RESUMO
The recently identified anion channel LRRC8 volume-regulated anion channels (VRACs) are heteromeric hexamers constituted with the obligate LRRC8A subunit paired with at least one of the accessory LRRC8B to LRRC8E subunits. In addition to transport chloride, taurine, and glutamate, LRRC8 VRACs also transport the anticancer agent cisplatin and STING agonists 2'3'-cyclic GMP-AMP (cGAMP) and cyclic dinucleotides; hence, they are implicated in a variety of physiological and pathological processes, such as cell swelling, stroke, cancer, and viral infection. Although the subunit composition largely determines VRAC substrate specificity, the opening of various VRAC pores under physiological and pathological settings remains enigmatic. In this study, we demonstrated that VRACs comprising LRRC8A and LRRC8E (LRRC8A/E-containing VRACs), specialized in cGAMP transport, can be opened by a protein component present in serum under resting condition. Serum depletion ablated the tonic activity of LRRC8A/E-containing VRACs, decreasing cGAMP transport in various human and murine cells. Also, heating or proteinase K treatment abolished the ability of serum to activate VRAC. Genetic analyses revealed a crucial role for cGAMP synthase (cGAS) in serum/TNF-promoted VRAC activation. Notably, the presence of cGAS on the plasma membrane, rather than its DNA-binding or enzymatic activity, enabled VRAC activation. Moreover, phospholipid PIP2 seemed to be instrumental in the membrane localization of cGAS and its association with VRACs. Corroborating a role for LRRC8A/D-containing VRACs in cisplatin transport, serum and TNF markedly potentiated cisplatin uptake and killing of cancer cells derived from human or mouse. Together, these observations provide new insights into the complex regulation of VRAC activation and suggest a novel approach to enhance the efficacy of cGAMP and cisplatin in treating infection and cancer.
Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Inflamação/tratamento farmacológico , Proteínas de Membrana/imunologia , Nucleotídeos Cíclicos/farmacologia , Animais , Antineoplásicos/imunologia , Cisplatino/imunologia , Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Nucleotídeos Cíclicos/imunologiaRESUMO
In metastatic cancer, the degree of heterogeneity of the tumor microenvironment (TME) and its molecular underpinnings remain largely unstudied. To characterize the tumor-immune interface at baseline and during neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (HGSOC), we performed immunogenomic analysis of treatment-naive and paired samples from before and after treatment with chemotherapy. In treatment-naive HGSOC, we found that immune-cell-excluded and inflammatory microenvironments coexist within the same individuals and within the same tumor sites, indicating ubiquitous variability in immune cell infiltration. Analysis of TME cell composition, DNA copy number, mutations and gene expression showed that immune cell exclusion was associated with amplification of Myc target genes and increased expression of canonical Wnt signaling in treatment-naive HGSOC. Following NACT, increased natural killer (NK) cell infiltration and oligoclonal expansion of T cells were detected. We demonstrate that the tumor-immune microenvironment of advanced HGSOC is intrinsically heterogeneous and that chemotherapy induces local immune activation, suggesting that chemotherapy can potentiate the immunogenicity of immune-excluded HGSOC tumors.
