RESUMEN
Dacarbazine (DTIC) is the drug of choice for melanoma treatment, but its systemic administration is related to several adverse effects. Here, DTIC topical delivery stimulated by iontophoresis is proposed to overcome such drawbacks. Hence, this work analyzed the impact of anodal iontophoresis on DTIC cutaneous delivery to provide an innovative topical alternative for melanoma treatment. The electrical stability of the drug was evaluated prior to the iontophoretic experiments, which demonstrated the need to add an antioxidant to the drug formulation. DTIC cutaneous permeation was evaluated in vitro for 6 h using three current densities (0.10, 0.25, and 0.50 mA/cm2). In addition, the effect of DTIC against skin cancer cells (MeWo and WM164) was investigated for 72 h of exposure to the drug. Iontophoresis stimulated skin drug permeation compared to the passive control. However, the antioxidant presence reduced DTIC permeation under the lower currents of 0.10 and 0.25 mA/cm2, which was compensated by increasing the current density to 0.50 mA/cm2. At 0.50 mA/cm2, iontophoresis enhanced topical cutaneous drug permeation 7-fold (p < 0.05) compared to the passive control. DTIC showed a concentration-dependent antiproliferative effect on melanoma cell lines. Thus, iontophoresis intensifies DTIC skin penetration in concentrations that can reduce cell viability and induce cell death. In conclusion, DTIC cutaneous delivery mediated by iontophoresis is a promising approach for treating melanomas and other skin tumors.
Asunto(s)
Administración Cutánea , Dacarbazina , Iontoforesis , Melanoma , Absorción Cutánea , Neoplasias Cutáneas , Iontoforesis/métodos , Melanoma/tratamiento farmacológico , Humanos , Neoplasias Cutáneas/tratamiento farmacológico , Línea Celular Tumoral , Dacarbazina/administración & dosificación , Dacarbazina/farmacocinética , Animales , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/farmacocinética , Supervivencia Celular/efectos de los fármacos , Piel/metabolismo , Antioxidantes/administración & dosificación , Antioxidantes/farmacocinética , Antioxidantes/farmacología , Sistemas de Liberación de MedicamentosRESUMEN
Dacarbazine (DTIC) is a widely prescribed oncolytic agent to treat advanced malignant melanomas. Nevertheless, the drug is known for exhibiting low and pH-dependent solubility, in addition to being photosensitive. These features imply the formation of the inactive photodegradation product 2-azahypoxanthine (2-AZA) during pharmaceutical manufacturing and even drug administration. We have focused on developing novel DTIC salt/cocrystal forms with enhanced solubility and dissolution behaviors to overcome or minimize this undesirable biopharmaceutical profile. By cocrystallization techniques, two salts, two cocrystals, and one salt-cocrystal have been successfully prepared through reactions with aliphatic carboxylic acids. A detailed structural study of these new multicomponent crystals was conducted using X-ray diffraction (SCXRD, PXRD), spectroscopic (FT-IR and 1H NMR), and thermal (TG and DSC) analyses. Most DTIC crystal forms reported display substantial enhancements in solubility (up to 19-fold), with faster intrinsic dissolution rates (from 1.3 to 22-fold), contributing positively to reducing the photodegradation of DTIC in solution. These findings reinforce the potential of these new solid forms to enhance the limited DTIC biopharmaceutical profile.
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Cristalización , Dacarbazina , Fotólisis , Solubilidad , Difracción de Rayos X , Dacarbazina/química , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Espectroscopía de Resonancia Magnética , Rastreo Diferencial de CalorimetríaRESUMEN
PURPOSE: To evaluate the chemotherapeutic activity of temozolomide counter to mammary carcinoma. METHODS: In-vitro anticancer activity has been conducted on MCF7 cells, and mammary carcinoma has been induced in Wistar rats by introduction of 7, 12-Dimethylbenz(a)anthracene (DMBA), which was sustained for 24 weeks. Histopathology, immunohistochemistry, cell proliferation study and apoptosis assay via TUNEL method was conducted to evaluate an antineoplastic activity of temozolomide in rat breast tissue. RESULTS: IC50 value of temozolomide in MCF7 cell has been obtained as 103 µM, which demonstrated an initiation of apoptosis. The temozolomide treatment facilitated cell cycle arrest in G2/M and S phase dose dependently. The treatment with temozolomide suggested decrease of the hyperplastic abrasions and renovation of the typical histological features of mammary tissue. Moreover, temozolomide therapy caused the downregulation of epidermal growth factor receptor, extracellular signal-regulated kinase, and metalloproteinase-1 expression and upstream of p53 and caspase-3 proliferation to indicate an initiation of apoptotic events. CONCLUSIONS: The occurrence of mammary carcinoma has been significantly decreased by activation of apoptotic pathway and abrogation of cellular propagation that allowable for developing a suitable mechanistic pathway of temozolomide in order to facilitate chemotherapeutic approach.
