Administration Of Oxaliplatin Research Articles

Nanoliposomal oxaliplatin ameliorates chemotherapy-induced neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is an important adverse effect of treatment with oxaliplatin (OXA). We have developed PEGylated nanoliposomal oxaliplatin (OXA-LIP) and tested its activity in an animal model of CIPN. OXA-LIPs were prepared using a combination of egg yolk lecithin, cholesterol, and DSPE-mPEG2000 (at ratios 400, 80, and 27 mg). These liposomes were characterized using several different methods (e.g., polydispersity index (PDI), and zeta potential, FESEM). The in vivo study was performed in 15 male rats comprising three groups: a negative control (normal saline) OXA, and OXA-LIP. These were injected intraperitoneally at a concentration of 4 mg/kg on two consecutive days every week, for 4 weeks. After that, CIPN was assessed using the hotplate and acetonedropmethods. Oxidative stress biomarkers such as SOD, catalase, MDA, and TTG were measured in the serum samples. The functional disturbances of the liver and kidney were assessed by measuring the serum levels of ALT, AST, creatinine, urea, and bilirubin. Furthermore, hematological parameters were determined in the three groups. The OXA-LIP had an average particle size, PDI, and zeta potential of 111.2 ± 1.35 nm, 0.15 ± 0.045, and −52.4 ± 17 mV, respectively. The encapsulation efficiency of OXA-LIP was 52% with low leakage rates at 25 °C.Thermal hyperalgesia changes showed OXA has significant effects in the induction of neuropathy on days 7, 14, and 21 compared to the control group. OXA had a significantly greater sensitivity than the OXA-LIP and control groups in the thermal allodynia test (P < 0.001). OXA-LIP administration did not show significant effects on the changes of oxidative stress, biochemical factors, and cell count. Our findings provide a proof of concept on the potential application of oxaliplatin encapsulated with PEGylated nanoliposome to ameliorate the severity of neuropathy, supporting further studies in clinical phases to explore the value of this agent for Chemotherapy-induced peripheral neuropathy.

Use of acupuncture with acupressure in addition to standard-of-care cryotherapy to decrease chemotherapy-associated neuropathy in patients with gastrointestinal malignancies receiving oxaliplatin-based chemotherapy: Study protocol for a randomized, controlled pilot and feasibility study

BackgroundOxaliplatin is a key chemotherapeutic agent in the treatment of local and metastatic gastrointestinal (GI) malignancies. Dose density and treatment adherence can be limited by chemotherapy-induced peripheral neuropathy (CIPN). Early research suggests CIPN incidence and severity may be mitigated by acupuncture, but rigorous data in GI oncology patients is limited. Here, we describe the protocol of a randomized, waitlist-controlled pilot study testing the use of preemptive of acupuncture plus acupressure to decrease CIPN and chemotherapy-related toxicities. MethodsPatients with a GI malignancy (n = 56) with planned 5-fluorouracil (5-FU) and oxaliplatin IV (FOLFOX, FOLFIRINOX) every 2 weeks are being recruited. Additional concurrent anti-neoplastic agents may be used. Enrolled patients are randomized 1:1 to a 3-month intervention of Arm A: acupuncture with acupressure and standard-of-care treatment, or Arm B: standard-of-care alone. In Arm A, on days 1 and 3 of each chemotherapy cycle a standardized acupuncture protocol is administered and patients are taught self-acupressure to perform daily between chemotherapy treatments. Patients in both arms are given standard-of-care oral and peripheral (hands/feet) ice chip cryotherapy during oxaliplatin administration. CIPN and other symptoms are assessed at baseline, 6 weeks, and 3 months from registration. The primary endpoint is CIPN severity at 3 months (EORTC-CIPN 20). Additional endpoints evaluate CIPN incidence (CTCAE, Neuropen, tuning fork); incidence of pain, fatigue, nausea, oral dysesthesia, and anxiety; and feasibility (recruitment, retention, adherence, acceptability). If warranted, trial results will inform the design of a multi-center trial to expand testing of the intervention to a larger patient cohort.