Assuntos
Cistadenocarcinoma Seroso/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas/tratamento farmacológico , Microambiente Tumoral/imunologia , Animais , Cisplatino/imunologia , Cisplatino/farmacologia , Estudos de Coortes , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/imunologia , Variações do Número de Cópias de DNA , Feminino , Perfilação da Expressão Gênica/estatística & dados numéricos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes myc , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Camundongos , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Análise de Componente Principal , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Via de Sinalização WntRESUMO
C4.4A (LYPD3) has been identified as a cancer- and metastasis-associated internalizing cell surface protein that is expressed in non-small cell lung cancer (NSCLC), with particularly high prevalence in the squamous cell carcinoma (SCC) subtype. With the exception of skin keratinocytes and esophageal endothelial cells, C4.4A expression is scarce in normal tissues, presenting an opportunity to selectively treat cancers with a C4.4A-directed antibody-drug conjugate (ADC). We have generated BAY 1129980 (C4.4A-ADC), an ADC consisting of a fully human C4.4A-targeting mAb conjugated to a novel, highly potent derivative of the microtubule-disrupting cytotoxic drug auristatin via a noncleavable alkyl hydrazide linker. In vitro, C4.4A-ADC demonstrated potent antiproliferative efficacy in cell lines endogenously expressing C4.4A and inhibited proliferation of C4.4A-transfected A549 lung cancer cells showing selectivity compared with a nontargeted control ADC. In vivo, C4.4A-ADC was efficacious in human NSCLC cell line (NCI-H292 and NCI-H322) and patient-derived xenograft (PDX) models (Lu7064, Lu7126, Lu7433, and Lu7466). C4.4A expression level correlated with in vivo efficacy, the most responsive being the models with C4.4A expression in over 50% of the cells. In the NCI-H292 NSCLC model, C4.4A-ADC demonstrated equal or superior efficacy compared to cisplatin, paclitaxel, and vinorelbine. Furthermore, an additive antitumor efficacy in combination with cisplatin was observed. Finally, a repeated dosing with C4.4A-ADC was well tolerated without changing the sensitivity to the treatment. Taken together, C4.4A-ADC is a promising therapeutic candidate for the treatment of NSCLC and other cancers expressing C4.4A. A phase I study (NCT02134197) with the C4.4A-ADC BAY 1129980 is currently ongoing. Mol Cancer Ther; 16(5); 893-904. ©2017 AACR.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Moléculas de Adesão Celular/imunologia , Imunoconjugados/administração & dosagem , Aminobenzoatos/química , Aminobenzoatos/imunologia , Animais , Anticorpos Monoclonais/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Moléculas de Adesão Celular/antagonistas & inibidores , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Cisplatino/imunologia , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/imunologia , Humanos , Imunoconjugados/química , Imunoconjugados/imunologia , Camundongos , Oligopeptídeos/química , Oligopeptídeos/imunologia , Paclitaxel/administração & dosagem , Paclitaxel/imunologia , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , Vimblastina/imunologia , Vinorelbina , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hypersensitivity reactions to chemotherapy drugs pose significant difficulties in management, especially when no suitable alternative is available or acceptable and delay in continuation of treatment may be life-threatening. Such reactions may be IgE- or non-IgE-mediated and have varied manifestations. Timely recognition and treatment of life-threatening hypersensitivity reactions are essential. Identification of patients at high risk of developing hypersensitivity reactions allows risk stratification to guide clinical decision-making. Skin testing for carboplatin hypersensitivity has good predictive value but is not yet established for oxaliplatin and taxane hypersensitivity. Rapid desensitisation may be considered if no suitable alternative drug is available. Available protocols have shown good safety and efficacy but must be performed in an appropriate setting with adequate monitoring. There are many avenues for research into the utility of skin testing for other chemotherapy agents as well as in vitro tests.
Assuntos
Antineoplásicos/efeitos adversos , Hidrocarbonetos Aromáticos com Pontes/imunologia , Cisplatino/imunologia , Hipersensibilidade a Drogas/diagnóstico , Taxoides/imunologia , Antineoplásicos/imunologia , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Cisplatino/efeitos adversos , Dessensibilização Imunológica , Relação Dose-Resposta Imunológica , Hipersensibilidade a Drogas/imunologia , Humanos , Encaminhamento e Consulta , Fatores de Risco , Testes Cutâneos , Taxoides/efeitos adversos , Resultado do TratamentoRESUMO
Contrary to the long held belief that chemotherapy is immunosuppressive, emerging evidence indicates that the anticancer activity of cisplatin is not limited to its ability to inhibit mitosis, but that cisplatin also has important immunomodulatory effects. We therefore methodically examined the relevant preclinical literature and identified four main mechanisms of cisplatin-induced antitumor immunomodulation: (i) MHC class I expression upregulation; (ii) recruitment and proliferation of effector cells; (iii) upregulation of the lytic activity of cytotoxic effectors; and (iv) downregulation of the immunosuppressive microenvironment. Cisplatin-based combination chemotherapy's antitumor immunomodulatory effects are also beginning to be harnessed in the clinic; we therefore additionally reviewed the applicable clinical literature and discussed how monitoring various components of the immune system (and their responses to cisplatin) can add new levels of sophistication to disease monitoring and prognostication. In summation, this growing body of literature on cisplatin-induced antitumor immunomodulation ultimately highlights the therapeutic potential of synergistic strategies that combine traditional chemotherapy with immunotherapy.
