Effectiveness of Gabapentinoids for Cancer-related Rectal and Vesical Tenesmus: Report of Four Cases.

Gabapentinoids could be assumed to relieve cancer-related rectal/vesical tenesmus based on their pharmacological mechanism. Four patients were refractory for cancer-related rectal/vesical tenesmus although their opioid doses were titrated up. Symptom intensity difference (SID) between initiation and follow-up after 24, 48, and 72 h and daily changes in the frequency of urination, defecation, opioid rescue doses, presence of sleep disruption, and dose of regular opioid medication were evaluated. The median reductions in daily discomfort measured as SID between baseline and follow-up after 24, 48, and 72 h were 87.5%, 70.0%, and 80.0%, respectively, while those in daily pain intensity were 75%, 66.7%, and 66.7%, respectively. The initiation dose of gabapentin was 200 or 400 mg/day and that of pregabalin was 75 mg/day in one patient. Gabapentinoids were effective at low doses administered over a short duration to patients with refractory cancer-related rectal/vesical tenesmus.

Negative pain management index scores do not necessarily indicate inadequate pain management: a cross-sectional study.

BACKGROUND: The Pain Management Index (PMI) is widely used in the assessment of pain management, and negative scores are traditionally considered to indicate inadequate pain management. However, it is not known whether negative PMI scores are always problematic. METHODS: In this prospective observational study, we examined the data of 1156 patients with cancer and pain who were hospitalized in a cancer care hospital in Japan from July 2012 to January 2015 and compared the proportion of patients with PI across various PMI scores in this cohort. We further evaluated the predictive validity of PMI scores for PI using different cutoffs. This study aimed to examine the association between PMI scores and the proportion of patients whose pain interferes with their daily lives (i.e., pain interference [PI]). RESULTS: We found that lower PMI scores were generally associated with a higher percentage of patients with PI. A smaller proportion of patients with PMI scores of - 1 (567/1550, 36.6%) reported PI compared with those with PMI scores of 0 (788/1505, 52.4%). The sensitivities of PMI scores < - 1 and < 0 for predicting PI were 0.16 and 0.37 and the corresponding specificities were 0.95 and 0.71, respectively. CONCLUSIONS: These findings suggest that PMI scores are inversely associated with the proportion of patients with PI. However, PMI scores of - 1 do not always indicate inadequate pain management; pain management should therefore be evaluated from multiple perspectives.

Efficacy and Safety of Oxycodone Injection for Relieving Cancer Pain: A Study in Japan Consisting of Two Open Trials for Intravenous and Subcutaneous Administration.

Pure oxycodone injection became increasingly necessary after oral oxycodone was launched in Japan in 2003. However, trials clarifying the efficacy and safety of injection are rare. Therefore, a multicenter open study on injection was designed and carried out in 2010, resulting in the launch of injection therapy in 2012. As published domestic case reports on efficacy already show widespread prescription, this study aimed to provide useful information for cancer pain relief in Japan and other countries. Our oxycodone injection study consisted of two trials, one of intravenous (S#9131) and the other of subcutaneous (S#9132) administration. The minimum required number of enrolled patients suffering cancer pain was determined to be 70 in S#9131 and 20 in S#9132. These studies had the same dose-titration protocol as the main endpoint, i.e., pain relief rate (PRR) defined as the rate of achieving adequate pain control (APC), as in prior oral oxycodone trials in Japan. In S#9131, PRR was 81.4% (95% confidence interval: 70.3-89.7%), therefore, the null hypothesis of PRR<70% was rejected using the binominal one-sided test (p=0.0217). In S#9132, PRR was 73.7% also surpassing 70%. Safety was also assessed in the same way as in prior trials. The majority of adverse effects were moderate or mild and recovered with no sequelae. As shown above, the injection was considered to be effective and safe in cancer pain treatment. The details of these trials, particularly the dose-titration protocol for achieving APC and route switching information, are expected to enhance injection convenience for prescribers.