A phase Ib adaptive study of dasatinib for the prevention of oxaliplatin-induced neuropathy in patients with gastrointestinal (GI) cancers receiving FOLFOX chemotherapy with or without bevacizumab.

e15613 Background: Neurotoxicity is one of the most significant and disabling side effects of oxaliplatin (OX) and frequently limits the amount of OX that can be used. OX uptake by organic cation transporter 2 (OCT2) into mouse and rat dorsal root ganglia is a prerequisite for OX-induced peripheral neuropathy (OIPN). Preclinical data in rat and mouse models from our group showed that by inhibiting YES1, pre-treatment with dasatinib (D) inactivated OCT2 and prevented acute and chronic OIPN. A phase I trial is ongoing investigating addition of D prior to OX to prevent OIPN. Methods: This is a Bayesian Phase 1b dose-finding study with adaptive dose selection using efficacy-toxicity trade-offs in patients (pts) with GI cancers who are candidates for mFOLFOX6 ± bevacizumab [NCT04164069]. Pts received chemotherapy on day 1 and 15 schedule, every 28 days. D was administered at one of 2 dose levels – 100mg or 140mg PO, given 24 hours and 30 mins prior to OX on C1D14, C1D15 respectively and repeated on C1D28 and C2D1. During cycle 1, pharmacokinetic and pharmacodynamic data was obtained at baseline, during, and up to 24 hours after D or OX administration. Recommended Phase 2 dose (RP2D) was defined as the lowest intermittent dose of D that increases serum biomarkers of OCT2, including methylnicotinamide (NMN) and creatinine, by ≥2-fold without influencing the clearance of oxaliplatin by ≥20%, toxicity profile was evaluated based on CTCAE v. 5.0. Results: 11 pts were screened. 5 pts enrolled in cohort 1 (D 100 mg) and 2 in cohort 2 (D 140 mg). In this preliminary analysis, 5 patients were evaluated for efficacy biomarkers and 4 pts were evaluated for both efficacy biomarkers and toxicity. There were no DLTs observed in either cohort. 3/5 pts had ≥2-fold increase in AUC of NMN, and 4/5 pts had ≥2-fold increase in AUC of creatinine. 4/5 pts had ≤20% change in the clearance of OX. Conclusions: Addition of D 140 mg to traditional FOLFOX regimen was safe and resulted in increasing levels of biomarkers as indication of inhibition of OCT2 in comparison to baseline for the majority of pts enrolled. Enrollment and analysis are ongoing at D 140mg dose to confirm the RP2D to prevent OPIN in a future randomized phase II study. Clinical trial information: NCT04164069 . [Table: see text]

Persistence of Oxaliplatin Transfer into Human Milk: A Case Report

Background: Oxaliplatin is an alkylating chemotherapeutic agent commonly used for malignancies in women of reproductive age, including colorectal cancer. No research previously exists regarding the transfer of platinum into milk after administration of oxaliplatin. Methods: We present a case of a lactating patient with stage 3a colorectal cancer requiring chemotherapy including oxaliplatin (130 mg/m2) infused every 4 weeks. Milk levels of platinum were tested at Lactation Lab, Inc., using a previously published mass spectrometry method. Results: Milk platinum concentrations 34 and 65 days after treatment were 7.8 and 10.3 ng/mL, respectively. Conclusion: These levels are similar to cisplatin or carboplatin in the immediate weeks after their administration, suggesting that the equivalent platinum exposure risk persists for longer with oxaliplatin than with other platinum analogues. Findings from this report support current recommendations to cease breastfeeding after oxaliplatin administration.

TRPM3 as a novel target to alleviate acute oxaliplatin-induced peripheral neuropathic pain.

Chemotherapy-induced peripheral neuropathic pain (CIPNP) is an adverse effect observed in up to 80% of patients of cancer on treatment with cytostatic drugs including paclitaxel and oxaliplatin. Chemotherapy-induced peripheral neuropathic pain can be so severe that it limits dose and choice of chemotherapy and has significant negative consequences on the quality of life of survivors. Current treatment options for CIPNP are limited and unsatisfactory. TRPM3 is a calcium-permeable ion channel functionally expressed in peripheral sensory neurons involved in the detection of thermal stimuli. Here, we focus on the possible involvement of TRPM3 in acute oxaliplatin-induced mechanical allodynia and cold hypersensitivity. In vitro calcium microfluorimetry and whole-cell patch-clamp experiments showed that TRPM3 is functionally upregulated in both heterologous and homologous expression systems after acute (24 hours) oxaliplatin treatment, whereas the direct application of oxaliplatin was without effect. In vivo behavioral studies using an acute oxaliplatin model for CIPNP showed the development of cold and mechano hypersensitivity in control mice, which was lacking in TRPM3 deficient mice. In addition, the levels of protein ERK, a marker for neuronal activity, were significantly reduced in dorsal root ganglion neurons derived from TRPM3 deficient mice compared with control after oxaliplatin administration. Moreover, intraperitoneal injection of a TRPM3 antagonist, isosakuranetin, effectively reduced the oxaliplatin-induced pain behavior in response to cold and mechanical stimulation in mice with an acute form of oxaliplatin-induced peripheral neuropathy. In summary, TRPM3 represents a potential new target for the treatment of neuropathic pain in patients undergoing chemotherapy.

