RESUMO
BACKGROUND: The optimal chemotherapy backbone for HER2-negative advanced esophagogastric cancer, either in combination with targeted therapies or as a comparator in clinical trials, is uncertain. The subtle yet crucial differences in platinum-based regimens' safety and synergy with combination treatments need consideration. METHODS: We analyzed cases from the AGAMENON-SEOM Spanish registry of HER2-negative advanced esophagogastric adenocarcinoma treated with platinum and fluoropyrimidine from 2008 to 2021. This study focused exclusively on patients receiving one of the four regimens: FOLFOX (5-FU and oxaliplatin), CAPOX (capecitabine and oxaliplatin), CP (capecitabine and cisplatin) and FP (5-FU and cisplatin). The aim was to determine the most effective and tolerable platinum and fluoropyrimidine-based chemotherapy regimen and to identify any prognostic factors. RESULTS: Among 1293 patients, 36% received either FOLFOX (n = 468) or CAPOX (n = 466), 20% CP (n = 252), and 8% FP (n = 107). FOLFOX significantly increased PFS (progression free survival) compared to CP, with a hazard ratio of 0.73 (95% CI 0.58-0.92, p = 0.009). The duration of treatment was similar across all groups. Survival outcomes among regimens were similar, but analysis revealed worse ECOG-PS (Eastern Cooperative Oncology Group-Performance Status), > 2 metastatic sites, bone metastases, hypoalbuminemia, higher NLR (neutrophil-to-lymphocyte ratio), and CP regimen as predictors of poor PFS. Fatigue was common in all treatments, with the highest incidence in FOLFOX (77%), followed by FP (72%), CAPOX (68%), and CP (60%). Other notable toxicities included neuropathy (FOLFOX 69%, CAPOX 62%), neutropenia (FOLFOX 52%, FP 55%), hand-foot syndrome in CP (46%), and thromboembolic events (FP 12%, CP 11%). CONCLUSIONS: FOLFOX shown better PFS than CP. Adverse effects varied: neuropathy was more common with oxaliplatin, while thromboembolism was more frequent with cisplatin.
Assuntos
Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Capecitabina , Cisplatino , Neoplasias Esofágicas , Fluoruracila , Leucovorina , Oxaliplatina , Receptor ErbB-2 , Sistema de Registros , Neoplasias Gástricas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Fluoruracila/uso terapêutico , Fluoruracila/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Capecitabina/uso terapêutico , Capecitabina/administração & dosagem , Receptor ErbB-2/metabolismo , Leucovorina/uso terapêutico , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Oxaliplatina/uso terapêutico , Oxaliplatina/administração & dosagem , Cisplatino/uso terapêutico , Cisplatino/administração & dosagem , Adulto , Compostos Organoplatínicos/uso terapêutico , Compostos Organoplatínicos/administração & dosagem , Intervalo Livre de Progressão , Junção Esofagogástrica/patologia , Idoso de 80 Anos ou mais , EspanhaRESUMO
Colorectal cancer (CRC) is the third most common and deadliest cancer globally. Regimens using 5-fluorouracil (5FU) and Oxaliplatin (OXA) are the first-line treatment for CRC, but tumor recurrence is frequent. It is plausible to hypothesize that differential cellular responses are triggered after treatments depending on the genetic background of CRC cells and that the rational modulation of cell tolerance mechanisms like autophagy may reduce the regrowth of CRC cells. This study proposes investigating the cellular mechanisms triggered by CRC cells exposed to 5FU and OXA using a preclinical experimental design mimicking one cycle of the clinical regimen (i.e., 48 h of treatment repeated every 2 weeks). To test this, we treated CRC human cell lines HCT116 and HT29 with the 5FU and OXA, combined or not, for 48 h, followed by analysis for two additional weeks. Compared to single-drug treatments, the co-treatment reduced tumor cell regrowth, clonogenicity and stemness, phenotypes associated with tumor aggressiveness and poor prognosis in clinics. This effect was exerted by the induction of apoptosis and senescence only in the co-treatment. However, a week after treatment, cells that tolerated the treatment had high levels of autophagy features and restored the proliferative phenotype, resembling tumor recurrence. The pharmacologic suppression of early autophagy during its peak of occurrence, but not concomitant with chemotherapeutics, strongly reduced cell regrowth. Overall, our experimental model provides new insights into the cellular mechanisms that underlie the response and tolerance of CRC cells to 5FU and OXA, suggesting optimized, time-specific autophagy inhibition as a new avenue for improving the efficacy of current treatments.