How Do Hospital Palliative Care Teams Use the WHO Guidelines to Manage Unrelieved Cancer Pain? A 1-Year, Multicenter Audit in Japan.

It has been reported that pain relief for patients with cancer is suboptimal in Japan. This has been mainly attributed to inadequate dissemination of the World Health Organization (WHO) guidelines for cancer pain management. To better understand this problem, we reviewed how 6 hospital palliative care teams (HPCTs) used the WHO guidelines for unrelieved pain in a 1-year audit that included 534 patients. The HPCT interventions were classified according to the contents of the WHO guidelines. In our study, HPCT interventions involved opioid prescriptions in >80% of referred patients, and "For the Individual" and "Attention to Detail" were the 2 most important principles. Our study indicates which parts of the WHO guidelines should be most heavily emphasized, when disseminating them in Japan.

[Screening for Pain in Cancer Patients].

The newly revised 2014 Set of Standards for"Designated Cancer Care Hospitals"mandated the screening of all cancer patients6 for their physical and psychological suffering systematically in both outpatient and inpatient settings as well as rapid response to the suffering detected. It is a step forward as a cancer control policy, but because the pain associated with cancer changes by time depending on factors such as disease progression and treatment, it must be evaluated repeatedly. Simply complying with the standard by measuring once, say on admission or at the initial visit, will not help patients. It is necessary to continuously monitor how the pain was treated and improved or worsened, and whether any new pain develops after admission. In the United States, campaigns to regard pain as the"fifth vital sign"have been are in action since 2001. They made the patient pain intensity be recorded on a numeric scale along with the body temperature on the same daily vital sign charts. However, the US experiences indicated that the simple screening for pain is not enough. One study reported that physicians took action to pain of moderate or greater intensity in only one-sixth of the time. Numerical evaluation of pain intensity captures only one aspect of pain. What matters more to patients with pain, thus is more important to their clinicians, is the degree of impairment of patients in their daily lives due to pain. Our study group set as the goal of pain treatment the elimination of"things one is unable to do or has trouble doing because of pain". We systematically presented the attending physicians the degree of impairment of patient lifestyle due to pain rather than numbers, and physicians became more engaged in the prescribing or increasing the dose of opioids.

The Association Between Pain and Quality of Life for Patients With Cancer in an Outpatient Clinic, an Inpatient Oncology Ward, and Inpatient Palliative Care Units.

PURPOSE: This study was designed to clarify the association between pain and quality of life (QOL) of Japanese patients with cancer using a cancer-specific QOL scale (European Organization for Research and Treatment of Cancer [EORTC] QLQ-C15-PAL) in 3 care settings (outpatient, inpatient, and palliative care units [PCUs]). METHODS: We examined the above-mentioned purpose for the total of 404 patients. RESULTS: In outpatients, physical, emotional functioning (EF), and global health status/QOL (QL item) were significantly correlated with average pain, and their correlation coefficients were -0.37 to -0.46 (P < .0001). In inpatients, they were -0.33 (P = .006), -0.26 (P = .030), and -0.31 (P = .012). In the PCU patients, they were -0.12 (P = .316), -0.30 (P = .009), and -0.28 (P = .015). CONCLUSION: Patients' pain had an association with physical and emotional QOL, and the association was smaller in the PCU patients than the others.

Tris-hydroxymethyl-aminomethane enhances capsaicin-induced intracellular Ca(2+) influx through transient receptor potential V1 (TRPV1) channels.