Asunto(s)
Antineoplásicos Alquilantes , Apoptosis , Receptores ErbB , Ratas Wistar , Temozolomida , Temozolomida/farmacología , Temozolomida/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Femenino , Receptores ErbB/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Metaloproteinasa 1 de la Matriz/efectos de los fármacos , Metaloproteinasa 1 de la Matriz/metabolismo , Proliferación Celular/efectos de los fármacos , Dacarbazina/análogos & derivados , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Humanos , Células MCF-7 , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/efectos de los fármacos , Inmunohistoquímica , Reproducibilidad de los Resultados , Ratas , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patologíaRESUMEN
The article "The impact of bleomycin deficit on survival in Hodgkin's lymphoma patients: A retrospective study" have presented the experience of AVD chemotherapy regimen in newly diagnosed Hodgkin's lymphoma (HL) in a single center in Brazil. Though being a small retrospective study, results from this study have provided the medical community a real-world data on HL in Brazil. ABVD has remained the standard of care for patients of newly diagnosed HL both in early and advance stages. Newer targeted molecules have also come for use in novel combinations with existing drugs. However, in a situation of temporary scarcity of bleomycin due to lack of supply during 2017 in Brazil led to use of incomplete ABVD regimen without bleomycin, i.e. AVD for HL. However, Soldi et al. utilized the opportunity to retrospectively study if the omission of bleomycin leads to subnormal treatment or unwarranted effects.
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Bleomicina , Enfermedad de Hodgkin , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/mortalidad , Bleomicina/uso terapéutico , Bleomicina/administración & dosificación , Humanos , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Vinblastina/uso terapéutico , Brasil/epidemiología , Doxorrubicina/uso terapéutico , Dacarbazina/uso terapéuticoRESUMEN
Currently, analysis of interim PET (iPET) according to the Deauville score (DS) is the most important predictive factor in Hodgkin lymphoma (HL); however, there is room for improvement in its prognostic power. This study aimed to evaluate the prognostic value of quantitative PET analysis (maximum standard uptake value [SUVmax], total metabolic tumor volume [TMTV] and total lesion glicolysis [TLG]) at baseline (PET0) and iPET in a retrospective cohort of newly diagnosed classical HL. For positive iPET (+ iPET), the reduction of quantitative parameters in relation to PET0 (ΔSUVmax, ΔTMTV and ΔTLG) was calculated. Between 2011 and 2017, 234 patients treated with ABVD were analyzed. Median age was 30 years-old, 59% had advanced stage disease, 57% a bulky mass and 25% a + iPET (DS 4-5). At baseline, high TLG was associated with an increased cumulative incidence of failure (CIF) (p = 0.032) while neither SUVmax, TMTV or TLG were associated with overall survival (OS) or progression-free survival (PFS). In multivariate analysis, only iPET was associated with CIF (p < 0.001). Among ΔSUVmax, ΔTMTV and ΔTLG, only a ΔSUVmax ≥ 68.8 was significant for PFS (HR: 0.31, CI95%: 0.11-0.86, p = 0.024). A subset of patients with improved PFS amongst + iPET was identified by the quantitative (ΔSUVmax ≥ 68.8%) analysis. In this real-world Brazilian cohort, with prevalent high-risk patients, quantitative analysis of PET0 did not demonstrate to be prognostic, while a dynamic approach incorporating the ΔSUVmax to + iPET succeeded in refining a subset with better prognosis. These findings warrant validation in larger series and indicate that not all patients with + iPET might need treatment intensification.