Assuntos
Neoplasias Colorretais , Humanos , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Neoplasias Colorretais/genética , Recidiva Local de Neoplasia , Células HT29 , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Apoptose , Autofagia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genéticaRESUMO
Oxaliplatin (OXA) is an antineoplastic agent used for the treatment of cisplatin-resistant tumours, presenting lower incidence of nephrotoxicity and myelotoxicity than other platinum-based drugs. However, OXA treatment is highly associated with painful peripheral neuropathy, a well-known and relevant side effect caused by mitochondrial dysfunction. The transfer of functional exogenous mitochondria (mitotherapy) is a promising therapeutic strategy for mitochondrial diseases. We investigated the effect of mitotherapy on oxaliplatin-induced painful peripheral neuropathy (OIPN) in male mice. OIPN was induced by i.p. injections of oxaliplatin (3 mg/kg) over 5 consecutive days. Mechanical (von Frey test) and cold (acetone drop test) allodynia were evaluated between 7 and 17 days after the first OXA treatment. Mitochondria was isolated from donor mouse livers and mitochondrial oxidative phosphorylation was assessed with high resolution respirometry. After confirming that the isolated mitochondria were functional, the organelles were administered at the dose of 0.5 mg/kg of mitochondrial protein on days 1, 3 and 5. Treatment with OXA caused both mechanical and cold allodynia in mice that were significant 7 days after the initial injection of OXA and persisted for up to 17 days. Mitotherapy significantly prevented the development of both sensory alterations, and attenuated body weight loss induced by OXA. Mitotherapy also prevented spinal cord ERK1/2 activation, microgliosis and the increase in TLR4 mRNA levels. Mitotherapy prevented OIPN by inhibiting neuroinflammation and the consequent cellular overactivity in the spinal cord, presenting a potential therapeutic strategy for pain management in oncologic patients undergoing OXA treatment.
Assuntos
Antineoplásicos , Dor , Doenças do Sistema Nervoso Periférico , Humanos , Masculino , Camundongos , Animais , Oxaliplatina/toxicidade , Hiperalgesia/induzido quimicamente , Hiperalgesia/prevenção & controle , Hiperalgesia/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Antineoplásicos/toxicidadeRESUMO
We present the case of a 64-year-old female with stage IV gastric adenocarcinoma, pulmonary, and abdominal wall metastases, and no history of cardiovascular disease. In palliative care, she received systemic cytotoxic treatment with fluorouracil, leucovorin, oxaliplatin, and docetaxel protocol, which was well tolerated over five cycles. During cycle 6, she presented with cardiovascular symptoms with hemodynamic consequences while receiving oxaliplatin injection without docetaxel or 5-fluorouracil. She was transferred to the emergency department and then to the intensive care unit. She developed no complications during the hospital stay and was discharged after 10 days with preserved systolic function and no structural changes at the myocardial level. The electrocardiogram, echocardiogram, cardiac catheterization, and magnetic resonance imaging findings indicated an oxaliplatin-associated Takotsubo syndrome. The immunochemistry analysis showed PD-L1 expression level TPS: 40% and the foundation one genomic profiling revealed high mutation load, microsatellite instability, and HER2 not found. The patient is currently asymptomatic and on pembrolizumab monotherapy with good tolerance and partial treatment response.
RESUMO
Peripheral neuropathy is an important adverse effect caused by some chemotherapeutic agents, including oxaliplatin (OXA). OXA-induced peripheral neuropathy (OIPN) is a challenging condition due to diagnostic complexities and a lack of effective treatment. In this study, we investigated the antiallodynic effect of ß-caryophyllene (BCP), a cannabinoid type 2 (CB2) receptor agonist, in a mouse model of OIPN. BCP treatment inhibited OXA-induced mechanical and cold allodynia in both preventive and therapeutic drug treatment regimens. Experiments with the CB2 receptor agonist GW405833 confirmed the role of CB2 receptors in OIPN. The CB2 antagonist SR144528 abrogated the anti-nociceptive effect of BCP on mechanical allodynia, without impacting OXA-induced sensitivity to cold. BCP decreased neuroinflammation, as inferred from TNF, IL-1ß, IL-6, and IL-10 profiling, and also reduced ROS production, lipid peroxidation, and 4-hydroxynonenal protein adduct formation in the spinal cords of OXA-treated mice. BCP did not affect the antitumor response to OXA or its impact on blood cell counts, implying that the cytotoxicity of OXA was preserved. These results underscore BCP as a candidate drug for OIPN treatment via CB2 receptor-dependent mechanisms, and anti-inflammatory and antioxidant responses in the spinal cord.