Assuntos
Antineoplásicos/imunologia , Cisplatino/imunologia , Imunomodulação/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Terapia Combinada/métodos , Avaliação Pré-Clínica de Medicamentos , Humanos , Imunoterapia/métodos , Neoplasias/terapiaRESUMO
BACKGROUND: Hypersensitivity reactions (HSR) to chemotherapeutic agents and monoclonal antibodies are common and may limit further therapeutic options. Drug desensitisation aims to induce a temporary clinical unresponsiveness to drug antigens so the causative drugs of HSR can continue to be administered. Rapid desensitisation using standardised protocols has been conducted by the Department of Immunology at The Canberra Hospital for patients who developed HSR to chemotherapeutic agents and monoclonal antibodies. AIMS: This retrospective audit reviewed the safety and efficacy of the desensitisation protocols used for patients across the Capital Region Cancer Service (CRCS). METHODS: Patients across the CRCS who received rapid desensitisation were identified through a search of archived correspondence. Clinical files and pharmacy records were analysed to determine protocol safety and efficacy. RESULTS: From June 2006 to July 2013, 13 patients underwent rapid desensitisations to oxaliplatin, carboplatin, docetaxel or rituximab. A total of 25 desensitisations was conducted with 21 (84%) achieving full target dose without inducing recurrent HSR. As a result, nine patients were successfully desensitised and continued to receive treatment without any further HSR. Desensitisation was aborted in three patients because of recurrence of HSR, which was not of a greater severity than the initial HSR. After successful desensitisation, seven patients were able to resume the regular protocols without requiring additional supervision. CONCLUSION: Rapid desensitisation to various chemotherapeutic agents and monoclonal antibodies with standardised protocols used across CRCS is safe and effective; it provides a feasible treatment option enabling continuation of effective regimens in the setting of HSR.
Assuntos
Anticorpos Monoclonais Murinos/efeitos adversos , Antineoplásicos/efeitos adversos , Dessensibilização Imunológica , Hipersensibilidade a Drogas/terapia , Idoso , Idoso de 80 Anos ou mais , Antialérgicos/administração & dosagem , Antialérgicos/uso terapêutico , Anticorpos Monoclonais Murinos/imunologia , Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/imunologia , Antineoplásicos/uso terapêutico , Território da Capital Australiana , Cisplatino/efeitos adversos , Cisplatino/imunologia , Cisplatino/uso terapêutico , Dessensibilização Imunológica/efeitos adversos , Docetaxel , Relação Dose-Resposta Imunológica , Feminino , Humanos , Masculino , Auditoria Médica , Pessoa de Meia-Idade , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/imunologia , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina , Pré-Medicação , Encaminhamento e Consulta , Estudos Retrospectivos , Rituximab , Taxoides/efeitos adversos , Taxoides/imunologia , Taxoides/uso terapêutico , Resultado do TratamentoAssuntos
Anafilaxia/induzido quimicamente , Cisplatino/efeitos adversos , Citostáticos/efeitos adversos , Dessensibilização Imunológica , Idoso , Anafilaxia/prevenção & controle , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia , Cisplatino/administração & dosagem , Cisplatino/imunologia , Citostáticos/administração & dosagem , Citostáticos/imunologia , Relação Dose-Resposta Imunológica , Humanos , Infusões Intravenosas/métodos , Neoplasias Pulmonares/terapia , Masculino , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , VinorelbinaRESUMO
BACKGROUND: The diagnosis of hypersensitivity reactions (HSR) to platins is based on the characterization of the reaction and the results of skin testing. Platins can be irritants when used in skin testing; therefore, in vitro testing may offer an alternative diagnostic tool. OBJECTIVE: To evaluate sensitivity and specificity of platin specific IgE (sIgE) in patients with HSRs and in controls. METHODS: Twenty-four patients with immediate HSR to platins were included (carboplatin, 12; oxaliplatin, 12): 19 women and 5 men (mean age, 61 years). The control group included 17 patients exposed to platin and with no HSR. Skin testing was performed on 22 patients. Carboplatin sIgE and oxaliplatin sIgE were measured in 24 patients and 17 controls; carboplatin sIgE was measured in 21 patients. RESULTS: Skin test results were positive in 22 patients (carboplatin, 12/12; oxaliplatin, 10/12). Seven of 12 patients sensitive to carboplatin (59%) had positive carboplatin sIgE, 2 also had positive cisplatin sIgE, and all had negative oxaliplatin sIgE; 9 of 12 patients sensitive to oxaliplatin (75%) had positive sIgE to oxaliplatin, 8 of 12 (67%) also had positive carboplatin and cisplatin sIgE, to which they had not been exposed. All 5 carboplatin controls had negative sIgE; 3 oxaliplatin controls (25%) had positive carboplatin sIgE, and 2 had positive oxaliplatin sIgE. CONCLUSION: Carboplatin sIgE is very specific but less sensitive. In contrast, oxaliplatin sIgE had higher sensitivity but lower specificity. Analysis of our data suggests that oxaliplatin exposure was more immunogenic. This could be clinically relevant because patients sensitized to carboplatin may be able to tolerate oxaliplatin, but patients sensitized to oxaliplatin may be at risk when exposed to carboplatin and cisplatin.