The involvement of Aurora-A and p53 in oxaliplatin-resistant colon cancer cells.

Resistance to chemotherapy is the deadlock in cancer treatment. In this study, we used wild-type LOVO (LOVOWT ), a human colon cancer cell line, and the oxaliplatin-resistant sub-clone LOVOOR cells to investigate the molecular mechanisms of the development of drug resistance in colon cancer. Compared with LOVOWT cells, LOVOOR cells had a high proliferation capacity and a high percentage on the G2/M phase. The expression and activation of Aurora-A, a critical kinase in G2/M phase, were higher in LOVOOR cells than in LOVOWT cells. The results from immunofluorescence indicated an irregular distribution of Aurora-A in LOVOOR cells. To evaluate the importance of Aurora-A in oxaliplatin-resistant property of LOVOOR cells, overexpression of Aurora-A in LOVOWT cells and otherwise knockdown of Aurora-A in LOVOOR cells were performed and followed by administration of oxaliplatin. The results indicated that Aurora-A might contribute to the resistance of LOVOOR cells to oxaliplatin treatment by depressing p53 signaling. The specific findings in this study provide a possibility that targeting Aurora-A might be a solution for patients who have failed oxaliplatin treatment.

Effect of Severe Renal Dysfunction on the Plasma Levels of DNA-Reactive Platinum after Oxaliplatin Administration.

Higher amounts of circulating ultrafilterable platinum (fPt) are found in patients with renal dysfunction receiving a constant dose of oxaliplatin. However, the increased systemic fPt levels do not increase oxaliplatin-induced toxicities. We hypothesized that renal dysfunction has minimal effect on the elimination rate of reactive fPt, and that the DNA-binding capacity is one of the properties of reactive Pt species. This study aimed to quantify DNA-reactive fPt in plasma and to evaluate the impact of severe renal dysfunction on its pharmacokinetics. The pharmacokinetics of oxaliplatin was assessed in rats with bilateral nephrectomy (BNx) and in a hemodialysis patient who received mFOLFOX7 therapy for advanced metastatic gastric cancer. The platinum concentrations were determined using inductively coupled plasma-mass spectrometry. The amount of DNA-reactive fPt in the plasma was evaluated by the reaction between plasma and calf thymus DNA. Compared to the sham group in rats, the BNx group had significantly higher plasma total fPt concentrations at 24 h after drug administration. However, there was no significant difference in the plasma levels of DNA-reactive fPt between the two groups. In a hemodialysis patient, the plasma levels of total fPt decreased to 35.9 and 7.3% at 2 and 14 d after treatment, respectively. The plasma level of DNA-reactive fPt also decreased to 1.9 and 0.6%, respectively, on these days. This study showed that severe renal dysfunction has a limited effect on the plasma levels of DNA-reactive fPt after oxaliplatin administration.

Impact of high-dose dexamethasone and prolonged infusion time to prevent hypersensitivity reaction related to oxaliplatin in patients with colorectal cancer.

