A case report of a prolonged decrease in tacrolimus clearance due to co-administration of nirmatrelvir/ritonavir in a lung transplant recipient receiving itraconazole prophylaxis.

BACKGROUND: Drug-drug interaction management is complex. Nirmatrelvir/ritonavir is a potent cytochrome P450 (CYP) 3A inhibitor and influences pharmacokinetics of co-administered drugs. Although there are several reports about drug-drug interactions of nirmatrelvir/ritonavir, an influence of a concomitant use of nirmatrelvir/ritonavir and another potent CYP3A inhibitor on tacrolimus remains unclear. Here, we experienced a lung transplant patient with the novel coronavirus disease 2019 (COVID-19). In this patient, nirmatrelvir/ritonavir was administered, and the inhibitory effect of itraconazole on CYP3A was prolonged. CASE PRESENTATION: We present a case in forties who had undergone lung transplantation. He was administered itraconazole and tacrolimus 1.0 mg/d, with a trough value of 8-12 ng/mL. The patient contracted the COVID-19, and a nirmatrelvir/ritonavir treatment was initiated. During the antiviral treatment, tacrolimus administration was discontinued for 5 d. Tacrolimus was resumed at 1.0 mg/d after completion of the nirmatrelvir/ritonavir treatment, but the trough value after 7 d was high at 31.6 ng/mL. Subsequently, the patient was placed on another 36-h tacrolimus discontinuation, but the trough value decreased to only 16.0 ng/mL. CONCLUSIONS: Co-administration of ritonavir caused a prolonged decrease in tacrolimus clearance through its inhibitory effects on CYP3A in a patient taking itraconazole. Management of drug-drug interaction by pharmacists can be important for patients with multiple medications.

Assessment of Suvorexant and Eszopiclone as Alternatives to Benzodiazepines for Treating Insomnia in Patients With Major Depressive Disorder.

OBJECTIVES: We investigated the utility of switching from benzodiazepines to suvorexant or eszopiclone to manage benzodiazepine-unresponsive insomnia in patients with major depressive disorder (MDD) in a randomized, open-label study. METHODS: Patients with MDD who have insomnia symptoms (a score of >7 on the Insomnia Severity Index Japanese version [ISI-J]), who had received benzodiazepine treatment for more than 2 weeks (n = 18) were randomized to 4 weeks of suvorexant (20 or 15 mg/d) or eszopiclone (3 or 2 mg/d) treatment. The primary endpoint was an improvement in insomnia severity from baseline assessed by the ISI-J score at 2 and 4 weeks after switching from benzodiazepines. The secondary endpoints included changes in the scores of the Pittsburgh Sleep Quality Index Japanese version, the Beck Depression Inventory II, Generalized Anxiety Disorder 7, the digit span test, and the digit symbol substitution test from baseline. Adverse events were recorded throughout the study. RESULTS: Patients taking suvorexant or eszopiclone had improved ISI-J scores (-4.3 for suvorexant and -4.1 for eszopiclone at week 4; P = 0.04 for eszopiclone). Both drugs tended to improve the Beck Depression Inventory II and Generalized Anxiety Disorder 7 scores 2 and 4 weeks after switching. The Pittsburgh Sleep Quality Index Japanese version, digit symbol substitution test, and digit span test scores and the incidence of adverse events did not change from baseline. CONCLUSIONS: Switching to suvorexant or eszopiclone was well tolerated and improved the severity of benzodiazepine-unresponsive insomnia in MDD patients. Both drugs could be beneficial alternatives to benzodiazepines for treating insomnia in MDD patients.

Pharmacist-physician collaborative care for outpatients with left ventricular assist devices using a cloud-based home medical management information-sharing system: a case report.

BACKGROUND: The standard anticoagulation therapy for patients implanted with left ventricular assist devices (LVADs) includes warfarin therapy. We developed a cloud-based home medical management information-sharing system named as LVAD@home. The LVAD@home system is an application designed to be used on iPad tablet computers. This system enables the sharing of daily information between a patient and care providers in real time. In this study, we reported cases of outpatients with LVADs using this system to manage anticoagulation therapy. CASE PRESENTATION: The patient, a man in his 40s with end-stage heart failure owing to non-ischemic dilated cardiomyopathy, underwent LVAD implantation and warfarin was started on postoperative day 1. He started to use LVAD@home to manage warfarin therapy after discharge (postoperative day 47). He sent his data to care providers daily. By using this system, the pharmacist observed his signs of reduced dietary intake 179 days after discharge, and after consulting the physician, told the patient to change the timing of the next measurement earlier than usual. On the next day, the prothrombin time-international normalized ratio increased from 2.0 to 3.0, and thus the dose was decreased by 0.5 mg. Four patients used this system to monitor warfarin therapy from October 2015 to March 2018. In these patients, the time in therapeutic range was 90.1 ± 1.3, which was higher than that observed in previous studies. Additionally, there were no thromboembolic events or bleeding events. CONCLUSIONS: The cloud-based home management system can be applied to share real-time patient information of factors, including dietary intake that interact with warfarin. It can help to improve long-term anticoagulation outcomes in patients implanted with LVAD.