Asunto(s)
Enfermedad de Hodgkin , Humanos , Adulto , Estudios Retrospectivos , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Fluorodesoxiglucosa F18 , Bleomicina , Dacarbazina , Doxorrubicina , Vinblastina , Pronóstico , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía de Emisión de PositronesRESUMEN
Metabolic adaptations are central for carcinogenesis and response to therapy, but little is known about the contribution of mitochondrial dynamics to the response of glioma cells to the standard treatment with temozolomide (TMZ). Glioma cells responded to TMZ with mitochondrial mass increased and the production of round structures of dysfunctional mitochondria. At single-cell level, asymmetric mitosis contributed to the heterogeneity of mitochondrial levels. It affected the fitness of cells in control and treated condition, indicating that the mitochondrial levels are relevant for glioma cell fitness in the presence of TMZ.
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Neoplasias Encefálicas , Glioma , Humanos , Temozolomida/farmacología , Temozolomida/uso terapéutico , Dacarbazina/farmacología , Dacarbazina/metabolismo , Dacarbazina/uso terapéutico , Apoptosis , Línea Celular Tumoral , Glioma/tratamiento farmacológico , Glioma/metabolismo , Mitocondrias/metabolismo , Antineoplásicos Alquilantes/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Resistencia a AntineoplásicosRESUMEN
The treatment of older patients with Hodgkin lymphoma (HL) remains a challenge. We sought to identify the treatment patterns and outcomes in older HL patients included in the Brazilian HL registry (NCT02589548). A total of 136 patients with HIV-negative classic HL, aged ≥ 60 years, diagnosed between 2009 and 2018, were analyzed. The median age was 66 years old (60-90), 72% had advanced disease, 62% had a high IPS, and 49% had a nodular sclerosis subtype. Median follow-up was 64 months for alive patients. ABVD was the front-line treatment in 96% of patients. Twenty-one patients (15%) died during front-line treatment. The 5-year PFS and 5-year OS rates were 55% and 59%, respectively. The 5-year OS rates in localized and advanced disease were 81% and 51% (p=0.013). Lung toxicity developed in 11% of the patients treated with ABVD. Bleomycin was administered for > 2 cycles in 65% of patients. Compared with 2009-2014, there was a decrease in the use of bleomycin for > 2 cycles in 2015-2018 (88% × 45%, p<0.0001). The impact of socioeconomic status (SES) on outcomes was studied in patients treated with ABVD. After adjusting for potential confounders, lower SES remained independently associated with poorer survival (HR 2.22 [1.14-4.31] for OS and HR 2.84 [1.48-5.45] for PFS). Treatment outcomes were inferior to those observed in developed countries. These inferior outcomes were due to an excess of deaths during front-line treatment and the excessive use of bleomycin. SES was an independent factor for shorter survival.
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Enfermedad de Hodgkin , Anciano , Humanos , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bleomicina/uso terapéutico , Brasil/epidemiología , Dacarbazina/uso terapéutico , Doxorrubicina/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/epidemiología , Estadificación de Neoplasias , Estudios Prospectivos , Sistema de Registros , Resultado del Tratamiento , Vinblastina/uso terapéutico , Anciano de 80 o más Años , Estudios Clínicos como AsuntoRESUMEN
Dacarbazine (DTIC) is a chemotherapeutic drug currently used for the systemic treatment of melanomas. Considering the easy access to these tumors, a topical route of drug administration could provide a more comfortable and less toxic treatment. However, DTIC quantification aiming at the design of topical formulations is challenging, pondering all the interferents present in the drug samples recovered from the skin. Hence, this work intended to validate a selective chromatographic method for DTIC determination in skin permeation studies. A reversed-phase C18 column was used as a stationary phase, and gradient elution of a mobile phase consisting of methanol and pH 6.5 sodium phosphate monohydrate buffer (0.01 mol/L) at a flow rate of 1.0 mL/min was implemented. DTIC was detected at 364 nm. The method was selective against skin interferents, linear (r = 0.9995) in a concentration range of 1.0-15.0 µg/mL, precise with an overall variation coefficient lower than 3.8%, accurate achieving recovery from the skin layers within 91-112%, and sensitive for the proposed application (detection limit = 0.10 µg/ mL, quantification limit = 0.30 µg/mL). Furthermore, the analytical method was successfully tested in in vitro skin permeation studies. In conclusion, the developed method is appropriate for DTIC analysis from the skin sample matrix.