Non-selective transient receptor potential vanilloid (TRPV) cation channels are activated by various insults, including exposure to heat, acidity, and the compound capsaicin, resulting in sensations of pain in the skin, visceral organs, and oral cavity. Recently, TRPV1 activation was also demonstrated in response to basic pH elicited by ammonia and intracellular alkalization. Tris-hydroxymethyl aminomethane (THAM) is widely used as an alkalizing agent; however, the effects of THAM on TRPV1 channels have not been defined. In this study, we characterized the effects of THAM-induced TRPV1 channel activation in baby hamster kidney cells expressing human TRPV1 (hTRPV1) and the Ca(2+)-sensitive fluorescent sensor GCaMP2 by real-time confocal microscopy. Notably, both capsaicin (1 µM) and pH 6.5 buffer elicited steep increases in the intracellular Ca(2+) concentration ([Ca(2+)]i), while treatment with THAM (pH 8.5) alone had no effect. However, treatment with THAM (pH 8.5) following capsaicin application elicited a profound, long-lasting increase in [Ca(2+)]i that was completely inhibited by the TRPV1 antagonist capsazepine. Taken together, these results suggest that hTRPV1 pre-activation is required to provoke enhanced, THAM-induced [Ca(2+)]i increases, which could be a mechanism underlying pain induced by basic pH.

The atypical antipsychotic, olanzapine, potentiates ghrelin-induced receptor signaling: An in vitro study with cells expressing cloned human growth hormone secretagogue receptor.

The growth hormone secretagogue receptor (GHS-R) belongs to Gαq-coupled G protein-coupled receptor (GPCR) that mediates growth hormone release, food intake, appetite, glucose metabolism and body composition. Ghrelin has been identified as an endogenous ligand for GHS-R, and it is the only orexigenic peptide found in the peripheral organs. Olanzapine, an atypical antipsychotic agent that binds to and inhibits the activation of GPCR for several neurotransmitters, has metabolic side effects such as excessive appetite and weight gain. Recently, studies have revealed that the orexigenic mechanism of olanzapine is mediated via GHS-R signaling, although the precise mechanisms have not been clarified. In this study, we investigated the effect of olanzapine on ghrelin-mediated GHS-R signaling by using an electrical impedance-based receptor biosensor assay system (CellKey™). Olanzapine at concentrations of 10(-7) and 10(-6)mol/L enhanced ghrelin-induced (10(-10)-10(-8)mol/L) GHS-R activation. A Ca(2+) imaging assay revealed that olanzapine (10(-7) and 10(-6)mol/L) enhanced ghrelin (10(-7) M)-induced GHS-R activity. In contrast, haloperidol (an antipsychotic agent) failed to enhance this ghrelin-mediated GHS-R activation, as demonstrated by both the CellKey™ and Ca(2+) imaging assays. Together, these results suggest that olanzapine, but not haloperidol, promotes appetite by enhancing ghrelin-mediated GHS-R signaling.

Distinct TRPV1- and TRPA1-based mechanisms underlying enhancement of oral ulcerative mucositis-induced pain by 5-fluorouracil.

In many patients with cancer, chemotherapy-induced severe oral ulcerative mucositis causes intractable pain, leading to delays and interruptions in therapy. However, the pain mechanism in oral ulcerative mucositis after chemotherapy has not been extensively studied. In this study, we investigated spontaneous pain and mechanical allodynia in a preclinical model of oral ulcerative mucositis after systemic administration of the chemotherapy drug 5-fluorouracil, using our proprietary pain assay system for conscious rats. 5-Fluorouracil caused leukopenia but did not induce pain-related behaviors. After 5-fluorouracil administration, oral ulcers were developed with topical acetic acid treatment. Compared with saline-treated rats, 5-fluorouracil-exposed rats showed more severe mucositis with excessive bacterial loading due to a lack of leukocyte infiltration, as well as enhancements of spontaneous pain and mechanical allodynia. Antibacterial drugs, the lipid A inhibitor polymyxin B and the TRPV1/TRPA1 channel pore-passing anesthetic QX-314, suppressed both the spontaneous pain and the mechanical allodynia. The cyclooxygenase inhibitor indomethacin and the TRPV1 antagonist SB-366791 inhibited the spontaneous pain, but not the mechanical allodynia. In contrast, the TRPA1 antagonist HC-030031 and the N-formylmethionine receptor FPR1 antagonist Boc MLF primarily suppressed the mechanical allodynia. These results suggest that 5-fluorouracil-associated leukopenia allows excessive oral bacterial infection in the oral ulcerative region, resulting in the enhancement of spontaneous pain through continuous TRPV1 activation and cyclooxygenase pathway, and mechanical allodynia through mechanical sensitization of TRPA1 caused by neuronal effects of bacterial toxins. These distinct pain mechanisms explain the difficulties encountered with general treatments for oral ulcerative mucositis-induced pain in patients with cancer and suggest more effective approaches.