Assuntos
Antineoplásicos/imunologia , Carboplatina/imunologia , Cisplatino/imunologia , Hipersensibilidade a Drogas/diagnóstico , Imunoglobulina E/imunologia , Compostos Organoplatínicos/imunologia , Idoso , Reações Cruzadas , Hipersensibilidade a Drogas/sangue , Hipersensibilidade a Drogas/imunologia , Feminino , Humanos , Imunoglobulina E/sangue , Masculino , Pessoa de Meia-Idade , Oxaliplatina , Testes CutâneosAssuntos
Carboplatina/imunologia , Cisplatino/imunologia , Hipersensibilidade a Drogas/imunologia , Compostos de Platina/imunologia , Adulto , Anafilaxia/induzido quimicamente , Anafilaxia/imunologia , Antineoplásicos/efeitos adversos , Antineoplásicos/imunologia , Antineoplásicos/uso terapêutico , Carboplatina/efeitos adversos , Carboplatina/uso terapêutico , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Reações Cruzadas/imunologia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Compostos de Platina/efeitos adversos , Compostos de Platina/uso terapêutico , Testes CutâneosRESUMO
BACKGROUND: Hypersensitivity reactions to platinum salts are potentially lethal adverse events in chemotherapy, and often require its discontinuation. Several preventive procedures have been proposed: premedication, desensitization regimens, or replacement with a different platinum salt. OBJECTIVE: We therefore assessed the value of skin tests with platinum salts. A positive result would confirm their responsibility in hypersensitivity reaction, whereas a negative result would identify candidates for continuation of therapy using a different platinum salt. METHODS: Patch tests, prick tests, and intradermal tests with cisplatin, carboplatin, and oxaliplatin were performed in 21 patients. RESULTS: Skin tests were positive in 14 of 21 cases. Prick tests were positive in 5 cases with the suspected platinum salt. Intradermal tests were positive in 12 of 19 cases, always when the hypersensitivity occurred less than 2 hours after infusion. Cross-reactions were observed in 4 cases. Delayed readings of skin tests at 24 hours and 48 hours were positive in 3 patients. Patch tests were negative in all the 21 patients tested. Replacement with another platinum salt was performed in 13 patients using one that gave a negative skin test. A relapse of symptoms occurred in 1 patient. CONCLUSION: Intradermal tests are particularly indicated for the diagnosis of immediate hypersensitivity reaction. Their good negative predictive value allows safe retreatment by detecting a potential cross-reaction. CLINICAL IMPLICATIONS: The frequency of cross-reactions among cisplatin, carboplatin, and oxaliplatin has not been clearly established. Skin tests allow different platinum salts to be given and avoid discontinuation of chemotherapy.