Asunto(s)
Dacarbazina , Melanoma , Humanos , Dacarbazina/análisis , Dacarbazina/metabolismo , Piel/metabolismo , Absorción Cutánea , Cromatografía Líquida de Alta Presión/métodosRESUMEN
BACKGROUND: Soft tissue sarcomas (STSs) are an uncommon and heterogeneous group of tumours. Several drugs and combinations have been used in clinical practice as second-line (2L) and third-line (3L) treatment. The growth modulation index (GMI) has previously been used as an exploratory efficacy endpoint of drug activity and represents an intra-patient comparison. METHODS: We performed a real-world retrospective study including all patients with advanced STS who had received at least 2 different lines of treatment for advanced disease between 2010 and 2020 at a single institution. The objective was to study the efficacy of both 2L and 3L treatments, analysing the time to progression (TTP) and the GMI (defined as the ratio of TTP between 2 consecutive lines of therapy). RESULTS: Eighty-one patients were included. The median TTP after 2L and 3L treatment was 3.16 and 3.06 months, and the median GMI was 0.81 and 0.74, respectively. The regimens most frequently used in both treatments were trabectedin, gemcitabine-dacarbazine, gemcitabine-docetaxel, pazopanib and ifosfamide. The median TTP by each of these regimens was 2.80, 2.23, 2.83, 4.10, and 5.00 months, and the median GMI was 0.78, 0.73, 0.67, 1.08, and 0.94, respectively. In terms of histotype, we highlight the activity (GMI > 1.33) of gemcitabine-dacarbazine in undifferentiated pleomorphic sarcoma (UPS) and in leiomyosarcoma, pazopanib in UPS, and ifosfamide in synovial sarcoma. CONCLUSIONS: In our cohort, regimens commonly used after first-line STS treatment showed only slight differences in efficacy, although we found significant activity of specific regimens by histotype.
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Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Ifosfamida/uso terapéutico , Estudios Retrospectivos , Desoxicitidina/uso terapéutico , Sarcoma/tratamiento farmacológico , Sarcoma/patología , Gemcitabina , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/patología , Dacarbazina/uso terapéuticoRESUMEN
Melanoma is the most aggressive type of skin cancer. Brain metastasis is the worst scenario in metastatic melanoma and the treatment options for these patients are limited. Temozolomide (TMZ) is a chemotherapy agent used to treat primary central nervous system tumors. Our objective was to develop chitosan-coated nanoemulsion containing temozolomide (CNE-TMZ) for nasal route administration to melanoma brain metastasis treatment. A preclinical model of metastatic brain melanoma was standardized, and the efficiency of the developed formulation was further determined in vitro and in vivo. The nanoemulsion was done by spontaneous emulsification method and the formulation was characterized by size, pH, polydispersity index, and zeta potential. Culture assessments to determine cell viability were done in the A375 human melanoma cell line. To determine the safety of formulation, healthy C57/BL6 mice were treated with a nanoemulsion without TMZ. The model in vivo used B16-F10 cells implanted by stereotaxic surgery in C57/BL6 mice brains. The results demonstrate that the preclinical model used showed to be useful to analyze the efficiency of new candidate drugs to treat melanoma brain metastasis. The chitosan-coated nanoemulsions with TMZ showed the expected physicochemical characteristics and demonstrated safety and efficacy, reducing around 70% the tumor size compared to control mice, and presenting a tendency in mitotic index reduction, becoming an interesting approach to treat melanoma brain metastasis.
