RESUMO
PURPOSE: Treatment with regorafenib, which inhibits vascular endothelial growth factor (VEGF) receptor, frequently results in hand-foot skin reaction (HFSR), requiring treatment discontinuation or dose reduction. In our prospective study of regorafenib on patients with metastatic colorectal cancer, 17% of patients developed grade 3 HFSR. Herein, we retrospectively examined genetic polymorphisms associated with regorafenib-induced severe HFSR. METHODS: To identify associated polymorphisms, exploratory whole-exome sequencing focusing on factors related to VEGF-mediated signaling pathways was first performed in seven patients each, with grade 3 HFSR and without HFSR. The identified HFSR-associated polymorphisms were analyzed in all the 40 patients. RESULTS: The genotype frequency of rs3025009 G/A or A/A in the gene encoding VEGF-A (VEGFA) in patients with ≥ grade 2 HFSR was significantly higher than in other patients (P = 0.0257, Pc = 0.0771 [Bonferroni correction]). The frequency of C-C motif of chemokine ligand 4-like 2 (CCL4L2) rs3744596 A/T or T/T in patients with grade 3 HFSR was significantly lower than in others (P = 0.00894, Pc = 0.0268). The combination of the risk genotypes VEGFA rs3025009 G/A or A/A and CCL4L2 rs3744596 A/A was significantly associated with a higher incidence of grade 3 (P = 0.000614, Pc = 0.00246) and a longer median progression-free survival (P = 0.0234) than others. CONCLUSIONS: These VEGF-related polymorphisms were found to be associated with HFSR and the survival benefits of regorafenib treatment. TRIAL REGISTRATION NUMBER AND DATE: UMIN000013939, registered on May 12, 2014, when 6 months after the approval by the Institutional Review Board of Showa University.
Assuntos
Antineoplásicos , Quimiocina CCL4 , Neoplasias Colorretais , Síndrome Mão-Pé , Fator A de Crescimento do Endotélio Vascular , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , População do Leste Asiático , Genótipo , Síndrome Mão-Pé/etiologia , Síndrome Mão-Pé/genética , Japão , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular/genética , Quimiocina CCL4/genéticaRESUMO
PURPOSE: Capecitabine is a prodrug that converts to 5-fluorouracil (5-FU) in three steps. A previous study showed that ABCA2 rs2271862 (C > T) and ABCG5 rs6720173 were associated with increased clearance of 5-FU and 5'-deoxy-5-fluorouridine, respectively, in Spanish patients with colorectal cancer (CRC) (Br J Clin Pharmacol 2021) and reported that ABCA2 rs2271862 was associated with decreased risk of capecitabine-induced neutropenia. Other studies have reported that ABCB1 rs1128503, rs2032592, and rs1045642 were associated with capecitabine-induced toxicity in Spanish CRC patients (Oncotarget 2015, Phamacogenomics 2010). Here, we prospectively examined the effects of ABC transporter genes polymorphisms on capecitabine pharmacokinetics and toxicity. METHODS: We enrolled patients with postoperative CRC treated with adjuvant capecitabine plus oxaliplatin (CapeOX) and patients with metastatic CRC receiving CapeOX. Pharmacokinetic analysis of the first capecitabine dose (1000 mg/m2) was performed on day 1. We analyzed plasma concentrations of capecitabine and its three metabolites by high-performance liquid chromatography and ABC transporter genes polymorphisms using direct sequencing. RESULTS: Patients with ABCA2 rs2271862 T/T genotype had significantly lower area under the plasma concentration-time curve of capecitabine, but not of its metabolites, which were divided by the dose of the parent drug, than patients with C/C or C/T genotype (P = 0.0238). Frequency of ≥ grade 2 neutropenia was significantly lower in patients with ABCA2 rs2271862 T/T genotype (P = 0.00915). Polymorphisms in ABCG5 and ABCB1 were not associated with capecitabine pharmacokinetics and toxicity. CONCLUSIONS: We found that ABCA2 polymorphism was significantly associated with systemic exposure to capecitabine and capecitabine-induced neutropenia in Japanese patients with CRC.
Assuntos
Capecitabina , Neoplasias Colorretais , Neutropenia , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , População do Leste Asiático , Fluoruracila/uso terapêutico , Neutropenia/induzido quimicamente , Neutropenia/genética , Neutropenia/tratamento farmacológico , Oxaliplatina/uso terapêutico , Transportadores de Cassetes de Ligação de ATP/genéticaRESUMO
Regorafenib improves the survival of patients with metastatic colorectal cancer (mCRC); however, it is also characterized by detrimental dermal side effects that may require treatment cessation or modified dosing. In our previous prospective pharmacokinetic, pharmacodynamic, and pharmacogenetic studies, 17.5% (7/40) of the patients with mCRC had grade 3 erythema multiforme (EM) that caused treatment discontinuation. Haplotypes in genes encoding human leukocyte antigen (HLA) are associated with EM following the administration of drugs, such as allopurinol. This study examined the association between HLA haplotypes and regorafenib-induced EM. Regorafenib was administered orally at 160 mg/body once daily for weeks 1-3 of each 4-week cycle. To determine the HLA haplotypes, we used the WAKFlow HLA Typing Kit HLA-A, -B, or -C. The carrier frequency of HLA-C*01:02 in patients with EM (6/7) was higher than that in tolerant controls (8/33; odds ratio [OR] = 18.8, 95% confidence interval [CI] = 1.95-180, p = 0.00437). HLA-B*46:01 was also associated with EM (OR = 11.6, 95% CI = 1.47-92.1, p = 0.0299). These associations were no longer significant after Bonferroni correction for multiple testing. Therefore, regorafenib-induced EM in Japanese patients appears to be associated with specific HLA haplotypes but further validation is needed.