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BACKGROUND: Contrary to the advantageous anticancer activities of curcumin (Cur), limited bioavailability and solubility hindered its efficacy. Here, nontoxic dendrosomal nano carrier with Cur was used to overcome these problems. Despite considerable antitumor properties of Oxaliplatin (Oxa), the limiting factors are drug resistance and adverse side-effects. The hypothesis of this study was to evaluate the possible synergism between dendrosomal nanocurcumin (DNC) and Oxa and these agents showed growth regulatory effects on SKOV3 and OVCAR3 cells. METHODS AND MATERIALS: In the present study, colony formation, wound healing motility, cell adhesion, transwell invasion and migration assay and cell cycle arrest with or without DNC, Oxa and Combination were defined. In addition to, real time PCR and Western blot were used to analyze AKT, PI3K, PKC, JNK, P38 and MMPs mRNAs and proteins expressions. Docking of MMP-2-Cur, MMP-2-DNC and MMP-2-Oxa was performed and the results of all three complexes were simulated by molecular dynamics. RESULTS: Our findings illustrated that DNC had the greatest effect on cell death as compared to the Cur alone. Moreover, the growth inhibitory effects (such as cell death correlated to apoptosis) were more intense if Oxa was added followed by DNC at 4 h interval. However, insignificant effects were observed upon simultaneous addition of these two agents in both cell lines. Besides, a combination of agents synergistically alters the relative expression of MMP-9. CONCLUSIONS: The docking results showed that His70 and Asp100 may play a key role at the MMP-2 binding site. The matrigel invasion as well as cell viability of ovarian cancer cell lines SKOV3 and OVCAR3 by DNC alone or in combination with Oxa was inhibited significantly. The inhibitory effects of these agents were due to the differential expression levels of MMP 2 and MMP 9 regulated by multiple downstream signaling cascades. From the molecular dynamic simulation studies, it was confirmed that DNC established a strong interaction with MMP-2.
Assuntos
Curcumina , Neoplasias Ovarianas , Humanos , Feminino , Oxaliplatina/farmacologia , Apoptose , Metaloproteinase 2 da Matriz/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Curcumina/farmacologia , Movimento CelularRESUMO
PURPOSE: Colorectal cancer (CRC) is a malignant tumor. Oxaliplatin (OXA) can inhibit cancer-associated fibroblasts (CAFs)-induced cancer progression. This study sought to explore the mechanism of OXA in CAFs-induced CRC development. METHODS: CRC cell lines (Caco-2, SW620), normal fibroblasts (NFs), and CAFs were treated with OXA. NFs and CAFs were cultured. CAFs were treated with/without OXA (0.4 mM), and the supernatant was extracted as the conditioned medium (CM) to culture CRC cells. Cell malignant episodes, E-cadherin and Vimentin levels, CXCL1, CXCL2, CXCL3, CXCL8, and CXCL11 mRNA levels, CXCL11 protein level, and extracellular release were assessed. CAFs were transfected with interfering RNA sh-CXCL11 to silence CXCL11 or transfected with CXCL11 overexpression plasmids and treated with OXA to explore the role of CXCL11 in OXA-mediated CRC cells through CAFs. CXCL11 receptor CXCR3 levels in CRC cells and the PI3K/AKT pathway changes were examined. The xenogeneic tumor was transplanted in nude mice. CXCL11 and CXCR3 levels in tumor tissues, tumor volume, shape, size, weight, and Ki67 positive expressions were assessed. RESULTS: CRC cell growths and epithelial-mesenchymal transformation were stimulated after culture with CAFs-CM, while OXA averted these trends. CXCL11 mRNA level was elevated most significantly, and its protein and extracellular secretion levels were raised, while OXA diminished the levels. CXCL11 silencing weakened the effects of CAFs-CM on promoting CRC proliferation and malignant episodes and CXCL11 overexpression averted OXA property on inhibiting CAFs-promoted CRC cell growth. CXCR3 and PI3K and AKT1 phosphorylation levels were raised in the CAFs-CM group but diminished by OXA. CXCL11 overexpression in CAFs averted OXA property on inhibiting CAFs-activated CXCR3/PI3K/AKT in CRC cells. OXA also inhibited the progression of xenograft tumors by limiting CAFs-secreted CXCL11. CONCLUSIONS: OXA repressed CRC progression by inhibiting CAFs-secreted CXCL11 and the CXCR3/PI3K/AKT pathway.