Asunto(s)
Neoplasias Encefálicas , Quitosano , Melanoma , Humanos , Animales , Ratones , Temozolomida/farmacología , Temozolomida/uso terapéutico , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Línea Celular TumoralRESUMEN
BACKGROUND AND PURPOSE: To predict treatment-related cardiovascular disease (CVD) and second cancer 30-year absolute mortality risks (AMR30) for patients with mediastinal Hodgkin lymphoma in a large multicentre radiation oncology network in Ireland. MATERIAL AND METHODS: This study includes consecutive patients treated for mediastinal lymphoma using chemotherapy and involved site radiotherapy (RT) 2016-2019. Radiation doses to heart, left ventricle, cardiac valves, lungs, oesophagus, carotid arteries and female breasts were calculated. Individual CVD and second cancer AMR30 were predicted using Irish background population rates and dose-response relationships. RESULTS: Forty-four patients with Hodgkin lymphoma were identified, 23 females, median age 28 years. Ninety-eight percent received anthracycline, 80% received 4-6 cycles ABVD. Volumetric modulated arc therapy (VMAT) ± deep inspiration breath hold (DIBH) was delivered, median total prescribed dose 30 Gy. Average mean heart dose 9.8 Gy (range 0.2-23.8 Gy). Excess treatment-related mean AMR30 from CVD was 2.18% (0.79, 0.90, 0.01, 0.13 and 0.35% for coronary disease, heart failure, valvular disease, stroke and other cardiac diseases), 1.07% due to chemotherapy and a further 1.11% from RT. Excess mean AMR30 for second cancers following RT were: lung cancer 2.20%, breast cancer in females 0.34%, and oesophageal cancer 0.28%. CONCLUSION: For patients with mediastinal lymphoma excess mortality risks from CVD and second cancers remain clinically significant despite contemporary chemotherapy and photon-RT. Efforts to reduce the toxicity of combined modality treatment, for example, using DIBH, reduced margins and advanced RT, e.g. proton beam therapy, should be continued to further reduce potentially fatal treatment effects.
Asunto(s)
Enfermedades Cardiovasculares , Enfermedad de Hodgkin , Linfoma , Neoplasias del Mediastino , Neoplasias Primarias Secundarias , Radioterapia de Intensidad Modulada , Humanos , Femenino , Adulto , Radioterapia de Intensidad Modulada/efectos adversos , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/radioterapia , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Contencion de la Respiración , Dosificación Radioterapéutica , Órganos en Riesgo/efectos de la radiación , Bleomicina , Dacarbazina , Doxorrubicina , Vinblastina , Corazón/efectos de la radiación , Neoplasias del Mediastino/etiología , Neoplasias del Mediastino/radioterapia , Enfermedades Cardiovasculares/etiología , Planificación de la Radioterapia Asistida por ComputadorRESUMEN
(1) Background: Glioblastoma is the most frequent and lethal primary tumor of the central nervous system. Through many years, research has brought various advances in glioblastoma treatment. At this time, glioblastoma management is based on maximal safe surgical resection, radiotherapy, and chemotherapy with temozolomide. Recently, bevacizumab has been added to the treatment arsenal for the recurrent scenario. Nevertheless, patients with glioblastoma still have a poor prognosis. Therefore, many efforts are being made in different clinical research areas to find a new alternative to improve overall survival, free-progression survival, and life quality in glioblastoma patients. (2) Methods: Our objective is to recap the actual state-of-the-art in glioblastoma treatment, resume the actual research and future perspectives on immunotherapy, as well as the new synthetic molecules and natural compounds that represent potential future therapies at preclinical stages. (3) Conclusions: Despite the great efforts in therapeutic research, glioblastoma management has suffered minimal changes, and the prognosis remains poor. Combined therapeutic strategies and delivery methods, including immunotherapy, synthetic molecules, natural compounds, and glioblastoma stem cell inhibition, may potentiate the standard of care therapy and represent the next step in glioblastoma management research.
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Neoplasias Encefálicas , Glioblastoma , Bevacizumab/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Dacarbazina/uso terapéutico , Glioblastoma/tratamiento farmacológico , Humanos , Temozolomida/uso terapéuticoRESUMEN
Melanoma is a highly metastatic and rapidly progressing cancer, a leading cause of mortality among skin cancers. The melanoma microenvironment, formed from the activity of malignant cells on the extracellular matrix and the recruitment of immune cells, plays an active role in the development of drug resistance and tumor recurrence, which are clinical challenges in cancer treatment. These tumoral metabolic processes are affected by proteins, including Galectin-3 (Gal-3), which is extensively involved in cancer development. Previously, we characterized a partially methylated mannogalactan (MG-Pe) with antimelanoma activities. In vivo models of melanoma were used to observe MG-Pe effects in survival, spontaneous, and experimental metastases and in tissue oxidative stress. Analytical assays for the molecular interaction of MG-Pe and Gal-3 were performed using a quartz crystal microbalance, atomic force microscopy, and contact angle tensiometer. MG-Pe exhibits an additive effect when administered together with the chemotherapeutic agent dacarbazine, leading to increased survival of treated mice, metastases reduction, and the modulation of oxidative stress. MG-Pe binds to galectin-3. Furthermore, MG-Pe antitumor effects were substantially reduced in Gal-3/KO mice. Our results showed that the novel Gal-3 ligand, MG-Pe, has both antitumor and antimetastatic effects, alone or in combination with chemotherapy.