Improvement of peripheral vascular impairment by a phosphodiesterase type 5 inhibitor tadalafil prevents oxaliplatin-induced peripheral neuropathy in mice.

Oxaliplatin, a platinum-based chemotherapeutic drug, frequently induces peripheral neuropathy. Accumulating evidences suggest a possible relationship between peripheral vascular impairment and peripheral neuropathy. In this study, we investigated the effects of vasodilators on cumulative peripheral neuropathy induced by repeated injections of oxaliplatin (10 mg/kg) once a week for 8 weeks in mice. Single injections of vasodilators, including a phosphodiesterase type 5 inhibitor tadalafil acutely alleviated oxaliplatin-induced cold hypersensitivity, while tadalafil had no effect on the mechanical hypersensitivity. By contrast, long-term administration of tadalafil (0.1% in chow diets) during the oxaliplatin injection period reduced the oxaliplatin-induced decreases in skin temperature and blood flow without affecting platinum concentrations in blood, sciatic nerves, and dorsal root ganglion. The long-term administration significantly suppressed cold, mechanical, and electrical current hypersensitivities as well as thermal hypoesthesia. Furthermore, it prevented the decreases in sensory nerve conductance velocity and the number of endoneurial microvessels, and axon degeneration in the sciatic nerves. In vitro studies confirmed that tadalafil does not interfere with the cytotoxicity of oxaliplatin against human cancer cell lines. Altogether, these results suggest that improvement of peripheral vascular impairment by tadalafil could alleviate and prevent oxaliplatin-induced peripheral neuropathy.

Serum Lipid Goal Attainment in Chronic Kidney Disease (CKD) Patients under the Japan Atherosclerosis Society (JAS) 2012 Guidelines.

AIM: According to the Japan Atherosclerosis Society 2012 guidelines (JAS2012-GL), chronic kidney disease (CKD) has newly been added to the high-risk group in terms of atherosclerotic cardiovascular diseases. We therefore explored the lipid target level achievement rates under the JAS2012-GL in real-world clinical practice. METHODS: We retrospectively reviewed the medical charts of patients who were hospitalized at the Nephrology Department at Kobe City Medical Center General Hospital in the period from April 1, 2012 to May 31, 2013 and explored the serum lipid target level achievement rates. Patients without lipid data or those undergoing regular dialysis because of chronic renal failure were excluded. In this study, the CKD group (CKD-G) did not include CKD patients under secondary prevention for coronary heart disease (CHD) or diabetes mellitus (DM). RESULTS: The CKD-G included 146 (81.1%) of the 180 enrolled patients. According to the JAS2012-GL, 100% of the CKD-G patients were categorized into the high-risk group, although only 12.1% of the CKD-G subjects were at high risk according to the JAS2007-GL. Under the JAS2012-GL, the LDL cholesterol (LDL-C) and non-HDL cholesterol (non-HDL-C) target level achievement rates for CKD-G were 71.4% and 68.1%, respectively. According to the JAS2007-GL, these rates were 81.3% and 79.1%, respectively, and, under both guidelines, these rates were 71.7% and 72.1% for primary prevention DM and 66.7% and 66.7% for CHD, respectively. CONCLUSIONS: After the revision of the JAS-GL in 2012, the LDL-C and non-HDL-C target level achievement rates for CKD-G were reduced by approximately 10%; however, they remained similar to those for DM and higher than those for CHD.

[Analysis of factors affecting the duration of treatment with sorafenib in patients with hepatocellular carcinoma].