Assuntos
Fibroblastos Associados a Câncer , Neoplasias Colorretais , Animais , Camundongos , Humanos , Oxaliplatina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Camundongos Nus , Células CACO-2 , Linhagem Celular Tumoral , Fibroblastos/metabolismo , Neoplasias Colorretais/genética , Proliferação de Células , Movimento Celular/genética , Quimiocina CXCL11/metabolismo , Quimiocina CXCL11/farmacologia , Receptores CXCR3/metabolismoRESUMO
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.
Assuntos
Antineoplásicos , Canabinoides , Neuralgia , Feminino , Masculino , Ratos , Animais , Endocanabinoides/metabolismo , Endocanabinoides/uso terapêutico , Caracteres Sexuais , Hiperalgesia/metabolismo , Oxaliplatina/toxicidade , Canais de Cátion TRPV/metabolismo , Neuralgia/metabolismo , Receptores de Canabinoides/metabolismo , Antineoplásicos/toxicidade , Antineoplásicos/uso terapêutico , RNA Mensageiro , Modelos Teóricos , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/uso terapêutico , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismoRESUMO
BACKGROUND: Contrary to the advantageous anticancer activities of curcumin (Cur), limited bioavailability and solubility hindered its efficacy. Here, nontoxic dendrosomal nano carrier with Cur was used to overcome these problems. Despite considerable antitumor properties of Oxaliplatin (Oxa), the limiting factors are drug resistance and adverse side-effects. The hypothesis of this study was to evaluate the possible synergism between dendrosomal nanocurcumin (DNC) and Oxa and these agents showed growth regulatory effects on SKOV3 and OVCAR3 cells. METHODS: and materials In the present study, colony formation, wound healing motility, cell adhesion, transwell invasion and migration assay and cell cycle arrest with or without DNC, Oxa and Combination were defined. In addition to, real time PCR and Western blot were used to analyze AKT, PI3K, PKC, JNK, P38 and MMPs mRNAs and proteins expressions. Docking of MMP-2-Cur, MMP-2-DNC and MMP-2-Oxa was performed and the results of all three complexes were simulated by molecular dynamics. RESULTS: Our findings illustrated that DNC had the greatest effect on cell death as compared to the Cur alone. Moreover, the growth inhibitory effects (such as cell death correlated to apoptosis) were more intense if Oxa was added followed by DNC at 4 h interval. However, insignificant effects were observed upon simultaneous addition of these two agents in both cell lines. Besides, a combination of agents synergistically alters the relative expression of MMP-9. CONCLUSIONS: The docking results showed that His70 and Asp100 may play a key role at the MMP-2 binding site. The matrigel invasion as well as cell viability of ovarian cancer cell lines SKOV3 and OVCAR3 by DNC alone or in combination with Oxa was inhibited significantly. The inhibitory effects of these agents were due to the differential expression levels of MMP 2 and MMP 9 regulated by multiple downstream signaling cascades. From the molecular dynamic simulation studies, it was confirmed that DNC established a strong interaction with MMP-2.
Assuntos
Humanos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Curcumina/farmacologia , Movimento Celular , Apoptose , Metaloproteinase 2 da Matriz/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Oxaliplatina/farmacologiaRESUMO
Trop-2 is a highly conserved one-pass transmembrane mammalian glycoprotein that is normally expressed in tissues such as the lung, intestines, and kidney during embryonic development. It is overexpressed in many epithelial cancers but is absent in non-epithelial tumors. Trop-2 is an intracellular calcium signal transducer that participates in the promotion of cell proliferation, migration, invasion, metastasis, and probably stemness. It also has some tumor suppressor effects. The pro-tumoral actions have been thoroughly investigated and reported. However, Trop-2's activity in chemoresistance is less well known. We review a possible relationship between Trop-2, chemotherapy, and chemoresistance. We conclude that there is a clear role for Trop-2 in some specific chemoresistance events. On the other hand, there is no clear evidence for its participation in multidrug resistance through direct drug transport. The development of antibody conjugate drugs (ACD) centered on anti-Trop-2 monoclonal antibodies opened the gates for the treatment of some tumors resistant to classic chemotherapies. Advanced urothelial tumors and breast cancer were among the first malignancies for which these ACDs have been employed. However, there is a wide group of other tumors that may benefit from anti-Trop-2 therapy as soon as clinical trials are completed.
Assuntos
Amiloidose Familiar , Resistencia a Medicamentos Antineoplásicos , Feminino , Gravidez , Animais , Transporte Biológico , Cálcio da Dieta , Proliferação de Células , MamíferosRESUMO
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.