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Antineoplásicos , Galectina 3 , Melanoma , Neoplasias Cutáneas , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Dacarbazina/metabolismo , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Galectina 3/metabolismo , Galectina 3/farmacología , Galectina 3/uso terapéutico , Ligandos , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Ratones , Recurrencia Local de Neoplasia , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/metabolismo , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/fisiologíaRESUMEN
Treatment of malignant melanoma has improved in the last few years owing to early detection and new therapeutic options. Still, management of advanced disease remains a challenge because it requires systemic treatment. In such cases, dacarbazine-based chemotherapy has been widely used, despite low efficacy. Neoadjuvant therapies emerge as alternative options that could help chemotherapy to achieve increased benefit. In this work, we evaluate LVR01, an attenuated Salmonella enterica serovar typhimurium, as neoadjuvant intralesional therapy in combination with dacarbazine in a preclinical melanoma model. B16F1 melanomaâbearing mice received intraperitoneal administration of dacarbazine for 3 consecutive days. LVR01 treatment, consisting of one single intratumoral injection, was applied 1 day before chemotherapy began. This therapeutic approach retarded tumor growth and prolonged overall survival, revealing a strong synergistic antitumor effect. Dacarbazine induced a drastic reduction of secondary lymphoid organ cellularity, which was partially restored by Salmonella, particularly potentiating activated cytotoxic cell compartments. Systemic immune reactivation could be a consequence of the intense inflammatory tumor microenvironment induced by LVR01. We propose that the use of LVR01 as neoadjuvant intralesional therapy could be considered as an interesting strategy with close clinical application to boost chemotherapy effect in patients with melanoma.
Asunto(s)
Melanoma , Neoplasias Cutáneas , Animales , Dacarbazina/uso terapéutico , Humanos , Melanoma/patología , Ratones , Terapia Neoadyuvante , Salmonella typhimurium , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Microambiente TumoralRESUMEN
Oxidative stress role on metformin process of dacarbazine (DTIC) inducing resistance of B16F10 melanoma murine cells are investigated. To induce resistance to DTIC, murine melanoma cells were exposed to increasing concentrations of dacarabazine (DTIC-res group). Metformin was administered before and during the induction of resistance to DTIC (MET-DTIC). The oxidative stress parameters of the DTIC-res group showed increased levels of malondialdehyde (MDA), thiol, and reduced nuclear p53, 8-hydroxy-2'-deoxyguanosine (8-OH-DG), nuclear factor kappa B (NF-ĸB), and Nrf2. In presence of metformin in the resistant induction process to DTIC, (MET-DTIC) cells had increased antioxidant thiols, MDA, nuclear p53, 8-OH-DG, Nrf2, and reducing NF-ĸB, weakening the DTIC-resistant phenotype. The exclusive administration of metformin (MET group) also induced the cellular resistance to DTIC. The MET group presented high levels of total thiols, MDA, and reduced percentage of nuclear p53. It also presented reduced nuclear 8-OH-DG, NF-ĸB, and Nrf2 when compared with the control. Oxidative stress and the studied biomarkers seem to be part of the alterations evidenced in DTIC-resistant B16F10 cells. In addition, metformin administration is able to play a dual role according to the experimental protocol, preventing or inducing a DTIC-resistant phenotype. These findings should help future research with the aim of investigating DTIC resistance in melanoma.
