Effects of α-adrenoceptor antagonists on ABCG2/BCRP-mediated resistance and transport.

Acquired resistance of cancer cells to various chemotherapeutic agents is known as multidrug resistance, and remains a critical factor in the success of cancer treatment. It is necessary to develop the inhibitors for multidrug resistance. The aim of this study was to examine the effects of eight α-adrenoceptor antagonists on ABCG2/BCRP-mediated resistance and transport.

Differential effects of calcium antagonists on ABCG2/BCRP-mediated drug resistance and transport in SN-38-resistant HeLa cells.

The effects of 9 calcium antagonists on ABCG2/BCRP-mediated resistance and transport were examined in HeLa and SN-38-resistant HeLa (HeLa/SN100) cells, overexpressing ABCG2/BCRP. Sensitivity to mitoxantrone, an ABCG2/BCRP substrate, in HeLa/SN100 cells was significantly reversed by the coexistence of the calcium antagonists, except for diltiazem and verapamil. The accelerated transport activity of Hoechst33342, an ABCG2/BCRP substrate, in HeLa/SN100 cells was significantly decreased by the presence of the calcium antagonists, except for diltiazem, nifedipine or verapamil, returning to the level of HeLa cells.

Treatment schedule-dependent effect of 5-fluorouracil and platinum derivatives in colorectal cancer cells.

Aim: Combination chemotherapy for treating cancer often is superior in clinical efficacy to monotherapy. The aim of this study was to investigate the schedule-dependent effect of 5-fluorouracil (5-FU) and platinum derivatives (cisplatin or oxaliplatin) in colorectal cancer (CRC) cell lines, and to explore factors affecting it.

Methods: Two human CRC-derived cell lines, DLD-1 and HCT116, were used.

Characterization, in vitro cytotoxicity and cellular accumulation of paclitaxel-loaded lipid nano-emulsions.

Lipid nano-emulsions (LNEs) having a mean droplet size of approximately 50 nm were investigated as drug carriers for paclitaxel (TXL) to achieve its satisfactory loadings and to develop a pharmaceutically acceptable alternative to the current formulation, Taxol. TXL was incorporated into the LNEs at 2.0 mg/ml without changes in particle size or drug precipitation.

Effects of alpha-adrenoceptor antagonist doxazosin on MDR1-mediated multidrug resistance and transcellular transport.

The purpose of this study is to examine the effects of doxazosin, an alpha-adrenoceptor antagonist, on P-glycoprotein/MDR1-mediated multidrug resistance (MDR) and the transport of anticancer drugs. The effects of doxazosin, prazosin, and terazosin on MDR1-mediated MDR were assessed in human cervical carcinoma HeLa cells and the MDR1-overexpressing derivative Hvrl00-6, established by stepwise increases of the vinblastine concentration in the culture medium. The effects of doxazosin on the transcellular transport and intracellular accumulation of [3H]vinblastine, [3H]daunorubicin, and [3H]digoxin, all MDR1 substrates, were evaluated using LLC-GA5-COL150 cell monolayers, established by transfection of human MDR1 cDNA into porcine kidney epithelial LLC-PK1 cells.

Effects of nonsteroidal anti-inflammatory drugs on the expression and function of P-glycoprotein/MDR1 in Caco-2 cells.

The aim of this study was to examine the effects of 16 kinds of nonsteroidal anti-inflammatory drugs (NSAIDs) on P-glycoprotein/MDR1 in Caco-2 cells as an intestinal epithelial cell model. Cells were treated with NSAIDs for 24 hours, and then, the expression of MDR1 mRNA was evaluated by reverse-transcriptase polymerase chain reaction. The function of MDR1 in cells pretreated with NSAIDs for 48 hours was evaluated by measuring the cellular amount of rhodamine123, which is a substrate of MDR1.

Molecular changes to HeLa cells on continuous exposure to SN-38, an active metabolite of irinotecan hydrochloride.

It is important to clarify the molecular characteristics of tumor cells showing multidrug resistance (MDR) and to identify the novel targets or biomarkers for chemotherapy. The aim of this study is to establish resistant HeLa sublines through exposure to SN-38, an active metabolite of irinotecan hydrochloride, and to investigate their molecular changes. HeLa cells were exposed to SN-38 at 1, 10, or 100 nM, and resistant clones were isolated and named HeLa/SN1, HeLa/SN10, and HeLa/SN100, respectively.

[Comparative survey on current status and the differences of treatment using modified FOLFOX6 regimen in patients with colorectal cancer in two general hospitals].

We surveyed the current status and the differences of treatment of colorectal cancer using modified FOLFOX6 regimen, in two general hospitals, Sakai City Hospital (A hospital) and Takarazuka Municipal Hospital (B hospital) between April 2005 and November 2006, retrospectively. The numbers of examined patients were 33 and 17 in A and B hospitals, respectively. The grade of myelosuppression and peripheral neuropathy were evaluated according to Common Terminology Criteria for Adverse Events v 3.