Assuntos
Antineoplásicos/imunologia , Hipersensibilidade a Drogas/diagnóstico , Platina/imunologia , Sais/imunologia , Testes Cutâneos , Adulto , Idoso , Carboplatina/imunologia , Cisplatino/imunologia , Reações Cruzadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/imunologia , Oxaliplatina , Prognóstico , Estudos ProspectivosRESUMO
Angiogenesis is critical to the growth and metastasis of solid tumors, and acquired drug resistance is one of the major hindrances to chemotherapy. Thus, we sought a rational strategy using the combination of antiangiogenic biotherapy and chemotherapy for cancer therapy. We explored the efficacy of a strategy combining low-dose cisplatin and a recombinant xenogeneic endoglin as a protein vaccine, which we previously demonstrated to have effective antiangiogenic effects in several mouse models. We found that both low-dosage cisplatin and xenogeneic endoglin vaccine individually resulted in effective suppression of tumor growth in 2 tumor models via inhibition of tumor angiogenesis. Remarkably, the combination therapy resulted in not only significant antiangiogenic effects but also additional promotion of tumor cell apoptosis and inhibition of tumor cell proliferation, without any ensuing increase in host toxicity during the course of treatment, which lasted for 6 months. In addition, the combination demonstrated a synergistic relationship, which was shown in all of the synergistic indexes, i.e., tumor volume, angiogenesis, apoptosis and proliferation. Both antibodies and antibody-producing B cells against mouse self-endoglin were observed in all mice immunized by the xenogeneic endoglin vaccine (alone and combination), which suggested that low-dose cisplatin did not suppress the host immune response but potentiated the antitumor activity of the xenogeneic endoglin vaccine. These observations may provide the basis for an effective alternative strategy for cancer therapy in the near future.
Assuntos
Antígenos Heterófilos/uso terapêutico , Antineoplásicos/uso terapêutico , Vacinas Anticâncer/imunologia , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Cisplatino/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neovascularização Patológica , Molécula 1 de Adesão de Célula Vascular/uso terapêutico , Animais , Antígenos CD , Antígenos Heterófilos/administração & dosagem , Antígenos Heterófilos/imunologia , Antineoplásicos/administração & dosagem , Antineoplásicos/imunologia , Apoptose/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/imunologia , Terapia Combinada , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Endoglina , Feminino , Humanos , Camundongos , Receptores de Superfície Celular , Transplante Heterólogo , Molécula 1 de Adesão de Célula Vascular/administração & dosagem , Molécula 1 de Adesão de Célula Vascular/imunologiaRESUMO
Research on autoimmune diseases has revealed that autoimmunity can be induced by heavy metals such as mercury and gold. Following the introduction of platinum-containing catalytic converters in automobiles, the emission of platinum compounds constitutes an abundant environmental pollutant, however, potential immunological hazards resulting from platinum-containing emissions were not yet examined. In our previous studies on molecular mechanisms of heavy metal-induced autoimmunity, we showed a platinum-dependent subcellular redistribution of the autoantigen fibrillarin from the nucleolus to the nucleoplasm. Since H-2s mice constitute a valuable model to study the role of heavy metals in the development of systemic autoimmunity, we treated susceptible B10.S mice with hexachloroplatinate (Na2PtCl6, Pt4+) to examine whether platinum induces the production of autoantibodies. The present study shows for the first time that chronic administration of Pt4+ generated an autoimmune response in mice which targets distinct nucleoplasmic antigens. Dual-labeling revealed substantial colocalization of these nucleoplasmic autoantigens with (i) nascent RNA, (ii) the active, phosphorylated form of RNA polymerase II, and partial overlap with (iii) acetylated histone 4 protein, and (iv) 20S proteasomes in dendritic cells isolated from platinum-treated mice. The results suggest that platinum elicits antibodies against antigens associated with active sites of transcription which may be subject to proteasomal processing during heavy metal-induced autoimmunity.