The current status of treatment with sorafenib, and factors affecting the duration of treatment in patients started on sorafenib for hepatocellular carcinoma from July 2009 until April 2011 in the Department of Gastroenterology at Kobe City Medical Center General Hospital, were examined. Of 21 patients, 12 were able to continue the administration of sorafenib for more than one month, but 9 had to be discontinued within one month due to disease progression, worsening of general condition, and severe adverse reactions. In the group that was discontinued early, the rate of discontinuation due to side effects such as general fatigue, diarrhea, and hepatic encephalopathy was higher than in the long-term treatment group. On the other hand, hand-foot syndrome developed only in one case in both groups. The median value of PIVKA- II at the start of treatment in the long-term and early discontinued treatment groups were 672.5 and 14, 203 mAU/mL, respectively, and the values in the long-term group were significantly lower than those in the early-discontinued group (p < 0.05). From these results, the values of PIVKA-II at the start of sorafenib were considered to be factors affecting the continuation of sorafenib treatment. In addition, the dosing period was considered to be extended to focus on measures to take against the side effects of sorafenib within the early phase. Therefore, it was considered that these factors improved the effect of treatment with sorafenib in patients with hepatocellular carcinoma.

[Safety of pemetrexed mono-therapy in elderly patients with non-small cell lung cancer].

Safety of pemetrexed mono-therapy in elderly patients with non-small-cell lung cancer was examined between May 2009 and April 2010 at Kobe City Medical Center General Hospital . The numbers of non-elderly and elderly(over 70 years old)patients were 14 and 19, respectively. Rates of neutropenia over Grade 3 were 14. 3% in the non-elderly group, and 36. 8% in the elderly group(p=0. 297). However, febrile neutropenia was only seen in one case in each group(p=0. 606), and no treatment-related death was observed. Although the rates of rash appearance were 28. 6% and 36. 8%(p=0. 347)for the non-elderly and the elderly, respectively, most rashes were relieved by steroids. From these results, pemetrexed mono-therapy is considered one of the applicable regimens for elderly patients.

[The role of pharmacy residents as preceptors on clinical training].

Long-term clinical training programs started as part of a 6-year pharmacy course in May 2010. In order to provide training approaches more appropriately and efficiently, it is necessary for teaching facilities to develop effective training systems and curriculums. In Kobe City Medical Center General Hospital, a pharmacy residency system was instituted in 2009, and, based on this, a preceptorship program for clinical training was adopted. In this study, the influence of pharmacy residents as preceptors on clinical training was evaluated based on training reports submitted by 26 students, consisting of a total of 1238 pages; residents' comments were observed in 31.3% of them. Changes in students' awareness were also noted; in the course of training, they became more aware of the responsibility and role of pharmacists, and such awareness appeared to provide a basis for their future goals. Further, although most of the residents' comments were initially made for encouragement, concrete advice gradually increased with time. Residents' commitment to clinical training as preceptors may have facilitated students' understanding of the significance of training, while promoting their own development.

Investigation on residual-related error and the effect of solution properties using protective devices for the reconstitution of cytotoxic agents in actual situations.

PURPOSE: Three products can be used in Japan for the reconstitution of cytotoxic agents: PhaSeal, Chemo CLAVE and Chemo Mini Spike (CMS). The low preparation volume may be affected by residual-related volume in their devices. In this study, the residual-related error in their devices was examined and compared. METHOD: The blank of each component of these devices was weighed using a precision electric balance. After ejecting distilled water (DW) for injection, each was weighed again with the balance. In addition, for etoposide in the cases of PhaSeal and Chemo CLAVE, the components of the devices were similarly weighed. RESULT: The weight gains of each device after ejecting DW were as follows: CMS-V (440 mg) greater than the combined components of Chemo CLAVE (128-171 mg)/CMS-MT (123 mg) greater than the combined components of PhaSeal (13-56 mg). For etoposide, the weight gains of PhaSeal (208 mg) and Chemo CLAVE (223 mg) showed no significant difference. The priming volume of each device was calculated from the specific gravity of water. The residual-related volume was 'CMS-V > Chemo CLAVE, CMS-MT > PhaSeal', although this was very slight in actual situations. CONCLUSION: The residual-related volume was marked in its low preparation volume. In water-soluble drugs, the residual volume of PhaSeal was lowest of the devices in this study, but in viscous drugs, such as etoposide, the residual volume of PhaSeal was almost identical to Chemo CLAVE; that is, the residual volume of these devices was affected by the solution property. The residual-related volume in the devices will lead to errors; therefore, residual-related errors need to be considered in the use of these devices.

[A retrospective survey on allergic reactions by oxaliplatin].