Comparative analysis of cell injury after exposure to antitumor platinum derivatives in kidney tubular epithelial cells.

Background: Platinum derivatives differ in effectiveness and safety. The purpose of this study is to compare differences in the mechanism of nephrotoxicity among these derivatives.

Methods: LLC-PK(1) cells were used as a model of tubular epithelial cells.

[Equalization of spread of breast cancer chemotherapy regimen at general hospitals--with EC and FEC regimens].

We investigated the differences in safety and management of adverse events of chemotherapy among three hospitals, Sakai Municipal Hospital, Takarazuka Municipal Hospital and National Hospital Organization Osaka-minami Medical Center. The main purpose of this study was to equalize the spread of breast cancer chemotherapy regimen. The following three regimens were evaluated; epirubicin (75 mg/m(2)) /cyclophosphamide (500 mg/m(2)) (EC75), epirubicin (75 mg/m(2)) /cyclophosphamide (500 mg/m(2)) /5-fluorouracil (500 mg/m(2)) (FEC75) and epirubicin (100 mg/m(2)) / cyclophosphamide (500 mg/m(2)) /5-fluorouracil (500 mg/m(2)) (FEC100).

Effects of turmeric extract on the pharmacokinetics of nifedipine after a single oral administration in healthy volunteers.

The effects of turmeric extracts on the pharmacokinetics of nifedipine were examined in 10 healthy volunteers. An open-label and randomized crossover study was performed at 2-week intervals. In the control experiment, after a 10 h overnight fast, 10 mg of nifedipine (Adalat® capsule) was administered orally and blood was collected at 0, 0.

Effects of Agaricus blazei Murill extract on sensitivity to chemotherapeutic agents in HeLa cells and its resistant sublines.

Agaricus blazei Murill (ABM; Japanese name: Kawahiratake or Agarikusutake) extract is a widely used dietary supplement. However, limited information is available on the effects of the extract on the effectiveness of the chemotherapeutic agents. In this study, we examined the effects of ABM extract (Kyowa Wellness Co.

Oxaliplatin-induced hypersensitivity reaction displaying marked elevation of immunoglobulin E.

A 74-year-old female has been diagnosed with stage IIIB rectal cancer in 2003. Following anterior resection, she received adjuvant chemotherapy with three different regimens. In August 2005, she was started on a modified FOLFOX6 regimen, and the sixth cycle of chemotherapy induced a severe hypersensitivity reaction (HSR).

Factors affecting sensitivity to antitumor platinum derivatives of human colorectal tumor cell lines.

Purpose: The aim of this study is to examine the factors affecting sensitivity to cisplatin, carboplatin, and oxaliplatin in human colorectal tumor cell lines.

Methods: Caco-2, DLD-1, HCT-15, HCT116, LS180, SW620, and WiDr cells were used. Their growth inhibition by platinum derivatives was evaluated with a WST-1 assay utilizing succinate dehydrogenase activity.

Effects of Sairei-to on the pharmacokinetics of nifedipine in rats.

Sairei-to is a traditional herbal medicine used to complement, and as an alternative to, Western drugs. The aim of this study was to evaluate the pharmacokinetic interactions between Sairei-to and nifedipine (NFP), a substrate for CYP3A, in rats. NFP-oxidizing activity and the pharmacokinetics of NFP were examined after a single or 1-week of administration of Sairei-to (EK-114).

Effects of propolis extract on sensitivity to chemotherapeutic agents in HeLa and resistant sublines.

The effects of a propolis extract obtained by supercritical fluid extraction on sensitivity to chemotherapeutic agents were examined in HeLa cells and resistant sublines thereof. In addition, the actions of propolis and caffeic acid phenethyl ester (CAPE), a constituent of propolis, on the multidrug efflux transporter P-glycoprotein/MDR1, were evaluated in paclitaxel-resistant HeLa/TXL cells (MDR1-overexpressing cells). In HeLa cells, the sensitivity to paclitaxel and doxorubicin, substrates of MDR1, was unchanged in the presence of propolis.

Molecular changes to HeLa cells on continuous exposure to cisplatin or paclitaxel.

Objective: To achieve a reversal of multidrug resistance (MDR) in cancer chemotherapy, it is crucial to clarify the characteristics of MDR cells generated by various types of chemotherapeutic agents and to find novel targets.

Methods: Cisplatin- and paclitaxel-resistant HeLa sublines (HeLa/CDDP and HeLa/TXL, respectively) were established by continuous exposure and their cellular changes were examined based on growth inhibition assays, the transport activity of P-glycoprotein/MDR1, and a RT-PCR analysis of MDR-related factors.

Results: HeLa/CDDP cells showed cross-resistance to platinum derivatives, whereas HeLa/TXL cells were resistant to a variety of MDR1 substrates.

Effects of 19 herbal extracts on the sensitivity to paclitaxel or 5-fluorouracil in HeLa cells.