Assuntos
Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Doenças Autoimunes/induzido quimicamente , Cisplatino/análogos & derivados , Cisplatino/toxicidade , Animais , Antígenos Nucleares/imunologia , Doenças Autoimunes/genética , Linhagem Celular , Cisplatino/imunologia , Cisteína Endopeptidases/ultraestrutura , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/ultraestrutura , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/ultraestrutura , Feminino , Histonas/imunologia , Humanos , Immunoblotting , Camundongos , Microscopia Confocal , Complexos Multienzimáticos/ultraestrutura , Complexo de Endopeptidases do Proteassoma , RNA/imunologia , RNA Polimerase II/imunologia , Baço/imunologia , Transcrição Gênica/genéticaRESUMO
OBJECTIVES: The aims of this study were to characterize hypersensitivity reactions to chemotherapy in patients with gynecologic malignancies and to determine the utility of oral and intravenous desensitization. METHODS: We retrospectively reviewed patients with hypersensitivity reactions identified by direct physician query and by review of charts with ICD9 code E933.1 (Adverse Effect Anti-Neoplastic). RESULTS: Thirty-two patients were identified: 27 with ovarian cancer, 4 with primary peritoneal cancer, and 1 with cervical cancer. Nine patients experienced hypersensitivity reactions during the primary regimen and 23 during chemotherapy for recurrent disease. Hypersensitivity occurred following an average of nine courses. Hypersensitivity occurred secondary to paclitaxel (10) carboplatin (16), cisplatin (4), bleomycin (1), and paclitaxel/carboplatin combination therapy (1). Patients had previously received the agent in 93.8% of carboplatin reactions, in 54.5% of paclitaxel reactions, and in all other agent reactions. Hypersensitivity reactions most commonly included flushing, dyspnea/bronchospasm, back pain, chest discomfort, pruritus, erythema, and nausea and occasionally included alterations in blood pressure or pulse rate. Reactions were successfully treated in 96.9% of patients by interrupting the infusion and administering steroids, antihistamines, benzodiazepines, nebulized beta-agonists, and/or pressors. Seventeen patients underwent desensitization, one to two agents, with 94% success. Nine of ten patients had successful iv desensitization, and 8/10 patients had successful oral desensitization. One failure on the oral regimen had previous successful iv desensitization. CONCLUSIONS: Hypersensitivity reactions to chemotherapeutic agents do not necessarily require exclusion of a compound from the treatment regimen. Intravenous and oral desensitization protocols are useful for successful and safe administration of paclitaxel and platinum compounds in patients with prior hypersensitivity reactions.
Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/imunologia , Dessensibilização Imunológica , Hipersensibilidade a Drogas/prevenção & controle , Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Femininos/imunologia , Administração Oral , Adolescente , Adulto , Idoso , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carboplatina/imunologia , Cisplatino/efeitos adversos , Cisplatino/imunologia , Cisplatino/uso terapêutico , Hipersensibilidade a Drogas/etiologia , Hipersensibilidade a Drogas/imunologia , Feminino , Humanos , Injeções Intravenosas , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Paclitaxel/imunologia , Estudos RetrospectivosRESUMO
BACKGROUND: A case of acute hemolysis following therapy with carboplatin, an anticancer chemotherapeutic agent, was investigated. Hemolytic anemia has been associated with cisplatin, a related drug, but not with carboplatin. CASE REPORT: An 8-year-old boy was treated for an astrocytoma by monthly intravenous injections of carboplatin. Lower back pain was noted after 26 monthly injections, and overt intravascular hemolysis occurred after the 27th injection. The direct antiglobulin test was 4+ with anti-IgG and 1+ with anti-C3d. RESULTS: Blood samples obtained on Days 28 and 56 after the last injection were tested for carboplatin-dependent antibody. The direct antiglobulin test was 1+ with anti-IgG; the eluate was 1+ with and without carboplatin. The serum indirect antiglobulin test was negative in the absence of carboplatin, 3+ to 4+ in the presence of carboplatin, and 1+ with carboplatin-coated cells. Day 56 serum antibody titer was 64 (agglutination at 37 degrees C), 512 (indirect antiglobulin test) in the presence of carboplatin, and 8 (indirect antiglobulin test) with carboplatin-coated cells. CONCLUSION: The findings indicate a carboplatin-induced antibody reacting in vitro by a complex mechanism combining elements of "immune complex," drug adsorption, and autoantibody mechanisms. Drug-dependent hemolysis is a previously unreported but potentially serious complication of carboplatin therapy.