49 Background: Oxaliplatin (OXA) is one of the major cytotoxic agents for the treatment of gastrointestinal tumors. Hypersensitivity reaction (HSR) is one of major reasons of not continuing OXA-based chemotherapy, similar to chemotherapy-induced peripheral neuropathy (CIPN). We developed prevention of the HSR protocol and evaluated its clinical application. Methods: We have retrospectively evaluated and characterized HSR reaction in metastatic colorectal cancer patients exposed to an OXA-containing regimen between 2005 and 2019. We also evaluated the clinical utility of a prevention of the HSR protocol for mCRC patients occurred in grade 1, grade 2 or grade 3 HSR after administration of OXA-based chemotherapy. The prevention of HSR protocol is based on increasing the dose of dexamethasone to 16.5 mg/body, chlorpheniramine to 5 mg, famotidine to 20mg, and the administration time of OXA is extended to 4 hours. Results: A total of 209 patients (median age 61 years, range: 27 to 80) were experienced grade 1 (106 patients, 50.7%), grade 2 (98 patients, 46.0%), or grade 3 HSR (5 patients, 3.3%). Most of the patients had been treated with the FOLFOX4 or modified FOLFOX6 regimen (86.6%). The median number of cycles of OXA administration until the initial onset of HSR was 11 (range: 2 to 48). 111 patients (53.1%) succeeded in OXA re-administration under the prevention of HSR protocol. The median OXA free interval was 23 days (range: 13 to 890). The median progression-free survival after OXA re-administration was 7.0 months (95%CI: 5.3 to 10.4). The reason for the prevention of HSR protocoldiscontinuation was HSR in 98 patients (46.9%), disease progression in 77 patients (36.9%) and CIPN in 17 patients (8.1%), respectively. Forty-eight patients (49.0%) had HSR during the first cycle of OXA re-administration and the median time to HSR after OXA re-administration was 14 days (95%CI 0-19). Grade 3 HSR after OXA re-administrationwere observed in only 6 patients (6.1%) and no one experienced Grade 4 or 5 HSR. Conclusions: Hi-dose dexamethasone and an increased infusion time may allow for OXA re-administration. The prevention of the HSR protocol may provide an alternative to permanent discontinuation of OXA.

Preoperative Radiochemotherapy in Rectal Cancer: Is There an Impact of Oxaliplatin on Pathologic Complete Response and Survival Rates under "Real World" Conditions?

This study aimed to evaluate the benefit of additional administration of oxaliplatin during fluorouracil-based neoadjuvant radiochemotherapy (nRCT) in terms of pathologic complete remission (pCR), disease-free survival (DFS), and overall survival (OS) in patients with advanced rectal cancer. Between 2006 and 2021, 669 patients (pts) were diagnosed with locally advanced rectal cancer, of whom a total of 414 pts with nRCT were identified and included in the study. A total of 283 pts were treated by nRCT using concurrent chemotherapy with fluorouracil or capecitabine; 131 pts were treated using a combination of fluorouracil or capecitabine and oxaliplatin. Propensity score matching analyses (PSM) with 114 pts in each group were used to balance the patients' characteristics. OS, DFS, pCR-rate, and potential prognostic factors were compared between the two groups. The median follow-up time was 59.5 weeks in the fluorouracil-group and 43 weeks in the fluorouracil/oxaliplatin group (p = 0.003). After PSM, the pCR-rate (including sustained clinical complete remission) was 27% (31/114 pts) in the fluorouracil/oxaliplatin group and 16% (18/114 pts) in the fluorouracil-group (p = 0.033). There was no difference between these two groups for both 10-year OS and DFS neither before nor after PSM, respectively (OS: 72.6% vs. 55.4%, p = 0.066, and 67.8% vs. 55.1%, p = 0.703, and DFS: 44.8% vs. 46.8%, p = 0.134, and 44.7% vs. 42.3%, p = 0.184). Multivariate analysis identified regression grading according to Dworak grade 4 (HR: 0.659; CI: 0.471-0.921; p = 0.015) and age over 60 years (HR: 2.231; CI: 1.245-4.001; p = 0.007) as independent predictors for OS. In conclusion, the addition of oxaliplatin to fluorouracil during nRCT significantly improved pCR-rate without having an impact on survival.

Prevention of Chemotherapy-Induced Peripheral Neuropathy by Inhibiting C-X-C Motif Chemokine Receptor 2.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major drawback in the use of chemotherapeutic agents for patients with cancer. Although studies have investigated a broad number of molecules that might be related to CIPN, the differences in the chemokine pathways between various chemotherapeutic agents, such as vincristine and oxaliplatin, which are some of the most widely used treatments, have not been fully elucidated. We confirmed that the administration (intraperitoneal injections for seven days) of vincristine (0.1 mg/kg) and oxaliplatin (3 mg/kg) induced pain by using the von Frey behavioral test. Subsequent applications with vincristine and oxaliplatin led to mechanical allodynia that lasted more than one week from the fifth day. After the induction of mechanical allodynia, the mRNA expression of CXCR2, CXCL1, CXCL3, and CXCL5 was examined in the dorsal root ganglia (DRG) and spinal cord of the CIPN models. As a result, the mRNA expression of CXCR2 robustly increased in the lumbar spinal cord in the oxaliplatin-treated mice. Next, to evaluate the involvement of CXCR2 in CIPN, reparixin, a CXCR1/2 inhibitor, was administered intrathecally or intraperitoneally with vincristine or oxaliplatin and was further verified by treatment with ruxolitinib, which inhibits Janus kinase 2 downstream of the CXCR1/2 pathway. Reparixin and ruxolitinib blocked oxaliplatin-induced allodynia but not vincristine-induced allodynia, which suggests that CXCR2-related pathways are associated with the development of oxaliplatin-induced neuropathy. Together with the above results, this suggests that the prevention of oxaliplatin-induced neuropathy by CXCR2 inhibition can lead to successful chemotherapy, and it is important to provide appropriate countermeasures against CIPN development for each specific chemotherapeutic agent.