Assuntos
Neuralgia , Canais de Cátion TRPM , Canais de Potencial de Receptor Transitório , Animais , Temperatura Baixa , Síndromes Periódicas Associadas à Criopirina , Feminino , Gânglios Espinais/metabolismo , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Masculino , Neuralgia/metabolismo , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/metabolismo , Oxaliplatina/efeitos adversos , RNA Mensageiro/metabolismo , Ratos , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPM/metabolismo , Canais de Potencial de Receptor Transitório/metabolismoRESUMO
O câncer colorretal é uma neoplasia com alta prevalência e letalidade. A razão desse elevado número de mortes é a detecção da doença em estágios metastáticos, de difícil cura e que necessitam de terapia quimioterápica adjuvante ou paliativa. Na atualidade, o principal tratamento quimioterápico dessa neoplasia tem como base as drogas Oxaliplatina ou Irinotecano, isolados ou combinados com outros medicamentos. O objetivo desta revisão sistemática é avaliar se há superioridade do esquema quimioterápico com Irinotecano sobre o regime com Oxaliplatina. Foi realizada a análise de ensaios clínicos randomizados, fase II ou III, nas bases de dados eletrônicas Central e PubMed. Critérios de inclusão: ensaios clínicos randomizados comparando regimes à base de irinotecano ou oxaliplatina como tratamentos de primeira linha para câncer colorretal metastático. O desfecho primário analisado foi a superioridade entre os quimioterápicos sobre a sobrevida global. Os desfechos secundários incluíram sobrevida livre de progressão, taxa de resposta e efeitos colaterais. Registro na PROSPERO: CRD42019130339. Não houve diferença significativa nos 13 estudos sobre a sobrevida dos pacientes. Sobre os efeitos colaterais dos medicamentos, os regimes baseados em irinotecano foram associados a uma alta incidência de neutropenia e diarreia grave. Já os associados com oxaliplatin cursaram com alta incidência de neuropatia sensitiva. Não houve diferença estatisticamente significativa sobre a sobrevida global, sobrevivência livre de progressão e na taxa de resposta quando comparamos os pacientes que receberam oxaliplatina e irinotecano (AU)
Colorectal cancer is a highly prevalent and lethal neoplasm. The reason for this high number of deaths is the detection of the disease in metastatic stages, which are difficult to cure and require adjuvant or palliative chemotherapy therapy. Currently, the main chemotherapeutic treatment of this neoplasm is based on the drugs Oxaliplatin or Irinotecan, alone or combined with other drugs. The objective of this systematic review is to evaluate whether there is superiority of the chemotherapy regimen with Irinotecan over that with Oxaliplatin. Analysis of randomized clinical trials, phase II or III, was performed in the electronic databases Central and PubMed. Inclusion criteria: randomized clinical trials comparing irinotecan- or oxaliplatin-based regimens as first-line treatments for metastatic colorectal cancer. The primary endpoint analyzed was the superiority between chemotherapies on overall survival. Secondary endpoints included progression-free survival, response rate, and side effects. PROSPERO registration: CRD42019130339. There was no significant difference in the 13 studies on patient survival. On drug side effects, irinotecan-based regimens were associated with a high incidence of neutropenia and severe diarrhea. Those associated with oxaliplatin were associated with a high incidence of sensory neuropathy. There was no statistically significant difference in overall survival, progression-free survival, and response rate when comparing patients receiving oxaliplatin and irinotecan (AU)
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Neoplasias Colorretais/tratamento farmacológico , Irinotecano/uso terapêutico , OxaliplatinaRESUMO
INTRODUCTION: The FOLFOX6 scheme is a combination drug chemotherapy that contains calcium leucovorin (folinic acid), fluorouracil, and oxaliplatin, the chronic use of chemotherapy with oxaliplatin can progress to focal nodular hyperplasia (FNH), which is a benign hepatic lesion. CASE REPORT: We present a case of a 26- year-old female diagnosed with an ovarian mixed germ cell tumor with extension to the peritoneum, treated with 12 cycles in 9 months with neoadjuvant chemotherapy FOLFOX 6 scheme and oophorectomy. A three-year follow-up CT showed three nodular and hypervascular hepatic lesions suspicious of metastatic disease; an MRI with liver-specific contrast confirmed the diagnosis of FNH. MANAGEMENT AND OUTCOME: The patient continued her follow-up without other treatment and metastatic disease. DISCUSSION: While most multiple liver lesions in a patient with cancer will be suspicious of metastasis, a careful drug history should be obtained, as an oxaliplatin-related side effect to develop FNH has been reported. MRI with liver-specific contrast has a positive predictive value of 95% because of the biliary excretion through OATP1B3 transporter, expressed in functional hepatocytes and overexpressed in some liver tumors such as FNH, so it should be performed when FNH is suspected.