Assuntos
Antineoplásicos , Neoplasias Colorretais , Eritema Multiforme , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , População do Leste Asiático , Eritema Multiforme/induzido quimicamente , Eritema Multiforme/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Antineoplásicos/efeitos adversosRESUMO
BACKGROUND/AIM: Carboplatin is a key drug in the treatment of ovarian cancer, but hypersensitivity reactions (HSRs) may occur with repeated use. PATIENTS AND METHODS: Thirty-seven ovarian cancer patients treated with carboplatin desensitization therapy were reviewed retrospectively. The treatment completion rate and toxicity were examined. RESULTS: The carboplatin desensitization completion rate was 86.5%. Toxicity was Grade 0, 1, 2, and 3 in 17, 5, 10, and 5 patients, respectively. Erythema was the most frequent toxicity (36.8%), most commonly affecting the arm (23.5%). Furthermore, all HSRs were classified into: skin, respiratory, digestive, circulatory, and neurological. The completion rate of desensitization was significantly lower in patients with two or more target organs affected (p<0.001). CONCLUSION: The main symptoms of HSRs, the most common sites of HSRs, and the criteria for discontinuing desensitization therapy identified in this study are useful information for the safe implementation of carboplatin desensitization therapy.
Assuntos
Carboplatina/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Dessensibilização Imunológica , Hipersensibilidade a Drogas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Carcinoma Epitelial do Ovário/epidemiologia , Dessensibilização Imunológica/métodos , Toxidermias/tratamento farmacológico , Toxidermias/epidemiologia , Hipersensibilidade a Drogas/epidemiologia , Feminino , Humanos , Japão/epidemiologia , Pessoa de Meia-Idade , Neoplasias Ovarianas/epidemiologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Tissue-resident mast cells (MCs) have important roles in IgE-associated and -independent allergic reactions. Although microenvironmental alterations in MC phenotypes affect the susceptibility to allergy, understanding of the regulation of MC maturation is still incomplete. We previously reported that group III secreted phospholipase A2 (sPLA2-III) released from immature MCs is functionally coupled with lipocalin-type prostaglandin D2 (PGD2) synthase in neighboring fibroblasts to supply a microenvironmental pool of PGD2, which in turn acts on the PGD2 receptor DP1 on MCs to promote their proper maturation. In the present study, we reevaluated the role of sPLA2-III in MCs using a newly generated MC-specific Pla2g3-deficient mouse strain. Mice lacking sPLA2-III specifically in MCs, like those lacking the enzyme in all tissues, had immature MCs and displayed reduced local and systemic anaphylactic responses. Furthermore, MC-specific Pla2g3-deficient mice, as well as MC-deficient KitW-sh mice reconstituted with MCs prepared from global Pla2g3-null mice, displayed a significant reduction in irritant contact dermatitis (ICD) and an aggravation of contact hypersensitivity (CHS). The increased CHS response by Pla2g3 deficiency depended at least partly on the reduced expression of hematopoietic PGD2 synthase and thereby reduced production of PGD2 due to immaturity of MCs. Overall, our present study has confirmed that MC-secreted sPLA2-III promotes MC maturation, thereby facilitating acute anaphylactic and ICD reactions and limiting delayed CHS response.
Assuntos
Diferenciação Celular , Deleção de Genes , Mastócitos/enzimologia , Mastócitos/patologia , Fosfolipases A2 Secretórias/metabolismo , Anafilaxia/patologia , Animais , Dermatite/patologia , Dermatite de Contato/patologia , Fibroblastos/patologia , Camundongos Endogâmicos C57BL , Fosfolipases A2 Secretórias/deficiênciaRESUMO
Polyunsaturated fatty acids (PUFAs) confer health benefits by preventing inflammation and obesity and by increasing thermogenesis in brown and beige adipocytes. As well as being supplied exogenously as nutrients, PUFAs are largely stored in membrane glycerophospholipids and released by phospholipase A2s (PLA2s). However, the molecular identity of the PLA2 subtype(s) that supplies endogenous PUFAs for metabolic homeostasis remains unclear. Here we show that PLA2G2D, a secreted PLA2 isoform, is constitutively expressed in M2-type macrophages in white adipose tissue (WAT) and shows a reciprocal correlation with obesity. Studies using global and macrophage-specific Pla2g2d-deficient mice reveal that PLA2G2D increases energy expenditure and thermogenesis by facilitating adipocyte browning, thereby ameliorating diet-induced obesity, insulin resistance, and WAT inflammation. Mechanistically, PLA2G2D constitutively supplies a pool of PUFAs, ω3 in particular, in WAT. Thus, our present findings underscore the contribution of the macrophage-driven PLA2G2D-ω3 PUFA axis to metabolic health.
