Pemetrexed, a chemotherapeutic drug, is highly active in non-small cell lung cancer and malignant pleural mesothelioma. Unfortunately, rashes are more commonly associated with pemetrexed than other chemotherapies, and it is recommended that patients receive corticosteroids (8 mg/d of dexamethasone) for 3 d, including the day of pemetrexed administration (day 1). However, the efficacy of corticosteroids in this context has not been fully verified. In this retrospective study, we evaluated the medical records of 78 patients who received pemetrexed between April 2009 and March 2014, to confirm whether supplementary corticosteroids prevented rash development. The incidence of rash was lower in the 47 patients who received supplementary corticosteroids (after day 1) compared with the incidence among the 31 patients who did not receive supplementary corticosteroids (19.1% vs. 38.7%). The average cutoff dosage of supplementary corticosteroids on day 2 and day 3 was 1.5 mg/d of dexamethasone, as calculated using the receiver operating characteristic curve, and the odds ratio was 0.33 (95% confidence interval: 0.12-0.94). Administration of ≥1.5 mg of corticosteroids on day 2 and day 3 significantly reduced the severity of the rash compared to no supplementary treatment (grades 2/3, 13.3% vs. 33.3%, p<0.05). However, increasing the dose of corticosteroids had no additional effect on rash development. These results suggest that ≥1.5 mg of supplementary dexamethasone on day 2 and day 3 (in addition to day 1) may be necessary for preventing pemetrexed-induced rash, but high doses of dexamethasone (e.g., 8 mg/d) are unnecessary.Key words pemetrexed; rash; dexamethasone; corticosteroid; risk factor Pemetrexed (Alimta, Eli Lilly and Co.) is a novel multitargeted antifolate that inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. 1,2) These multiple targets may explain the broad and preferable antitumor activity of pemetrexed, which has been evaluated in non-small cell lung cancer (NSCLC), malignant pleural mesothelioma (MPM), head, neck, cervical, breast, gastric, colorectal, pancreatic, and bladder cancers. [3][4][5][6][7][8][9][10][11][12][13][14] Pemetrexed is currently approved in combination with platinum (cisplatin or carboplatin) as a first-line treatment, and as a single-agent second-line treatment, for MPM and NSCLC. 15,16) Moreover, cisplatin plus pemetrexed provides improved survival and reduced toxicity in patients with non-squamous NSCLC, compared to cisplatin plus gemcitabine. 17) Interestingly, multivariate analysis has revealed that increasing levels of homocysteine and methylmalonic acid are correlated with a toxic increase in pemetrexed. 18) The risks associated with severe pemetrexed toxicity, such as neutropenia, thrombocytopenia, infection, and diarrhea, can be reduced by decreasing homocysteine and methylmalonic acid levels by supplementing patients with folic acid and vitamin B 12 . 18) Unfortunately, rash is one of the most common adverse events that ...

BackgroundIn chemotherapy, the full round of treatment must be completed as scheduled to achieve the strongest therapeutic effect. However, peripheral neuropathy, a severe side effect of the chemotherapeutic agent paclitaxel, can force the premature discontinuation of treatment. As some kampo practitioners have suggested that it may be possible to counteract such side effects, we analyzed the effects of Kamishoyosan, Shakuyakukanzoto, and Goshajinkigan in an in vitro model of paclitaxel-induced peripheral neuropathy.MethodsPaclitaxel-treated PC12 cells were assessed for neurite length and performed Western blot analysis for growth-associated protein-43 (GAP-43) and light neurofilament protein (NF-L) levels in the presence of nerve growth factor (NGF); they were re-assessed, with additional testing for acetylcholinesterase levels, after application of one of the kampo. We also compared phosphorylation of extracellular signal-regulated kinase (Erk)1/2 and Akt via Western blot analysis. About effect of kampo to anticancer efficacy, we confirmed cell cytotoxicity in A549 cells using MTT assay.ResultsAddition of Kamishoyosan or Shakuyakukanzoto, but not Goshajinkigan, significantly improved neurite length and GAP-43 and NF-L levels from paclitaxel-treated PC12 cells, relative to those of only NGF-treated PC12 cells. The promoting effect of Kamishoyosan and Shakuyakukanzoto in neurite outgrowth is confirmed when NGF promoted neurite outgrowth, and it was inhibited partially when Erk1/2 and Akt were blocked by Erk1/2 inhibitor or Akt inhibitor alone. Furthermore, neurite outgrowth induced by TJ24 and TJ68 was inhibited more strongly when Erk1/2 inhibitor and Akt inhibitor were treated at the same time. NGF with Kamishoyosan or Shakuyakukanzoto promoted the proportion of phosphorylated Erk1/2 and phosphorylated Akt compare with NGF only. On the other hand, Kamishoyosan or Shakuyakukanzoto didn’t influence cytotoxicity of paclitaxel in A549 cells.ConclusionsKamishoyosan or Shakuyakukanzoto promotes neurite outgrowth with NGF via increasing the proportion of phosphorylated Erk1/2 and phosphorylated Akt in PC12 cells. The effect applies to recovery from paclitaxel-induced axonal involvement and might promote recovery from paclitaxel-induced neuropathy without influence of anticancer effect of paclitaxel.