ANTI-TUMORAL EFFECT OF 5-FLUOROURACIL AND OXALIPLATIN IN A LIVER REGENERATION MODEL

Abstract Introduction Colorectal cancer liver metastases (CRCLM) continue to be a therapeutic challenge, since their resectability is usually limited by the functionality of the liver remnant. In this context, it is necessary to study the regenerative response of the liver in a selective portal vein ligation (PVL) model, after the administration of 5-fluorouracil and oxaliplatin, and to assess the effect of compensatory hypertrophy on tumor progression. Methods Twenty-eight WAG/RijHsd rats carrying CRCLM were divided into four groups: control, PVL, 5FU (50mg/kg) and 5FU+Oxaliplatin (50mg/kg+10mg/kg). After 18 days of tumor development, a dose of the corresponding treatment was administered, performing a PVL of 50% 72h later. Seven days later, tumor size was quantified and a biochemical profile was performed. Results The 5FU+Oxaliplatin and 5FU alone treatment decreased tumor growth by 6 and 3 times compared to the PVL and control groups, respectively (p&amp;lt;0.001). At a biochemical level, the combination of drugs resulted in a decrease in albumin levels (3.3 ± 0.39 mg/dl; p&amp;lt;0.02) and a significant weight loss of 10%; however, glucose (152±6.6 mg/dl), AST (161±27.1 IU/L), and ALT (46.7±9.4 IU/L) were not significantly altered. Seven days after PVL, the liver remnant did not change in either group (5FU+Oxaliplatin: 8±1; 5FU: 9.7±1.2; control 9.4±1.9 g; p&amp;gt;0.05). Conclusion In our model, the combined therapy of 5-Fluorouracil and oxaliplatin, prior to PVL, does not affect the necessary hepatic regeneration; while the volume of tumor implants decreases, no significant alteration of the biochemical parameters is detected.

2-Bromopalmitate decreases spinal inflammation and attenuates oxaliplatin-induced neuropathic pain via reducing Drp1-mediated mitochondrial dysfunction.

Oxaliplatin (OXA) is a third-generation platinum compound with clinical activity in multiple solid tumors. Due to the repetition of chemotherapy cycle, OXA-induced chronic neuropathy presenting as paresthesia and pain. This study explored the neuropathy of chemotherapy pain and investigated the analgesic effect of 2-bromopalmitate (2-BP) on the pain behavior of OXA-induced rats. The chemotherapy pain rat model was established by the five consecutive administration of OXA (intraperitoneal, 4 mg/kg). After the establishment of OXA-induced rats, the pain behavior test, inflammatory signal analysis and mitochondrial function measurement were conducted. OXA-induced rats exhibited mechanical allodynia and spinal inflammatory infiltration. Our fluorescence and western blot analysis revealed spinal astrocytes were activated in OXA rats with up-regulation of astrocytic markers. In addition, NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome mediated inflammatory signal cascade was also activated. Inflammation was triggered by dysfunctional mitochondria which represented by increase in cyclooxygenase-2 (COX-2) level and manganese superoxide dismutase (Mn-SOD) activity. Intrathecally injection of 2-BP significantly attenuated dynamin-related protein 1 (Drp1) mediated mitochondrial fission, recovered mitochondrial function, suppressed NLRP3 inflammasome cascade, and consequently decreased mechanical pain sensitivity. For cell research, 2-BP treatment significantly reversed tumor necrosis factor-α (TNF-α) induced mitochondria membrane potential deficiency and high reactive oxygen species (ROS) level. These findings indicate 2-BP decreases spinal inflammation and relieves OXA-induced neuropathic pain via reducing Drp1-mediated mitochondrial dysfunction.