Assuntos
Hiperplasia Nodular Focal do Fígado , Neoplasias Hepáticas , Neoplasias Gástricas , Humanos , Feminino , Adulto , Hiperplasia Nodular Focal do Fígado/induzido quimicamente , Hiperplasia Nodular Focal do Fígado/diagnóstico , Hiperplasia Nodular Focal do Fígado/patologia , Oxaliplatina , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Neoplasias Hepáticas/diagnóstico , FígadoRESUMO
Supramolecular strategies as well as combinatorial approaches have been proposed to improve cancer therapeutics. In this work, we investigated the encapsulation of the photosensitizer acridine orange (AO) and the chemotherapeutic drug oxaliplatin (OxPt) in cucurbit[8]uril (CB[8]), and tested their effect both separate and combined on tumoral cells cultivated in vitro. Binding constants and enthalpies of reaction for the AO@CB[8], (AO)2@CB[8] and OxPt@CB[8] complexes were determined by isothermal titration calorimetry. In the case of AO, a negative cooperativity for the binding of the second AO molecule was found, in agreement with previous fluorescence titration data. We show herein that the AO@CB[8] complex was effectively incorporated within the cells and showed important phototoxicity, while the OxPt@CB[8] complex was cytotoxic only at long incubation times (24 h). Pre-treatment of the cells with the OxPt@CB[8] complex for 24 h inhibited any photodynamic action by the later treatment with the AO@CB[8] complex. However, when both complexes were co-incubated for 90 min, the combined cytotoxicity/phototoxicity was superior to any of the treatments individually. A cooperative effect was identified that added up to an extra 30% cytotoxicity/phototoxicity. The results point to an interesting system where a photosensitizer and chemotherapeutic drug are co-encapsulated in a macrocycle to develop chemophototherapy applications.
Assuntos
Antineoplásicos , Fármacos Fotossensibilizantes , Antineoplásicos/química , Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Compostos Heterocíclicos com 2 Anéis , Imidazóis/química , Imidazóis/farmacologia , Imidazolidinas , Compostos Macrocíclicos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologiaRESUMO
Almost 90% of patients develop pain immediately after oxaliplatin (OXA) treatment. Here, the impact of aging on OXA-induced acute peripheral neuropathy and the potential of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) as a new therapeutic strategy were evaluated. In Swiss mice, the oxidative damage and its influence on Mg2+-ATPase and Na+, K+-ATPase activities were investigated. The relationship between the reactive oxygen species (ROS) and nitrate and nitrite (NOx) levels, the activity of glutathione peroxidase (GPx), and superoxide dismutase (SOD) with the development of OXA-induced acute peripheral neuropathy was also studied. In this study, it was evidenced that OXA-induced acute peripheral neuropathy was exacerbated by aging through increased oxidative damage as well as Na+, K+-ATPase, and Mg+2-ATPase inhibition. 4-PSQ reversed hypersensitivity induced by OXA and aging-aggravated by reducing ROS and NOx levels, through modulation of GPx and SOD activities. 4-PSQ partially reestablish Na+, K+-ATPase activity, but not Mg 2+-ATPase activity. Locomotor and exploratory activities were not affected. This study is the first of its kind, providing new insight into the aging impact on mechanisms involved in OXA-induced acute peripheral neuropathy. Also, it provides evidence on promising 4-PSQ effects on this condition, mainly on aging.