Assuntos
Tecido Adiposo Branco/metabolismo , Ácidos Graxos Insaturados/metabolismo , Fosfolipases A2 do Grupo II/metabolismo , Fosfolipases/metabolismo , Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Metabolismo Energético , Ácidos Graxos Ômega-3/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Camundongos , Obesidade/metabolismo , Termogênese/fisiologiaRESUMO
Contact dermatitis is a common skin disease, with various treatments available to dermatologists. According to general guidelines, the first line of treatment involves topical steroids; however, this treatment has application-site restrictions in order to avoid adverse cutaneous events. Accordingly, increased demand exists for the development of new treatments. In Japan, the recent use of catechin-containing health foods and their beneficial effects has attracted attention. Indeed, several studies have examined the anticancer, anti-obesity, anti-inflammatory, and antioxidant effects of catechins. In this study, we synthesized planar catechin (PC) from natural (+)-catechin, and further chemically modified it with the intent to clarify the anti-inflammatory and antioxidant effects of new catechin derivatives. Methylate-PC (methyl PC) and acetylate-PC (acetyl PC) were modified to increase lipid solubility. Their antioxidant effects were examined with electron spin resonance by evaluating the ability to remove hydroxyl radicals. In vitro, the antioxidant effects were in the order of PCâ¯>â¯(+)-catechinâ¯>â¯acetyl PCâ¯>â¯methyl PC. In addition, we used a 1-fluoro-2,4-dinitrobenzene (DNFB)-induced allergic contact dermatitis model in BALB/c mice. Our results demonstrated that catechin derivatives inhibited ear swelling induced by DNFB, with acetyl PC demonstrating a greater inhibitory effect than PC and methyl PC. Moreover, acetyl PC downregulated the mRNA levels of inflammatory cytokines, including tumor necrosis factor-alpha, interleukin (IL)-1ß, and IL-4, as well as myeloperoxidase activity, in the ear tissue of DNFB-treated mice. Collectively, our novel findings suggest that catechin derivatives may be a promising new choice for the treatment of contact dermatitis.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Catequina/uso terapêutico , Dermatite Alérgica de Contato/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Catequina/análogos & derivados , Catequina/síntese química , Catequina/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Espectroscopia de Ressonância de Spin Eletrônica/métodos , Haptenos , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Lipid mediators play pivotal roles in colorectal cancer and colitis, but only a limited member of the phospholipase A2 (PLA2) subtypes, which lie upstream of various lipid mediators, have been implicated in the positive or negative regulation of these diseases. Clinical and biochemical evidence suggests that secreted PLA2 group III (sPLA2-III) is associated with colorectal cancer, although its precise role remains obscure. Here we have found that sPLA2-III-null (Pla2g3 -/-) mice are highly resistant to colon carcinogenesis. Furthermore, Pla2g3 -/- mice are less susceptible to dextran sulfate-induced colitis, implying that the amelioration of colonic inflammation by sPLA2-III ablation may underlie the protective effect against colon cancer. Lipidomics analysis of the colon revealed significant reduction of pro-inflammatory/pro-tumorigenic lysophosholipids as well as unusual steady-state elevation of colon-protective fatty acids and their oxygenated metabolites in Pla2g3 -/- mice. Overall, our results establish a role of sPLA2-III in the promotion of colorectal inflammation and cancer, expand our understanding of the divergent roles of multiple PLA2 enzymes in the gastrointestinal tract, and point to sPLA2-III as a novel druggable target for colorectal diseases.
Assuntos
Colite/fisiopatologia , Neoplasias Colorretais/fisiopatologia , Suscetibilidade a Doenças , Fosfolipases A2/metabolismo , Animais , Colite/patologia , Colo/patologia , Neoplasias Colorretais/patologia , Camundongos , Camundongos Knockout , Fosfolipases A2/deficiênciaRESUMO
Microenvironment-based alterations in phenotypes of mast cells influence the susceptibility to anaphylaxis, yet the mechanisms underlying proper maturation of mast cells toward an anaphylaxis-sensitive phenotype are incompletely understood. Here we report that PLA2G3, a mammalian homolog of anaphylactic bee venom phospholipase A2, regulates this process. PLA2G3 secreted from mast cells is coupled with fibroblastic lipocalin-type PGD2 synthase (L-PGDS) to provide PGD2, which facilitates mast-cell maturation via PGD2 receptor DP1. Mice lacking PLA2G3, L-PGDS or DP1, mast cell-deficient mice reconstituted with PLA2G3-null or DP1-null mast cells, or mast cells cultured with L-PGDS-ablated fibroblasts exhibited impaired maturation and anaphylaxis of mast cells. Thus, we describe a lipid-driven PLA2G3-L-PGDS-DP1 loop that drives mast cell maturation.