A case of percutaneous transhepatic stomal varices embolization and partial splenic artery embolization for rectal cancer after CAPOX/BEV chemotherapy: the summary of the stomal varices related to oxaliplatin administration

Capecitabine and oxaliplatin (CAPOX) plus bevacizumab (BEV) therapy (CAPOX/BEV) is a standard treatment recommended as the first-line treatment for colorectal cancer recurrence. Recently, sinusoidal obstruction syndrome (SOS) and resulting portal hypertension have been reported as important side effects of oxaliplatin. We herein report a rectal cancer patient who underwent percutaneous transhepatic stoma variceal embolization (PTO) and partial splenic artery embolization (PSE) for stomal variceal bleeding and splenomegaly due to portal hypertension caused by SOS after CAPOX therapy. A 43-year-old man who underwent robot-assisted laparoscopic abdominoperineal resection for advanced lower rectal cancer was started on CAPOX/BEV therapy for early recurrence 1 month after surgery. In the sixth course, splenomegaly rapidly worsened, stomal varices appeared, and the stoma began bleeding. At 5 months after the appearance of stomal varices, the splenomegaly worsened, the frequency of stomal bleeding increased, and PTO was performed. Five months later, PSE was performed for splenomegaly and thrombocytopenia. At 5 months since the PSE, the stoma bleeding has not recurred, and the thrombocytopenia has been corrected. The patient has been able to continue chemotherapy. We suggest that staged treatment by PTO and PSE be considered an important treatment option for stomal varices and splenomegaly associated with SOS.

Emodin suppresses oxaliplatin-induced neuropathic pain by inhibiting COX2/NF-κB mediated spinal inflammation.

Oxaliplatin (OXA) is a common chemotherapy drug for colorectal, gastric, and pancreatic cancers. The anticancer effect of OXAis often accompanied by neurotoxicity and acute and chronic neuropathy. The symptoms present as paresthesia and pain which adversely affect patients' quality of life. Herein, five consecutive intraperitoneal injections of OXA at a dose of 4 mg/kg were used to mimic chemotherapy. OXA administration induced mechanical allodynia, activated spinal astrocytes, and increased inflammatory response. To develop an effective therapeutic measure for OXA-induced neuropathic pain, emodin was intrathecally injected into OXA rats. Emodin developed an analgesic effect, as demonstrated by a significant increase in the paw withdrawal threshold of OXA rats. Moreover, emodin treatment reduced thepro-inflammatory cytokines (tumor necrosis factor-α and interleukin-1β) which upregulated in OXA rats. Furthermore, autodock data showed four hydrogen bonds were formed between emodin and cyclooxygenase-2(COX2), and emodin treatment decreased COX2 expression in OXA rats. Cell research further proved that emodin suppressed nuclear factor κB (NF-κB)-mediated inflammatory signal and reactive oxygen specieslevel. Taken together, emodin reduced spinal COX2/NF-κB mediated inflammatory signal and oxidative stress in the spinal cord of OXA rats which consequently relieved OXA-induced neuropathic pain.

Changes in the expression of endocannabinoid system components in an experimental model of chemotherapy-induced peripheral neuropathic pain: Evaluation of sex-related differences

Chemotherapy-induced neuropathic pain is a serious clinical problem and one of the major side effects in cancer treatment. The endocannabinoid system (ECS) plays a crucial role in regulating pain neurotransmission, and changes in the expression of different components of the ECS have been reported in experimental models of persistent pain. In addition, sex differences have been observed in ECS regulation and function. The aim of our study was to evaluate whether administration of oxaliplatin, a neurotoxic antineoplastic agent, induced changes in the expression of ECS components in peripheral and central stations of the pain pathway, and if those changes exhibited sexual dimorphism.Adult male and female rats were injected with oxaliplatin or saline, and mechanical and cold hypersensitivity and allodynia were evaluated using Von Frey and Choi Tests. The mRNA levels corresponding to cannabinoid receptors (CB1, CB2), cannabinoid-related receptors (GPR55, 5HT1A, TRPV1) and to the main enzymes involved in the synthesis (DAGL, DAGL, NAPE-PLD) and degradation (MGL, FAAH) of endocannabinoids were assessed in lumbar dorsal root ganglia (DRGs) and spinal cord by using real time RT-PCR. In addition, the levels of the main endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), were evaluated using commercial ELISA kits.Oxaliplatin administration induced the development of mechanical and cold hypersensitivity and allodynia in male and female animals. Oxaliplatin also induced early and robust changes in the expression of several components of the ECS in DRGs. A marked upregulation of CB1, CB2, 5HT1A and TRPV1 was detected in both sexes. Interestingly, while DAGL mRNA levels remained unchanged, DAGL was downregulated in male and upregulated in female rats. Finally, MGL and NAPE-PLD showed increased levels only in male animals, while FAAH resulted upregulated in both sexes. In parallel, reduced 2-AG and AEA levels were detected in DRGs from male or female rats, respectively. In the lumbar spinal cord, only TRPV1 mRNA levels were found to be upregulated in both sexes.Our results reveal previously unreported changes in the expression of cannabinoid receptors, ligands and enzymes occurring mainly in the peripheral nervous system and displaying certain sexual dimorphism. These changes may contribute to the physiopathology of oxaliplatin-induced neuropathic pain in male and female rats. A better understanding of these dynamic changes will facilitate the development of mechanism- and sex-specific approaches to optimize the use of cannabinoid-based medicines for the treatment of chemotherapy-induced pain.