Assuntos
Adenosina Trifosfatases , Doenças do Sistema Nervoso Periférico , Envelhecimento , Animais , Humanos , Camundongos , Oxaliplatina/efeitos adversos , Estresse Oxidativo , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Quinolinas , ATPase Trocadora de Sódio-PotássioRESUMO
In the present study it was hypothesized that 5-((4-methoxyphenyl)thio)benzo[c][1,2,5] thiodiazole (MTDZ), a new acetylcholinesterase inhibitor, exerts antinociceptive action and reduces the oxaliplatin (OXA)-induced peripheral neuropathy and its comorbidities (anxiety and cognitive deficits). Indeed, the acute antinociceptive activity of MTDZ (1 and 10 mg/kg; per oral route) was observed for the first time in male Swiss mice in formalin and hot plate tests and on mechanical withdrawal threshold induced by Complete Freund's Adjuvant (CFA). To evaluate the MTDZ effect on OXA-induced peripheral neuropathy and its comorbidities, male and female Swiss mice received OXA (10 mg/kg) or vehicle intraperitoneally, on days 0 and 2 of the experimental protocol. Oral administration of MTDZ (1 mg/kg) or vehicle was performed on days 2-14. OXA caused cognitive impairment, anxious-like behaviour, mechanical and thermal hypersensitivity in animals, with females more susceptible to thermal sensitivity. MTDZ reversed the hypersensitivity, cognitive impairment and anxious-like behaviour induced by OXA. Here, the negative correlation between the paw withdrawal threshold caused by OXA and acetylcholinesterase (AChE) activity was demonstrated in the cortex, hippocampus, and spinal cord. OXA inhibited the activity of total ATPase, Na+ K+ - ATPase, Ca2+ - ATPase and altered Mg2+ - ATPase in the cortex, hippocampus, and spinal cord. OXA exposure increased reactive species (RS) levels and superoxide dismutase (SOD) activity in the cortex, hippocampus, and spinal cord. MTDZ modulated ion pumps and reduced the oxidative stress induced by OXA. In conclusion, MTDZ is an antinociceptive molecule promising to treat OXA-induced neurotoxicity since it reduced nociceptive and anxious-like behaviours, and cognitive deficit in male and female mice.
Assuntos
Benzoatos/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/enzimologia , Tiadiazóis/uso terapêutico , Tiazóis/uso terapêutico , Adenosina Trifosfatases/metabolismo , Analgésicos/química , Analgésicos/uso terapêutico , Animais , Ansiedade/induzido quimicamente , Ansiedade/tratamento farmacológico , Benzoatos/química , Carbamatos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/enzimologia , Inibidores da Colinesterase/química , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Indóis , Masculino , Camundongos , Oxaliplatina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Medula Espinal/efeitos dos fármacos , Medula Espinal/enzimologia , Tiadiazóis/química , Tiazóis/químicaRESUMO
A quimioterapia com FOLFOX (oxaliplatina, leucovorina e 5-fluorouracilo) é frequentemente utilizada em doentes com cancro colorretal. Os sais de platina são conhecidos por serem uma classe de quimioterápicos que comumente induzem neurotoxicidade periférica. Na toxicidade induzida pela oxaliplatina, os sintomas sensitivos são os mais frequentes. Neste artigo, apresentamos dois casos clínicos de pacientes com adenocarcinoma de cólon, ambos submetidos à quimioterapia com FOLFOX4, e que desenvolveram neurotoxicidade incomum, apresentando pé pendente após o terceiro ciclo de tratamento. Esta manifestação clínica pode ser explicada por dano axonal nos neurônios motores periféricos do nervo peroneal comum (fibular), que fornece inervação motora aos músculos do pé. A paralisia do nervo fibular causa fraqueza súbita nos músculos do pé, que parece ser temporária. Ambos os doentes recuperaram completamente do evento sem necessidade de ajustes no tratamento, nem introdução de medicamentos diferentes. A apresentação de pé pendente como toxicidade da quimioterapia ainda é pouco compreendida. Os casos relatados mostram o pé pendente como uma manifestação grave e incomum de neuropatia induzida por FOLFOX, que pode ser transitória, e não requer necessariamente intervenção específica.
Chemotherapy based on FOLFOX (oxaliplatin, leucovorin, and 5-fluorouracil) regimen is frequently used in colorectal cancer patients. Oxaliplatin and other platinum agents are known to be a class of chemotherapy drugs that commonly induce peripheral neurotoxicity. The most frequent oxaliplatin related neurotoxicity is sensitive symptoms. Here, we present two cases of patients with colon adenocarcinoma, both undergoing chemotherapy with FOLFOX4, who developed uncommon neurotoxicity, presenting with foot drop after the third treatment cycle. Foot drop may be explained by axonal damage of peripheral motor neurons of the common peroneal (fibular) nerve, which provides motor innervation to the foot muscles. Peroneal nerve palsy causes sudden weakness in the muscles of the foot that seems to be temporary. Both patients completely recovered from the event. There was no need for treatment adjustments, neither introduction of different drugs. Foot drop as chemotherapy toxicity is still poorly understood. The reported cases show foot drop as a severe and uncommon manifestation of FOLFOX-induced neuropathy, that might be transitory, and does not necessarily requires specific intervention.
