional methods of administration limit their efficacy. In our study, we determined the efficacy of paclitaxel (Tx)-loaded biodegradable nanoparticles (NPs) on tumor inhibition. We hypothesized that NPs following conjugation to transferrin (Tf) ligand (NPs-Tf) would enhance the therapeutic efficacy of the encapsulated drug. The antiproliferative activity of NPs was determined in human prostate cancer cell line (PC3) and their effect on tumor inhibition in a murine model of prostate cancer. NPs (approximately 220 nm in diameter, 5.4% w/w drug loading) under in vitro conditions exhibited sustained release of the encapsulated drug (60% release in 60 days). The IC50 (concentration of drug for 50% inhibition of cell growth) of the drug with Tf-conjugated NPs (Tx-NPs-Tf) was about 5-fold lower than that with unconjugated NPs (Tx-NPs) or drug in solution. Animals that received a single-dose intratumoral injection of Tx-NPs-Tf (Tx dose= 4 mg/kg) demonstrated complete tumor regression and greater survival rate than those that received either Tx-NPs or Tx-Cremophor EL formulation. In conclusion, sustained release NPs demonstrated greater antitumor activity following their conjugation to Tf ligand.
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PMID:Efficacy of transferrin-conjugated paclitaxel-loaded nanoparticles in a murine model of prostate cancer. 1535 49

Despite the advances in tumor therapy, patients with primary brain tumors and brain metastases have a very poor prognosis. Low responses to chemotherapy are mainly attributed to impermeability of the blood-brain barrier to cytotoxic agents. Paclitaxel has been shown to be active against gliomas and various brain metastases. However, its use in treatment of brain tumors is limited due to low blood-brain barrier permeability and serious side effects associated with administration of the paclitaxel solvent, Cremophor EL. Lack of paclitaxel brain uptake is thought to be associated with the p-glycoprotein (p-gp) efflux transporter. In this work, paclitaxel (PX) was entrapped in novel cetyl alcohol/polysorbate nanoparticles. Paclitaxel nanoparticles (PX NPs) were characterized by means of size, short-term stability, drug entrapment efficiency, and release profile. The PX NP cytotoxicity profile was monitored using two different cell lines, U-118 and HCT-15. Brain uptake of PX NPs was evaluated using an in situ rat brain perfusion model. The results suggest that entrapment of paclitaxel in nanoparticles significantly increases the drug brain uptake and its toxicity toward p-glycoprotein expressing tumor cells. It was hypothesized that PX NPs could mask paclitaxel characteristics and thus limit its binding to p-gp, which consequently would lead to higher brain and tumor cell uptake of the otherwise effluxed drug.
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PMID:Paclitaxel nanoparticles for the potential treatment of brain tumors. 1538 Jun 35


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