HeLa/CDDP cells showed decreased activity and expression of MDR1 and overexpression of gamma-GT but not gamma-GCS whereas the activity of MDR1 in HeLa/TXL cells was significantly enhanced. Thus, the molecular changes to HeLa cells caused by continuous exposure to cisplatin or paclitaxel were in part clarified, and therefore an understanding of the cellular changes induced by chemotherapeutic agents will be necessary to establish a strategy for reversing MDR.

Some factors affecting the sensitivity of tumor cells to platinum derivatives were proposed, and will provide useful information for cancer chemotherapy with platinum derivatives.

No abstract

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. The expression of MDR1 mRNA was increased by diclofenac, fenbufen, indomethacin, and nimesulide and the tended to be increased by meloxicam, mepirizole, and sulindac. However, pretreatment for 48 hours with diclofenac, indomethacin, or nimesulide, but not fenbufen, resulted in a significant increase in the amount of rhodamine123 accumulated. Although NSAIDs without effects on the expression of MDR1 mRNA altered the accumulation of rhodamine123 significantly, the efflux of rhodamine123 from cells was unchanged. In conclusion, the expression of MDR1 mRNA in Caco-2 cells was demonstrated to be increased by treatment with some NSAIDs, although the transport function of MDR1 was unchanged. These findings imply that the NSAIDs did not cause the drug interaction via MDR1 induction.

No abstract

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. In HeLa/TXL cells, propolis increased sensitivity to these MDR1 substrates. The accumulation of Rhodamine123, also a substrate for MDR1, by HeLa/TXL cells increased in the presence of 50 microg/mL, but not 10 microg/mL, of the extract. However, the growth inhibition of HeLa/TXL cells by paclitaxel was not changed by CAPE, although the accumulation of Rhodamine123 increased significantly in the presence of 100 microm, but not 1 nM or 1 microm, CAPE. Collectively, the extract was suggested to inhibit the function of MDR1 and to increase the sensitivity to MDR1 substrates in HeLa/TXL cells, effects likely to be caused by constituents other than CAPE.

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-PK₁ cells were used as a model of tubular epithelial cells. Cytotoxicity was evaluated by WST-1 assay, and cellular accumulation of platinum was examined by inductively coupled plasma mass spectrometer. As indexes of necrosis and apoptosis, lactate dehydrogenase release, DNA fragmentation and caspase 3 activation were examined. Results: In terms of cytotoxicity, the derivatives ranked in the order of oxaliplatin > cisplatin > nedaplatin > carboplatin, being comparable with that for the level of platinum accumulated in LLC-PK₁ cells. Lactate dehydrogenase release and DNA fragmentation were observed following treatment with all the derivatives, but were lowest for carboplatin. In terms of activating caspase 3, the order was cisplatin > nedaplatin > oxaliplatin > carboplatin. Conclusion: Cytotoxicity by the derivatives was dependent on cellular accumulation of platinum and suggested to be mediated by apoptosis and necrosis; however, contributions differed among the derivatives.

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). Immediate cessation of the infusion resulted in a disappearance of the allergic reaction 60 min later. Blood tests just after the reaction demonstrated a marked elevation of immunoglobulin E to 300 IU L(-1) (normal range: <170 IU L(-1)). This change implies the involvement of a type I reaction in the HSR. In addition, a drug lymphocyte stimulating test against oxaliplatin and levofolinate calcium (an isomer of leucovorin calcium) gave values of 696% and 107 % respectively, as compared with control serum. This suggests that the patient had an adverse reaction not only of type I but partly of type IV allergic reaction also. Oxaliplatin appears to have caused a HSR in this Japanese patient, and thus pharmacists, physicians, and other medical staff must keep a careful watch of a patient's clinical condition during chemotherapy including oxaliplatin.