A national profile of the impact of parental cancer on their children in Japan.

OBJECTIVE: Dependent children under the age of 18 are particularly vulnerable to the stress of parental death from cancer or of having a parent diagnosed and treated for the disease. More and more Japanese couples are postponing parenthood, which increases their chances of developing cancer while they still have a dependent child. However, the problem has not received enough attention from healthcare professionals and policy-makers because the extent and breadth of the problem has never been examined in the Japanese population. Therefore, we aimed to estimate the nationwide incidence of cancer patients who have children under the age of 18 years, as well as the incidence of children who have a parent diagnosed with cancer in Japan. STUDY DESIGN: We calculated the proportion of patients who have children stratified by age, gender and cancer type using electronic medical records of cancer patients (20-59 years old) admitted to the National Cancer Center Hospital (NCCH) for the first time between January 2009 and December 2013. We projected these estimates onto the Japanese population using 2010 population-based cancer registry data, and repeated the projection using 2011 hospital-based cancer registry data so that estimates of patients receiving care at Designated Cancer Care (DCC) hospitals could be obtained. RESULTS: We found that an estimated 56,143 cancer patients who have 87,017 dependent children are diagnosed with cancer every year in Japan. The proportion of children in Japan who had a parent newly diagnosed with cancer in 2010 was approximately 0.38%. We estimated that in 2011 there were on average about 82 cancer patients with minor children and 128 minor children who have at least one parent diagnosed with cancer in every DCC hospital in Japan. CONCLUSION: Parental cancer is common. We have identified that many adults diagnosed with cancer have the double burden of coping with the diagnosis and treatment as well as supporting their children through this experience. Additional data on socioeconomic characteristics and needs assessment of these patients are required to understand how best to help children and families cope with cancer.

Accuracy of using Diagnosis Procedure Combination administrative claims data for estimating the amount of opioid consumption among cancer patients in Japan.

OBJECTIVE: The state of opioid consumption among cancer patients has never been comprehensively investigated in Japan. The Diagnosis Procedure Combination claims data may be used to measure and monitor opioid consumption among cancer patients, but the accuracy of using the Diagnosis Procedure Combination data for this purpose has never been tested. METHODS: We aimed to ascertain the accuracy of using the Diagnosis Procedure Combination claims data for estimating total opioid analgesic consumption by cancer patients compared with electronic medical records at Aomori Prefectural Central Hospital. We calculated percent differences between estimates obtained from electronic medical records and Diagnosis Procedure Combination claims data by month and drug type (morphine, oxycodone, fentanyl, buprenorphine, codeine and tramadol) between 1 October 2012 and 30 September 2013, and further examined the causes of discrepancy by reviewing medical and administrative charts between April and July 2013. RESULTS: Percent differences varied by month for drug types with small prescription volumes, but less so for drugs with larger prescription volumes. Differences also tended to diminish when consumption was compared for a year instead of a month. Total percent difference between electronic medical records and Diagnosis Procedure Combination data during the study period was -0.1% (4721 mg per year per hospital), as electronic medical records as baseline. Half of the discrepancy was caused by errors in data entry. CONCLUSION: Our study showed that Diagnosis Procedure Combination claims data can be used to accurately estimate opioid consumption among a population of cancer patients, although the same conclusion cannot be made for individual estimates or when making estimates for a group of patients over a short period of time.