Fifty-six patients treated with oxaliplatin were examined in order to clarify the factors that influence the appearance of allergic reactions by oxaliplatin at Kyoto City Hospital between January 2009 and December 2009, retrospectively. The number of patients in allergic and non-allergic group was 10 and 46, respectively. Patients' characteristics, the presence of hepatic metastasis, hepatic failure and kidney failure, albumin and white blood cell counts were compared in both groups. In the allergic group, the rate of hepatic metastasis was significantly higher than that in the non-allergic group (p=0.011). In conclusion, hepatic metastasis was suggested to be a factor that causes allergic reactions after administration of oxaliplatin.

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. 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.

[Equalization of breast cancer chemotherapy at general hospital( II )-evaluation of safety in FEC and TC regimens].

The safety of epirubicin (75 mg/m(2)), 5-fluorouracil (500 mg/m(2)) plus cyclophosphamide (500 mg/m(2)) (FEC75 therapy) and docetaxel (75 mg/m(2)) plus cyclophosphamide (600 mg/m(2)) (TC therapy) every three weeks as neoadjuvant or adjuvant chemotherapy was evaluated. Six or 9 patients received FEC75 or TC therapy, respectively. The nadir of white blood cells and neutrocyte counts in FEC75 and TC therapy were after 11-15 days and 8-11 days of chemotherapy, respectively. On the other hand, those of monocyte and reticulocyte counts were after 8-11 and 4-8 days for FEC75 and TC therapy, respectively. This suggests that there is a lag time in these parameters for the evaluation of myelosuppression in each chemotherapy regimen, resulting in the prediction of the degree of myelotoxicity by these profiles. Although 2 patients who received TC therapy encountered febrile neutropenia, the symptoms were improved by quinolones, and so granulocyte colony-stimulating factor was not needed. In addition, remarkable non-hematological side effects were not observed, and, therefore, almost all chemotherapy was performed as scheduled. From these results, FEC75 and TC therapy are considered to be safe.

[A case of drug-induced liver injury caused by entecavir for treatment of hepatitis B virus reactivation during RCHOP in a patient with non-Hodgkin lymphoma].

A 49-year-old-man, a healthy carrier of hepatitis B virus (HBV), received chemotherapy with a rituximab/cyclo- phosphamide/doxorubicin/vincristine/prednisolone (R-CHOP) regimen for non-Hodgkin's lymphoma. At the first course of chemotherapy, not only the liver function but the HBV DNA level was elevated. These symptoms were diagnosed as hepatic injury induced by HBV reactivation, and, therefore, entecavir (ETV) was started. As a result, although the treatment with ETV decreased the HBV DNA level, liver function values were remarkably elevated again (over 3 times the levels before beginning ETV). ETV was discontinued because of suspicion regarding the onset of hepatic injury it caused. After switching to lamivudine (LVD), the liver function quickly improved and no problems were observed with renewal of the R-CHOP regimen. In addition, the HBV DNA level decreased and 3 courses of R-CHOP were performed successfully. In our case, the hepatic injury was induced by ETV, although anti-HBV medicine was used for the treatment of HBV reactivation according to the guideline. Therefore, the medical staff must carefully and consistently observe patients with HBV infection after chemotherapy.

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. Their cellular changes were examined based on growth inhibition assays, the function of ABCG2/BCRP, and a RT-PCR analysis of MDR-related protein. The sublines showed a decrease in sensitivity to not only SN-38 but also other chemotherapeutic agents as compared with HeLa cells. mRNA and protein levels of ABCG2/BCRP were increased, and the transport activity of ABCG2/BCRP was enhanced, in the resistant cells. In addition, the expression levels of ABCC1/MRP1, ABCC3/MRP3, and ABCC5/MRP5 were higher than in HeLa cells. The mRNA levels of GGT1 encoding a gamma-glutamyl transferase, but not GCS encoding a gamma-glutamyl cysteine synthetase, were also higher. Other factors examined, i.e., topoisomerase, SLCO1B1, and apoptosis-regulating factors, were comparable among the cells. The overexpression of ABCG2/BCRP was involved in the mechanism of resistance in SN-38-tolerant cells, and ABCC1/MRP1, ABCC3/MRP3, ABCC5/MRP5, and GGT1 may also have participated.