Assuntos
Anemia Hemolítica Autoimune/induzido quimicamente , Antineoplásicos/efeitos adversos , Autoanticorpos/imunologia , Carboplatina/efeitos adversos , Anemia Hemolítica Autoimune/imunologia , Antineoplásicos/administração & dosagem , Antineoplásicos/imunologia , Antineoplásicos/uso terapêutico , Astrocitoma/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Carboplatina/administração & dosagem , Carboplatina/imunologia , Carboplatina/uso terapêutico , Criança , Cisplatino/imunologia , Humanos , Injeções Intravenosas , Masculino , Neurofibromatoses/tratamento farmacológicoRESUMO
Two monoclonal antibodies raised against Pt(II)(1R,2R-cyclohexanediamine)-DNA were prepared, and the specificity of the monoclonal antibodies against Pt(II)(cyclohexanediamine)-DNA derivatives was determined by competitive enzyme-linked immunosorbent assay. The binding affinity of the monoclonal antibodies is apparently influenced by the cyclohexanediamine moiety of Pt(II)(cyclohexanediamine)-DNA adducts, but the monoclonal antibodies can not bind to the low molecular analogue, Pt(II)(1R,2R-cyclohexanediamine)-d(GpG), which is the intrastrand binding model compound of Pt(II)(1R,2R-cyclohexanediamine)-DNA. Therefore, the monoclonal antibodies recognize the macromolecular parts, including DNA duplex, in addition to the cyclohexane moieties of the platinum complexes on Pt(II)(cyclohexanediamine)-DNA adducts.
Assuntos
Anticorpos Monoclonais/química , Antineoplásicos/química , Cisplatino/química , Adutos de DNA/química , Anticorpos Monoclonais/biossíntese , Especificidade de Anticorpos , Antineoplásicos/imunologia , Cisplatino/imunologia , Adutos de DNA/imunologia , Ensaio de Imunoadsorção EnzimáticaRESUMO
We report on a 49-year-old woman with relapsing ovarian cancer who developed a hypersensitivity reaction (HSR) to carboplatin and, subsequently, to cisplatin. This patient was known to be allergic to Co-Amoxiclav and talc, both giving rise to a transient macular skin rash, but had no other history of atopy. Similar cases, including some of life-threatening severity, have been reported in the literature. These severe reactions may prevent a small population of young patients from receiving effective therapy with cisplatin or its analogues, treatment known to be associated with a significant improvement in survival in germ-cell tumours, ovarian cancer and osteogenic sarcoma.
Assuntos
Carboplatina/efeitos adversos , Cisplatino/efeitos adversos , Hipersensibilidade a Drogas/etiologia , Carboplatina/imunologia , Cisplatino/imunologia , Reações Cruzadas , Hipersensibilidade a Drogas/imunologia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológicoRESUMO
A monoclonal antibody, MAb62-5, was prepared and used to detect DNA damage due to the anticancer drug cis-diamminedichloroplatinum (II) (or cisplatin). ELISA competition indicated that the binding of MAb62-5 to cisplatin-DNA was competitively inhibited (50% control) by 210 nM of cisplatin bound to DNA, cisplatin/nucleotide (D/N) = 0.2. Using a DNA mobility shift assay, MAb62-5 binding activity was inhibited by 50% by approximately 50-fold molar excess of cisplatin-DNA adducts (D/N = 0.08), whereas there was less than 5% inhibition by UV-DNA adducts or mock-treated DNA. In addition, MAb62-5 showed a similar affinity to the cisplatin-DNA adducts as compared to an endogenous cisplatin-damaged DNA recognition protein. Using ELISA with this antibody, we have demonstrated a 2-fold enhancement in excision repair of cisplatin-DNA adducts in resistant HeLa cells. This is supported by the measurement of repair-associated DNA strand breaks using alkaline elution and host cell reactivation of transfected plasmid DNA carrying cisplatin damage. These findings also provide explanation for the complexicity of immunoassay in cells.
Assuntos
Anticorpos Monoclonais , Cisplatino/análise , Cisplatino/farmacologia , Adutos de DNA/análise , Dano ao DNA , Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos , Ligação Competitiva , Cisplatino/imunologia , Cisplatino/metabolismo , Adutos de DNA/imunologia , Adutos de DNA/metabolismo , Reparo do DNA , Células HeLa , HumanosRESUMO
We previously described a cisplatin-resistant HeLa variant cell line that also exhibited cross-resistance to UV radiation and an enhancement in repair of UV-DNA adducts. In this study, excision repair of cisplatin-DNA adducts in the resistant cell line was investigated by different methods. Using a monoclonal antibody specific for cisplatin-DNA adducts, we found a 2-3-fold decrease in the accumulation of cisplatin-DNA adducts in the resistant cells. This was supported by the direct measurement of the number of cisplatin molecules in cells by atomic absorption spectrophotometry. The repair kinetic curves were composed of two phases, i.e., a rapid phase within the first 4 hr of repair incubation, followed by a slow phase for the cisplatin-DNA adducts. There was a 2.6-fold enhancement in the rapid repair rate in the resistant cells. Dose-response curves from these direct measurements indicated a 2.3-fold reduction in adduct accumulation in the resistant cells. In addition, repair-associated DNA strand breaks, measured using alkaline elution, showed a 1.6-fold increase in the resistant cells. Indirect detection of DNA excision repair, using host cell reactivation of transfected plasmid DNA carrying cisplatin damage, also showed 2.4-fold enhancement in the resistant cells. A phenotypic revertant of the cisplatin-resistant cells displayed reduced DNA repair, compared with the resistant cells. Furthermore, immediately after cisplatin treatment the resistant cells accumulated only 50-60% of the cisplatin-DNA adducts of the parental cells. The results suggest multifactorial mechanisms in cisplatin resistance, including reduced adduct formation and improved excision repair. The findings are also consistent with the notion that the early stage of DNA excision repair is a rate-limiting step in drug resistance.