Tramadol and its metabolite m1 selectively suppress transient receptor potential ankyrin 1 activity, but not transient receptor potential vanilloid 1 activity.

BACKGROUND: The transient receptor potential vanilloid 1 (TRPV1) and the transient receptor potential ankyrin 1 (TRPA1), which are expressed in sensory neurons, are polymodal nonselective cation channels that sense noxious stimuli. Recent reports showed that these channels play important roles in inflammatory, neuropathic, or cancer pain, suggesting that they may serve as attractive analgesic pharmacological targets. Tramadol is an effective analgesic that is widely used in clinical practice. Reportedly, tramadol and its metabolite (M1) bind to µ-opioid receptors and/or inhibit reuptake of monoamines in the central nervous system, resulting in the activation of the descending inhibitory system. However, the fundamental mechanisms of tramadol in pain control remain unclear. TRPV1 and TRPA1 may be targets of tramadol; however, they have not been studied extensively. METHODS: We examined whether and how tramadol and M1 act on human embryonic kidney 293 (HEK293) cells expressing human TRPV1 (hTRPV1) or hTRPA1 by using a Ca imaging assay and whole-cell patch-clamp recording. RESULTS: Tramadol and M1 (0.01-10 µM) alone did not increase in intracellular Ca concentration ([Ca]i) in HEK293 cells expressing hTRPV1 or hTRPA1 compared with capsaicin (a TRPV1 agonist) or the allyl isothiocyanate (AITC, a TRPA1 agonist), respectively. Furthermore, in HEK293 cells expressing hTRPV1, pretreatment with tramadol or M1 for 5 minutes did not change the increase in [Ca]i induced by capsaicin. Conversely, pretreatment with tramadol (0.1-10 µM) and M1 (1-10 µM) significantly suppressed the AITC-induced [Ca]i increases in HEK293 cells expressing hTRPA1. In addition, the patch-clamp study showed that pretreatment with tramadol and M1 (10 µM) decreased the inward currents induced by AITC. CONCLUSIONS: These data indicate that tramadol and M1 selectively inhibit the function of hTRPA1, but not that of hTRPV1, and that hTRPA1 may play a role in the analgesic effects of these compounds.

Breakthrough pain management using fentanyl buccal tablet (FBT) in combination with around-the-clock (ATC) opioids based on the efficacy and safety of FBT, and its relationship with ATC opioids: results from an open-label, multi-center study in Japanese cancer patients with detailed evaluation.

OBJECTIVE: Rapid analgesic onset opioids, particularly fentanyl buccal tablet, is preferable for managing breakthrough pain. The efficacy and safety of fentanyl buccal tablet and its association with around-the-clock opioids needs to be explored with an option of dose adjustments, more closely reflecting administration in clinical practice. The aim of the study was to assess the safety and efficacy of fentanyl buccal tablet in breakthrough pain management in combination with around-the-clock opioids with the dose adjustment option, and explore the dose adjustment's influence on breakthrough pain management using detailed evaluation. METHODS: The 12-week open-label, multi-center study was conducted throughout Japan. Cancer patients aged 20 years or older, experiencing persistent pain controlled with around-the-clock opioids and breakthrough pain with supplemental medications were enrolled. Fentanyl buccal tablet and around-the-clock opioid doses could be adjusted under protocol-specified conditions. Efficacy variables were assessed at each fentanyl buccal tablet administration. Safety was assessed mainly by adverse events. RESULTS: All efficacy variables showed sustained analgesic effect. Nearly half the patients stayed on the same dose; most fentanyl buccal tablet administrations did not require additional supplemental medications. Dose increase of fentanyl buccal tablet and around-the-clock opioids seemed to improve breakthrough pain intensity and frequency, respectively. Fentanyl buccal tablet and around-the-clock opioid doses were not strongly associated. Treatment-related adverse events were all common with opioid treatment and did not increase over time. CONCLUSIONS: Fentanyl buccal tablet can stably and safely manage breakthrough pain in cancer patients with independent dose adjustment based on detailed evaluation of each patient's condition. Breakthrough pain management using fentanyl buccal tablet with around-the-clock opioids at optimal doses may be an important factor in palliative care for cancer patients with breakthrough pain.