[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 3.0(CTCAE v 3.0)and Neurotoxicity Criteria of DEBIOPHARM(DEB-NTC). The setting of dosage was differed in two hospitals. In A hospital, the dosages of oxaliplatin, 5-FU bolus and 5-FU continuous infusion were more than 90% of the standard one at first time, and were reduced with almost same degree in the appearance of adverse effects. On the other hand, in B hospital, the dosages of these drugs were reduced about 20% even at first administration and, especially, the dose of 5-FU bolus tended to be remarkable reduction. Of adverse events, the rates of the appearance of neutropenia more than grade 3 was 21.2% and 47.1%, in A and B hospitals, respectively. No difference in peripheral neuropathy was detected at both hospitals. In conclusion, the differences in these two hospitals were detected in the dosage setting and myelosuppression, not in non-hematological adverse effects.

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. 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-PK(1) 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.

[Determining S-1 dosage at hospitals prioritizing cancer chemotherapy].

Although it is recommended that the standard S-1 dosage should be based on how large the body surface area is, an on-site setting of the appropriate dosage is often lower than the standard one, depending on the individual's condition and considering possible side effects and so, on. Here, we investigated usage conditions for S-1 as a part of field training for expert pharmacists at our hospital that performs total clinical treatments. Decreases in dosage per day for elderly patients were although the standard dosage is generally determined according to the amount of a patient's body surface. We conducted a retrospective survey with a total 90 patients by creating a tree-diagram to identify a reduction standard. It was found that the S-1 dosage was decreased when there were side effects, aggravation in performance status, decrease in kidney function, old age, combined injection chemotherapy, and a decrease in radiation therapy performance. The dosage decreases without such medical reasons were seen in only 4 of the 90 patients. The individual target dosage on the basis of daily medical examination.

[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). Sixty-three patients were evaluated. We studied the level of myelosuppression after each regimen. As a result, there was no significant difference in neutrocyte counts at nadir after chemotherapy among hospitals and regimens. However, the values tended to be ranked EC75>FEC75>FEC100. In addition, we examined the risk of febrile neutropenia (FN) according to the multi- national association for supportive care in cancer (MASCC) scoring system. Almost all patients (61/63) were in the low risk group of FN, and only two patients had developed FN. At one hospital, patients receiving chemotherapy were prescribed ciprofloxacin tablets prophylactically for prexia over 38 deg C, and the patients learned from it. Thus, no marked difference in the safety (side effects such as myelosuppression) was recognized. However, management of side effects was different among these hospitals. In conclusion, it is very important to provide patients with adequate information on side effects.

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. Cellular accumulation and DNA-binding of platinum were measured with an inductively coupled plasma mass spectrometer. The mRNA levels of copper transporters (hCtr1, ATP7A, and ATP7B) and organic cation transporters (hOCT1, hOCT2, and hOCT3) were evaluated by the real-time reverse transcription-PCR method using SYBR green. RESULTS: The cytotoxicity of platinum derivatives ranked oxaliplatin > cisplatin > carboplatin in almost all cells used. Cellular accumulation and DNA-binding of platinum varied among the types of cells, but levels were similar on treatment with cisplatin and oxaliplatin, and lower in response to carboplatin. The levels of copper and organic cation transporter mRNAs also differed with cell type. A correlation analysis revealed that sensitivity to platinum derivatives was dependent in part on the amount of platinum bound to DNA. In addition, the cellular accumulation of platinum and level of ATP7A mRNA may be factors affecting the cytotoxicity of cisplatin, while the cytotoxicity of oxaliplatin was suggested to be affected by the levels of ATP7A and hOCT1 mRNAs. CONCLUSION: Some factors affecting the sensitivity of tumor cells to platinum derivatives were proposed, and will provide useful information for cancer chemotherapy with platinum derivatives.

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., Ltd.) on sensitivity to chemotherapeutic agents, paclitaxel and doxorubicin as MDR1/P-glycoprotein substrates, and cisplatin and 5-fluorouracil as non-substrates, in human cervical carcinoma HeLa cells, and paclitaxel-resistant and cisplatin-resistant derivatives (HeLa/TXL and HeLa/CDDP, respectively). The extract had no growth inhibitory effects on HeLa and the resistant cells at concentrations ranging from 7.6 × 10(-4) µ g/ml to 8.0 × 10(2)µ g/ml, indicating no remarkable cytotoxic activity in vitro. In the presence of 0.1, 0.5, and 1 µ g/ml of ABM extract, sensitivity to paclitaxel, cisplatin and 5-fluorouracil did not change in HeLa, HeLa/TXL and HeLa/CDDP cells. However, the extract reduced sensitivity to doxorubicin in HeLa/TXL and HeLa/CDDP cells in a concentration-dependent manner. In conclusion, the concomitant use of ABM extract minimally affected sensitivity to various chemotherapeutic agents in HeLa cells and resistant sublines in vitro.