The popularity of traditional herbal medicine (THM) being used as complementary medicines or alternative medicines is increasing. On the other hand, the development of multidrug resistance (MDR) remains a major hurdle to successful cancer chemotherapy. Some THMs capable of reversing MDR may contribute to the improvement of clinical outcomes in cancer chemotherapy.

Studies on interactions between functional foods or dietary supplements and medicines. III. Effects of ginkgo biloba leaf extract on the pharmacokinetics of nifedipine in rats.

The effects of Ginkgo biloba leaf extract (GBE), one of the most widely used herbal dietary supplements in Japan and the United States, on the pharmacokinetics of nifedipine (NFP), a typical probe of P450 (CYP) 3A, but not a substrate of the multidrug transporter P-glycoprotein (P-gp), were studied using rats. Simultaneous oral treatment with GBE (20 mg/kg) did not affect the pharmacokinetics after intravenous administration of NFP (2.5 mg/kg).

Studies on interactions between functional foods or dietary supplements and medicines. IV. Effects of ginkgo biloba leaf extract on the pharmacokinetics and pharmacodynamics of nifedipine in healthy volunteers.

The effects of Ginkgo biloba leaf extract (GBE), a widely used herbal dietary supplement in Japan, on the pharmacokinetics and pharmacodynamics of nifedipine (NFP), a calcium-channel blocker, were studied using 8 healthy volunteers. Simultaneous oral ingestion of GBE (240 mg) did not significantly affect any of the mean pharmacokinetic parameters of either NFP or dehydronifedipine, a major metabolite of NFP, after oral administration of NFP (10 mg). However, the maximal plasma NFP concentrations in 2 subjects were approximately doubled by GBE, and they had severer and longer-lasting headaches with GBE than without GBE, with dizziness or hot flushes in combination with GBE.

Interactions between medicines and functional foods or dietary supplements.

Recently, the demand for supplements has steadily been increasing with the diffusion of alternative and supplemental medicines throughout the world. Therefore, the supplements have frequently been taken with many drugs. Here, we have introduced the pharmacokinetic and pharmacological interactions between them.

Effect of rabeprazole on MDR1-mediated transport of Rhodamine 123 in Caco-2 and Hvr100-6 cells.

The aim of our study was to investigate the effects of rabeprazole, a proton pump inhibitor, on MDR1 expressed on human colon carcinoma cell line, Caco-2, and MDR1-overexpressing human cervical carcinoma cell line, HeLa cells selected by exposure to 100 nM vinblastine (Hvr100-6 cells). Inhibitory effects of rabeprazole on MDR1-mediated transport of Rhodamine123 were examined in these cells. A thousand micro molar rabeprazole increased Rhodamine 123 uptakes in Caco-2 and Hvr100-6 cells by 68% and 185%, respectively.

Expression profiles of drug-metabolizing enzyme CYP3A and drug efflux transporter multidrug resistance 1 subfamily mRNAS in small intestine.

The purpose of this study is to examine the expression profiles of CYP3A1, CYP3A2, CYP3A9, and CYP3A18 mRNAs as well as multidrug resistance (mdr)1a and mdr1b mRNAs in the liver and small intestine of normal male Wistar rats using a reverse transcription-polymerase chain reaction (PCR). In the rat liver, the PCR products for CYP3A1, CYP3A2, and CYP3A18 were readily detectable, whereas CYP3A9 was slightly and mdr1a and mdr1b barely detected. Surprisingly, no PCR products for CYP3A1 and CYP3A2 were detected in the small intestine, but those for CYP3A9, CYP3A18, and mdr1a were readily detectable, and a faint band for mdr1b was also observed.

Studies on interactions between functional foods or dietary supplements and medicines. I. Effects of Ginkgo biloba leaf extract on the pharmacokinetics of diltiazem in rats.

The effects of Ginkgo biloba leaf extract (GBE), one of the most widely used herbal dietary supplements in Japan, on the pharmacokinetics of diltiazem (DTZ), a typical probe of cytochrome P450 (CYP) 3A, were examined in rats. The simultaneous addition of GBE to small intestine and liver microsomes inhibited the formation of N-demethyl DTZ (MA), an active metabolite of DTZ produced by CYP3A, in a concentration-dependent manner, with an IC(50) of about 50 and 182 microg/ml, respectively. This inhibition appeared to be caused, at least in part, by a mechanism-based inhibition.

Effects of continuous exposure to digoxin on MDR1 function and expression in Caco-2 cells.

The Caco-2 cell line has been used widely for studying intestinal permeability and several transport functions, and express the multidrug resistance transporter MDR1/P-glycoprotein. Previously, the transient exposure to digoxin for 24 h was found to induce MDR1 mRNA in Caco-2 cells. Here, a digoxin-tolerant Caco-2 subline (Caco/DX) was newly established by the continuous exposure of Caco-2 cells to digoxin, and the effects of continuous exposure to digoxin on MDR1 were examined.