Novel methods of applying direct chemical and mechanical stimulation to the oral mucosa for traditional behavioral pain assays in conscious rats.

BACKGROUND: Stomatitis induces severe and painful hypersensitivity to pungency and physical contact during meals. Many studies have used anesthetized animals to examine evoked nociception in the oral mucosa, but no reports have used traditional behavioral assays to evaluate nociception in conscious animals. NEW METHODS: We developed two new methods of applying chemical or mechanical stimulation directly to the oral mucosa of the mandibular vestibule of conscious rats. Nociceptive evaluations were performed by measuring facial grooming time and the head withdrawal threshold to von Frey stimulations. (1) For the intraoral dropping method, rat mucosa was transiently exposed by hand, and a drop of a pungent solution was applied. (2) For the stable intraoral opening method, rat mucosa was long-term exposed following piercing surgery of the mental skin after habitual training for 2-3 weeks. RESULTS: In the intraoral dropping method, the application of 100 µM capsaicin or 100 mM allyl isothiocyanate prolonged mouth-rubbing time. Capsaicin-induced mouth-rubbing time was further enhanced following the development of an acetic acid-induced ulcer. The stable intraoral opening method enabled stable measurements of the mechanical withdrawal threshold in the oral mucosa of conscious rats. Ulcer development decreased the mechanical threshold, whereas topical lidocaine treatment increased the threshold. COMPARISON WITH EXISTING METHODS: These new methods enable the evaluations of motivational nocifensive behaviors in response to intraoral stimulations without any anesthetic effects. CONCLUSIONS: The intraoral dropping and stable intraoral opening methods can be used in combination with traditional behavioral assays to evaluate nociception in the oral mucosa of conscious rats.

Difference in the timing of cessation of palliative chemotherapy between patients with incurable cancer receiving therapy only in a local hospital and those transitioned from a tertiary medical center to a local hospital.

BACKGROUND: It is important to know when to decide to end palliative chemotherapy (PC) for the quality of life of patients. However, there is currently no clear agreement on when to terminate PC. OBJECTIVES: To determine whether the difference of the period between the completion of PC and death affects patients' trajectory of supportive care near end of life. METHODS: This retrospective study included 52 adult patients with incurable cancer who had received PC and who were referred to our palliative care team and died in our local hospital between July 2011 and June 2014. Group A comprised patients who received anticancer therapy such as surgery and PC only in our hospital and eventually died there. Group B comprised patients who were transitioned to our hospital from tertiary medical centers after cessation of PC. RESULTS: 17 of 22 patients (77%) in Group A conveyed the intention of continuing PC in the first interview with a physician of the palliative care team, whereas 4 of 30 patients (13%) in Group B conveyed a similar intention. The patients in Group B stopped PC a median of 43 days earlier than did the patients in Group A (𝑃 < .0001). CONCLUSIONS: These data showed that more patients in Group A wanted to continue PC and had a shorter interval between last PC and death. Change in the hospital where the patients are given supportive care might contribute to the cessation of futile PC at an appropriate time.

Pharmacokinetics of oxycodone after intravenous and subcutaneous administration in Japanese patients with cancer pain.