Uridine 5′-diphospho-glucuronosyltransferase (UGT), a metabolic enzyme of irinotecan active metabolite, has two genetic polymorphisms (UGT1A1*6 and UGT1A1*28). In UGT1A1 homozygous or heterozygous patients, metabolism is delayed and the risk of developing adverse effects is increased, and therefore, dose reduction of irinotecan is considered. However, the specific dose reduction rate of irinotecan for heterozygous patients is uncertain. We studied the necessity of irinotecan dose reduction and its optimal dose in UGT1A1 heterozygous patients with lung cancer. Patients with lung cancer treated with irinotecan in the Tokushima University Hospital or Tokushima Municipal Hospital were included in this study. The dose of irinotecan was evaluated based on the relative dose intensity (RDI). The time to treatment failure (TTF) was defined as the period until treatment change, death, or progressive disease based on response evaluation criteria of solid tumors. We targeted 31 patients treated with irinotecan: 12 wild types (WT), 14 heterozygotes, and 1 complex heterozygote and 4 homozygotes. There was no significant difference in the TTF, but the mean RDI during the entire treatment period was significantly different in the wild type (79%), heterozygous (62%), and complex heterozygous and homozygous groups (46%). In addition, the proportion of patients who completed treatment without dose reduction in the WT group tended to be higher than that in the other groups. For lung cancer patients with UGT1A1 heterozygote types who start irinotecan therapy, reducing the initial dose by approximately 20% might be a safer chemotherapy without decreasing the therapeutic effect.

Aim Vinorelbine is an anticancer drug associated with vascular injury. The mechanism of vascular injury is associated with the decrease of endothelial nitric oxide synthase (eNOS), which regulates oxidative stress. Kakkonto, a traditional Japanese medicine, has anti‐inflammatory and anti‐oxidative effects. We evaluated the effect of kakkonto on vinorelbine‐induced vascular injury and its mechanism of action. Methods Human umbilical vein endothelial cells were used as the endothelial model. We compared vinorelbine‐induced cytotoxicity after pre‐incubation with the seven kakkonto components using ATP assay. Mitochondrial membrane potential was assessed using Mitochondrial Membrane Potential Assay Kit. Intracellular calcium ion concentration ([Ca2+]i) was measured with a calcium‐sensitive dye, Fluo‐4 AM. eNOS and Akt phosphorylation after ephedra extract or vinorelbine treatment were investigated on western blot. Results Ephedra, a kakkonto component, protected cells against vinorelbine‐induced cytotoxicity. Ephedra extract preserved eNOS phosphorylation by increasing [Ca2+]i, but it had no effect on Akt phosphorylation. The increase in [Ca2+]i was mediated by Ca2+ influx via l‐type calcium channels. Additionally, inhibition of Ca2+ influx or eNOS phosphorylation abolished the effects of ephedra extract. Conclusion Ephedra extract preserved eNOS phosphorylation following vinorelbine‐induced oxidative stress, thereby protecting cells from vinorelbine‐induced cytotoxicity. Moreover, the protective effect of ephedra extract is dependent on the increase of [Ca2+]i and the Ca2+/calmodulin‐dependent signal transduction pathway.