Assuntos
Cisplatino/metabolismo , Adutos de DNA , Reparo do DNA , Anticorpos Monoclonais , Especificidade de Anticorpos , Cisplatino/imunologia , Cisplatino/farmacologia , DNA/imunologia , Resistência a Medicamentos , Células HeLa , HumanosRESUMO
Polyclonal antibodies that bind selectively to DNA modified by antitumour cisplatin and its analogues were isolated. The reactivity of the antibodies with the epitope was enhanced by thermal denaturation of DNA that had been modified by cisplatin before its denaturation. On the other hand, denaturation of DNA before its modification resulted in considerably less reaction of the antibodies. The conversion of monofunctional cisplatin-DNA adducts to bifunctional lesions increased the capability of the modified DNA to competitively inhibit the antibodies. The double-helical oligonucleotides containing a unique bifunctional adduct formed by cisplatin at the d(GG) site cross-reacted with the antibodies in contrast to the oligonucleotide containing a single monofunctional adduct formed at the d(G) site. In addition, poly(dG-dC) . poly(dG-dC) modified by cisplatin did not react with the antibodies. It was concluded that the antibodies recognized monodentate lesions, intrastrand cross-links between two purine nucleosides separated by one or more nucleosides and interstrand cross-links negligibly. The antibodies apparently recognized a chemical nature of the bifunctional adduct formed between two adjacent purines and not an unusual conformational feature of DNA resulting from the formation of this adduct. The antibodies were used to analyse the adducts formed by cisplatin on DNA of cultured cells exposed to this drug. During the subsequent incubation of the already exposed cells in the drug-free medium, a part of the bifunctional adducts of cisplatin was completely removed from DNA or transformed to the adducts not recognized by the antibodies.
Assuntos
Cisplatino/química , Dano ao DNA , DNA de Neoplasias/química , Animais , Anticorpos/imunologia , Sequência de Bases , Ligação Competitiva , Cisplatino/imunologia , Cisplatino/metabolismo , DNA de Neoplasias/imunologia , DNA de Neoplasias/metabolismo , Ensaio de Imunoadsorção Enzimática , Glioma , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos/química , Oligodesoxirribonucleotídeos/imunologia , Oligodesoxirribonucleotídeos/metabolismo , Ratos , Células Tumorais CultivadasRESUMO
Mature macrophages derived in vitro from bone marrow progenitors under the influence of either L929 CM (a source of M-CSF) or GM-CSF have been shown to differ morphologically and functionally. Treatment of these bone marrow-derived macrophages with cisplatin or LPS resulted in the expression of enhanced tumoricidal activity and the production of significant amounts of extracellular and membrane-associated IL-1 and TNF. rGM-CSF-derived bone marrow macrophages produced higher amounts of TNF and IL-1 activity than L929CM-derived macrophages. Untreated bone marrow-derived macrophages showed little IL-1 and TNF activity. Bone marrow macrophages cultured with medium alone also did not respond to cisplatin or LPS for the production of IL-1 and TNF. Neutralization studies with anti-IL-1 and anti-TNF antibodies inhibited the IL-1 and TNF activity of bone marrow-derived macrophages. These results suggest that cisplatin or LPS treatment of murine bone marrow-derived macrophages results in increased expression of both released and membrane-associated IL-1 and TNF.