Assuntos
Humanos , Neoplasias do Colo/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Agentes Neurotóxicos/toxicidade , Pé/inervação , Adenocarcinoma , Neuropatias Fibulares , Oxaliplatina/uso terapêuticoRESUMO
Oxaliplatin-induced neurotoxicity is expressed as a dose-limiting peripheral sensory neuropathy (PSN). Cannabinoid substances have been investigated for the analgesic effect. This study aimed to investigate the role of cannabinoid receptors in oxaliplatin-associated PSN. Swiss male mice received nine oxaliplatin injections (2 mg/kg, i.v.). Mechanical and thermal nociceptive tests were performed for 56 days. CB1, CB2, and c-Fos expression were assessed in dorsal root ganglia (DRG), spinal cord (SC), trigeminal ganglia (TG), spinal trigeminal nucleus caudalis (Sp5C), and periaqueductal gray (PAG). Iba-1 expression was assessed in DRG and ATF3 in TG. Cannabidiol (10 mg/kg, p.o.) or a CB1/CB2 non-selective agonist (WIN 55,212-2; 0.5 mg/kg, s.c.) or AM251 (CB1 antagonist) or AM630 (CB2 antagonist) (3 mg/kg, i.p.) were injected before oxaliplatin. Oxaliplatin increased CB1 in DRG, SC, TG, Sp5C, and ventrolateral PAG, with no interference in CB2 expression. Cannabidiol increased CB1 in DRG, reduced mechanical hyperalgesia and c-Fos expression in DRG and SC. Additionally, WIN 55,212-2 increased CB1 in DRG, reduced mechanical hyperalgesia, cold allodynia and c-Fos expression in DRG and SC. CB1 blockage hastened the cold allodynia response, but the CB2 antagonist failed to modulate the oxaliplatin-induced nociceptive behavior. Oxaliplatin also increased Iba-1 in DRG, suggesting immune response modulation which was reduced by cannabidiol and enhanced by AM630. The modulation of the endocannabinoid system, through the CB1 receptor, attenuates the oxaliplatin-associated PNS. The activation of the endocannabinoid system could be considered as a therapeutic target for controlling oxaliplatin-associated neuropathy.
Assuntos
Endocanabinoides/metabolismo , Nociceptividade/efeitos dos fármacos , Oxaliplatina/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Receptor CB1 de Canabinoide/agonistas , Animais , Imunofluorescência , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/patologia , Gânglios Espinais/fisiopatologia , Masculino , Camundongos , Oxaliplatina/antagonistas & inibidores , Medição da Dor , Doenças do Sistema Nervoso Periférico/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Teste de Desempenho do Rota-RodRESUMO
Oxaliplatin is a chemotherapeutic agent with direct toxic action on deoxyribonucleic acid (DNA), which is known to cause an arrest in its synthesis and inducing cell death. It is a crucial medication for colorectal carcinoma, and in combination with other medications has demonstrated to exhibit synergism, managing to increase patients' survival, especially when compared to monotherapy with 5-fluoracil. Neurotoxicity is its most well-known adverse effect. However, other less frequent secondary effects have been described in case reports, among them liver injury, which is usually secondary to liver sinusoid injury. Despite the wide frequency of the use of this drug, the relationship of oxaliplatin with the development of portal non-cirrhotic hypertension is largely unknown, which translates into a sub-diagnosis, representing an additional risk to patients who develop this complication. We present the case of an adult patient, who during treatment with the FOLFOX scheme for colorectal carcinoma, presents signs suggestive of portal hypertension, without other risk factors besides the administration of oxaliplatin.
RESUMO
The object of this study was to evaluate the relationship between oxidative damage induced by oxaliplatin (OXA) and the therapeutic potential of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) in kidney of mice. Mice received OXA (10 mg/kg) or vehicle intraperitoneally (days 0 and 2). Oral administration of 4-PSQ (1 mg/kg) or vehicle was performed on days 2 to 14. On day 15 the animals were euthanized and the kidneys and blood were collected. The effect of OXA and (or) 4-PSQ on urea, thiobarbituric acid reactive species, nonprotein thiol (NPSH), and protein carbonyl (PC) levels were investigated. Moreover, renal superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), δ-aminolevulinic acid dehydratase (δ-ALA-D), and Na+,K+ ATPase activities were evaluated. Our findings revealed an increase on urea levels and significant renal oxidative damage in OXA-induced mice. OXA exposure increased SOD, GPx, and GST activities and caused a reduction on NPSH levels and CAT and GR activities. Na+,K+ ATPase and δ-ALA-D activities were reduced by OXA. 4-PSQ decreased plasmatic urea levels and renal oxidative damage. SOD, GPx, CAT, GR, and Na+,K+ ATPase activities were restored by 4-PSQ. 4-PSQ may be a good prototype for the treatment of OXA-induced renal injury.