Fatty acids homeostasis during fasting predicts protection from chemotherapy toxicity

Fasting exerts beneficial effects in mice and humans, including protection from chemotherapy toxicity. To explore the involved mechanisms, we collect blood from humans and mice before and after 36 or 24 hours of fasting, respectively, and measure lipid composition of erythrocyte membranes, circulating micro RNAs (miRNAs), and RNA expression at peripheral blood mononuclear cells (PBMCs). Fasting coordinately affects the proportion of polyunsaturated versus saturated and monounsaturated fatty acids at the erythrocyte membrane; and reduces the expression of insulin signaling-related genes in PBMCs. When fasted for 24 hours before and 24 hours after administration of oxaliplatin or doxorubicin, mice show a strong protection from toxicity in several tissues. Erythrocyte membrane lipids and PBMC gene expression define two separate groups of individuals that accurately predict a differential protection from chemotherapy toxicity, with important clinical implications. Our results reveal a mechanism of fasting associated with lipid homeostasis, and provide biomarkers of fasting to predict fasting-mediated protection from chemotherapy toxicity.

Sex-related differences in oxaliplatin-induced changes in the expression of transient receptor potential channels and their contribution to cold hypersensitivity

Transient receptor potential (TRP) channels are involved in the development of oxaliplatin-induced neuropathic pain, a frequent and debilitating side effect of cancer therapy. Here we explored whether oxaliplatin-induced changes in the expression of TRP channels, as well as the development of pain-related behaviours, differed between male and female animals. Adult rats were injected with oxaliplatin or saline and mechanical and cold allodynia were evaluated using Von Frey and Choi Tests. The mRNA levels of TRPV1, TRPM8 and TRPA1 were assessed in lumbar ganglia and spinal cord by using real time RT-PCR. Oxaliplatin administration induced mechanical and cold hypersensitivity and allodynia in both sexes, with more severe responses to cold stimulation detected in females. Oxaliplatin also induced a significant increase in the expression of TRPV1, TRPM8 and TRPA1 in lumbar dorsal root ganglia. Interestingly, while TRPV1 and TRPA1 upregulation showed no sex difference, the increase in TRPM8 mRNA levels was more pronounced in female ganglia, correlating with the increased sensitivity to innocuous cold stimuli observed in females. TRPV1 and TRPM8 were also found to be upregulated in the spinal cord of animals of both sexes. Our results reveal previously undescribed changes in the expression of TRP channels occurring in peripheral ganglia and spinal cord of both male and female oxaliplatin-treated animals, with some of these changes exhibiting sex-related differences that could underlie the development of sex-specific patterns of pain-related behaviours.

RNA editing facilitates the enhanced production of neoantigens during the simultaneous administration of oxaliplatin and radiotherapy in colorectal cancer