ABSTRACT In Japan, Oxycodone hydrochloride injection formulation has been approved in 2012. However, its pharmacokinetics has been poorly studied. The aim of this study is to evaluate the pharmacokinetics of oxycodone after intravenous and subcutaneous administration of oxycodone hydrochloride injection in Japanese patients with cancer pain. Noncompartmental analysis and population pharmacokinetic analysis were performed. We conducted a multicenter open-label study of oxycodone hydrochloride administered as constant infusion with the dose titrated individually according to the pain intensity in patients with cancer pain. Pharmacokinetic parameters for plasma oxycodone and its metabolites were estimated using pharmacokinetics of oxycodone was evaluated using a total of 344 plasma concentrations obtained from 89 patients. The estimated geometric mean clearance (CL) of oxycodone was 24.3 L per hour after constant intravenous infusion and 29.5 L per hour after constant subcutaneous infusion, respectively. Population pharmacokinetic analysis indicated that body surface area was the influencing factor on CL and there were no pharmacokinetic differences for CL between intravenous and subcutaneous infusion. These results provide important information for the clinical use of oxycodone injection.

Neutrophil recruitment is critical for 5-fluorouracil-induced diarrhea and the decrease in aquaporins in the colon.

Diarrhea is a common side effect experienced by cancer patients undergoing clinical chemotherapy, such as with 5-fluorouracil (5-FU). However, the precise mechanisms underlying 5-FU-induced diarrhea remain unclear. In the present study, we examined the role of neutrophil in 5-FU-induced diarrhea. Mice were given 5-FU (50mg/kg, i.p.) daily for 4 days. Sivelestat sodium (100 or 300 mg/kg, i.p., neutorophil elastase inhibitor) or SB225002 (3 or 9 mg/kg, i.p., CXCR2 antagonist) was administered before the administration of 5-FU. Gene expression levels of aquaporin (AQP) 4 and 8, CXCL1, CXCL2, CXCL3, neutrophil elastase (Elane) and myeloperoxidase (MPO) in the colon were examined by real-time RT-PCR. The neutrophil (Ly-6G positive cell) number in the mucosa of colon was measured by flow-cytometric analysis. Administration of 5-FU induced diarrhea and decreased the expression levels of AQP 4 and 8 in the colon. Under the present conditions, the expression levels of CXCL1, CXCL2, CXCL3, the neutrophil markers Elane and MPO, as well as Ly-6G-positive neutrophils, in the colon were significantly increased by 5-FU. Neutrophil recruitment with decreased levels of AQP 4 and 8 were dramatically inhibited by either sivelestat sodium or SB225002. Furthermore, these reagents reduced the 5-FU-induced body weight loss and diarrhea. These findings provide evidence that neutrophil recruitment and neutrophil elastase may decrease the levels of AQP 4 and 8 in the colon of mice treated with 5-FU and contribute to the pathophysiology of 5-FU-induced body weight loss and diarrhea.

Mechanisms of cisplatin-induced muscle atrophy.

Fatigue is the most common side effect of chemotherapy. However, the mechanisms of "muscle fatigue" induced by anti-cancer drugs are not fully understood. We therefore investigated the muscle-atrophic effect of cisplatin, a platinum-based anti-cancer drug, in mice. C57BL/6J mice were treated with cisplatin (3mg/kg, i.p.) or saline for 4 consecutive days. On Day 5, hindlimb and quadriceps muscles were isolated from mice. The loss of body weight and food intake under the administration of cisplatin was the same as those in a dietary restriction (DR) group. Under the present conditions, the administration of cisplatin significantly decreased not only the muscle mass of the hindlimb and quadriceps but also the myofiber diameter, compared to those in the DR group. The mRNA expression levels of muscle atrophy F-box (MAFbx), muscle RING finger-1 (MuRF1) and forkhead box O3 (FOXO3) were significantly and further increased by cisplatin treated group, compared to DR. Furthermore, the mRNA levels of myostatin and p21 were significantly upregulated by the administration of cisplatin, compared to DR. On the other hand, the phosphorylation of Akt and FOXO3a, which leads to the blockade of the upregulation of MuRF1 and MAFbx, was significantly and dramatically decreased by cisplatin. These findings suggest that the administration of cisplatin increases atrophic gene expression, and may lead to an imbalance between protein synthesis and protein degradation pathways, which would lead to muscle atrophy. This phenomenon could, at least in part, explain the mechanism of cisplatin-induced muscle fatigue.