Most cases of colorectal cancers (CRCs) are microsatellite stable (MSS), which frequently demonstrate lower response rates to immune checkpoint inhibitors (ICIs). RNA editing produces neoantigens by altering amino acid sequences. In this study, RNA editing was induced artificially by chemoradiation therapy (CRT) to generate neoantigens in MSS CRCs. Altogether, 543 CRC specimens were systematically analyzed, and the expression pattern of ADAR1 was investigated. In vitro and in vivo experiments were also performed. The RNA editing enzyme ADAR1 was upregulated in microsatellite instability–high CRCs, leading to their high affinity for ICIs. Although ADAR1 expression was low in MSS CRC, CRT including oxaliplatin (OX) treatment upregulated RNA editing levels by inducing ADAR1. Immunohistochemistry analyses showed the upregulation of ADAR1 in patients with CRC treated with CAPOX (capecitabine + OX) radiation therapy relative to ADAR1 expression in patients with CRC treated only by surgery (p < 0.001). Compared with other regimens, CRT with OX effectively induced RNA editing in MSS CRC cell lines (HT29 and Caco2, p < 0.001) via the induction of type 1 interferon-triggered ADAR1 expression. CRT with OX promoted the RNA editing of cyclin I, a neoantigen candidate. Neoantigens can be artificially induced by RNA editing via an OX–CRT regimen. CRT can promote proteomic diversity via RNA editing.

A Fe(III)-porphyrin-oxaliplatin(IV) nanoplatform for enhanced ferroptosis and combined therapy.

Since there are several limitations in cancer treatment for traditional chemotherapy, such as side effects, poor prognosis and drug resistance, developing new combined therapy is urgently needed. In this work, a biocompatible, simple and tumor microenvironment-responsive nanotheranostics (PCN-Oxpt/PEG) was built to favor the chemotherapy/ferroptosis/immunomodulation synergism in cancer. This nanotheranostics is constructed by modifying oxaliplatin prodrug and PEG on Fe(III)-porphyrin metal-organic frameworks (PCN(Fe) MOFs). After intravenous injection, the cloak of PEG leads to long circulation, and the Fe(III)-porphyrin MOFs enables dual-model guidance with fluorescence (FL) and magnetic resonance imaging (MRI). Inside the tumor, the intracellular H2O2 would be transferred into hydroxyl radicals (•OH) by iron ions released from MOFs, which could trigger the lethal ferroptosis to cancer cells. Meanwhile, oxaliplatin(II) transformed from the loaded oxaliplatin prodrug would result in the chemotherapy, as well as immunogenic cell death (ICD), and the prodrug strategy could also avoid the occurring of liver damage by the direct administration of oxaliplatin(II). It was noticed that the ferroptosis effect was enhanced by triple-assistance during the combined therapy, as followed: (1) glutathione (GSH) would be consumed in the process of oxaliplatin(II) generation from oxaliplatin prodrug; (2) the increased CD8+ T cells induced by ICD were able to produce interferon-γ (IFN-γ), which could inhibit the transport of cystine by tumor cells, and impair the activation of glutathione peroxidase 4 (GPX4); (3) the amount of H2O2 could be increased by the internalized oxaliplatin and thus further promote the Fenton reaction and ferroptosis. Both in vivo and in vitro results revealed that tumor growing was significantly inhibited by PCN-Oxpt/PEG, taken together, the concomitant of oxaliplatin-mediated chemotherapy and ICD with triple-enhanced ferroptosis offer great prospect in the clinical treatment of cancer.

Resveratrol ameliorates oxaliplatin-induced neuropathic pain via anti-inflammatory effects in rats.

Oxaliplatin (OXA) is a common chemotherapy drug and exhibits clinical activity in several cancer types. Its anticancer clinical effect is frequently accompanied by neurotoxicity. The symptoms include paresthesia and pain, which adversely affect the quality of life of patients. In the present study, five consecutive intraperitoneal injections of 4 mg/kg OXA were used to mimic chemotherapy in rats. OXA administration induced mechanical allodynia, activated spinal astrocytes and triggered the inflammatory response. To explore potential therapeutic options for OXA-induced neuropathic pain, resveratrol (Res) was intrathecally injected into the spinal cord of OXA-treated rats. Paw withdrawal threshold values of OXA-treated rats were increased, indicating an antinociception effect of Res on OXA-induced pain. Additionally, Res treatment reduced the levels of glial fibrillary acidic protein, TNF-α, IL-1β and NF-κB, which were upregulated in OXA-treated rats (compared with control). Furthermore, Auto Dock data showed that Res binds to cyclooxygenase-2 (COX-2) through six hydrogen bonds. Western blot analysis and reactive oxygen species (ROS) assays indicated that Res treatment decreased COX-2 expression and suppressed ROS production. In summary, intrathecal injection of Res reduced the spinal COX-2-mediated ROS generation and inflammatory reaction, suppressed astrocytic activation, and alleviated OXA-induced neuropathic pain.