Asunto(s)
Antineoplásicos Alquilantes/farmacología , Antioxidantes/farmacología , Dacarbazina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Melanoma Experimental/tratamiento farmacológico , Metformina/farmacología , Neoplasias Cutáneas/tratamiento farmacológico , 8-Hidroxi-2'-Desoxicoguanosina/metabolismo , Animales , Línea Celular Tumoral , Malondialdehído/metabolismo , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
OBJECTIVES: Advanced melanoma accounts for 4% of malignant skin tumors, and approximately 80% of deaths are attributed to it. The most frequent mutation of the RAF gene is BRAFV600, which has been associated with a worse prognosis. The objective of the research was to evaluate the cost-effectiveness of the combined regimen of dabrafenib plus trametinib (D + T) compared with other targeted therapies, immunotherapy, and dacarbazine for the treatment of unresectable/metastatic melanoma with BRAFV600 mutation from the perspective of the Colombian health system. METHODS: A partitioned survival model with 3 states (progression-free survival, progression, and death) was used to evaluate the cost-effectiveness for a time horizon of 20 years. Owing to the perspective of the analysis, only direct medical costs were taken into account. The efficacy of the evaluated treatment and the comparators were measured in terms of overall survival and progression-free survival. All costs were expressed in Colombian pesos as of 2018, and outcomes and costs were discounted at 5% annually. Two analysis scenarios were considered, one in which only monitoring and follow-up costs were included in the progression phase and another in which costs of acquisition of possible treatment sequences were also included. RESULTS: In the first scenario (without postprogression medication costs), the combined D + T regimen was a dominant alternative to vemurafenib + cobimetinib but was not a cost-effective option compared with vemurafenib, nivolumab, ipilimumab, nivolumab + ipilimumab, pembrolizumab, and dacarbazine. In the second scenario (with drug costs in postprogression), D + T was dominant compared with vemurafenib + cobimetinib and cost-effective compared with nivolumab and pembrolizumab. Compared with other schemes, the incremental cost-effectiveness ratio was above the threshold of 3 gross domestic product per capita. Probabilistic sensitivity analyses showed that a willingness-to-pay threshold of Col$56 484 300 (US$19 108) per quality-adjusted life-year would not be reached at the current price of schema in Colombia. CONCLUSIONS: The combined scheme could be a cost-effective and even a cost-saving alternative to vemurafenib + cobimetinib, nivolumab, and pembrolizumab if the costs associated with the use of other medications are taken into account after progression to the first line of treatment. Compared with the other comparators, it produces a greater number of quality-adjusted life-years, but the incremental cost-effectiveness ratio is above that of the willingness to pay.
Asunto(s)
Dacarbazina , Melanoma , Colombia , Análisis Costo-Beneficio , Humanos , Imidazoles , Inmunoterapia , Melanoma/tratamiento farmacológico , Melanoma/genética , Mutación , Oximas , Piridonas , PirimidinonasRESUMEN
PURPOSE: Melanoma is an invasive and very aggressive skin cancer due to its multi-drug resistance that results in poor patient survival. There is a need to test new treatment approaches to improve therapeutic efficacy and reduce side effects of conventional treatments. METHODS: PLA/PVA nanoparticles carrying both Dacarbazine and zinc phthalocyanine was produced by double emulsion technique. The characterization was performed by dynamic light scattering and atomic force microscopy. In vitro photodynamic therapy test assay using MV3 melanoma cells as a model has been performed. In vitro cell viability (MTT) was performed to measure cell toxicity of of nanoparticles with and without drugs using human endothelial cells as a model. The in vivo assay (biodistribution/tissue deposition) has been performed using radiolabeled PLA/PVA NPs. RESULTS: The nanoparticles produced showed a mean diameter of about 259 nm with a spherical shape. The in-vitro photodynamic therapy tests demonstrated that the combination is critical to enhance the therapeutic efficacy and it is dose dependent. The in vitro cell toxicity assay using endothelial cells demonstrated that the drug encapsulated into nanoparticles had no significant toxicity compared to control samples. In-vivo results demonstrated that the drug loading affects the biodistribution of the nanoparticle formulations (NPs). Low accumulation of the NPs into the stomach, heart, brain, and kidneys suggested that common side effects of Dacarbazine could be reduced. CONCLUSION: This work reports a robust nanoparticle formulation with the objective to leveraging the synergistic effects of chemo and photodynamic therapies to potentially suppressing the drug resistance and reducing side effects associated with Dacarbazine. The data corroborates that the dual encapsulated NPs showed better in-vitro efficacy when compared with the both compounds alone. The results support the need to have a dual modality NP formulation for melanoma therapy by combining chemotherapy and photodynamic therapy.
Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Portadores de Fármacos/química , Melanoma/tratamiento farmacológico , Fármacos Fotosensibilizantes/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/farmacocinética , Línea Celular Tumoral , Supervivencia Celular , Dacarbazina/administración & dosificación , Dacarbazina/farmacocinética , Composición de Medicamentos/métodos , Células Endoteliales , Humanos , Isoindoles/administración & dosificación , Isoindoles/farmacocinética , Masculino , Melanoma/patología , Ratones , Nanopartículas/química , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/farmacocinética , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacocinética , Poliésteres/química , Alcohol Polivinílico/química , Neoplasias Cutáneas/patología , Distribución Tisular , Compuestos de Zinc/administración & dosificación , Compuestos de Zinc/farmacocinéticaRESUMEN
PURPOSE: Considering the increased cancer patient survivorship, the focus is now on addressing the impacts of treatment on quality of life. In young people, altered reproductive function is a major issue and its effects in young males are largely neglected by novel research. To improve clinician awareness, we systematically reviewed side effects of chemotherapy for Hodgkin lymphoma (HL) in young males. METHODS: The review was prospectively registered (PROSPERO N. CRD42019122868). Three databases (Medline via PUBMED, SCOPUS, and Cochrane Library) were searched for studies featuring males aged 13-51-years who underwent chemotherapy for HL using ABVD (Adriamycin® (doxorubicin), bleomycin, vinblastine, and dacarbazine) or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone) regimens. These chemotherapy regimens were compared against each other using sperm characteristics, FSH, and inhibin B levels to measure fertility levels. RESULTS: Data were extracted from five studies featuring 1344 patients. 6 months post-ABVD saw marked deterioration in sperm count, further reduced by more cycles (P = 0.05). Patients treated with BEACOPP rather than ABVD were more prone to oligospermia. Receiving fewer cycles of both regimens increased the likelihood of sperm production recovering. Patients treated with 6-8 cycles of BEACOPP did not recover spermiogenesis. CONCLUSIONS: ABVD and BEACOPP regimens significantly reduce fertility function to varying effects depending on treatment duration. ABVD temporarily causes significant reductions in male fertility, whereas BEACOPP's effects are more permanent. Therefore, clinicians should discuss fertility preservation with male patients receiving infertility-inducing gonadotoxic therapy. Further high-quality studies are required to more adequality describe the risk to fertility by chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Fertilidad/efectos de los fármacos , Enfermedad de Hodgkin/tratamiento farmacológico , Infertilidad Masculina/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bleomicina/efectos adversos , Bleomicina/farmacología , Bleomicina/uso terapéutico , Ciclofosfamida/efectos adversos , Ciclofosfamida/farmacología , Ciclofosfamida/uso terapéutico , Dacarbazina/efectos adversos , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Doxorrubicina/efectos adversos , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Etopósido/efectos adversos , Etopósido/farmacología , Etopósido/uso terapéutico , Humanos , Masculino , Prednisona/efectos adversos , Prednisona/farmacología , Prednisona/uso terapéutico , Procarbazina/efectos adversos , Procarbazina/farmacología , Procarbazina/uso terapéutico , Vinblastina/efectos adversos , Vinblastina/farmacología , Vinblastina/uso terapéutico , Vincristina/efectos adversos , Vincristina/farmacología , Vincristina/uso terapéuticoRESUMEN
INTRODUÇÃO: Embora não esteja entre os tumores malignos com maior incidência, o melanoma é considerado o tipo mais agressivo de câncer de pele devido ao grande potencial de disseminação à distância e consequente elevada letalidade. Em 2018, um total de 6.260 casos novos de melanoma maligno de pele foram estimados no Brasil, com aproximadamente 26% dos casos em estágio metastático e 1.794 óbitos registrados em 2015. O presente estudo avaliou as opções terapêuticas sistêmicas aprovadas pela Agência Nacional de Vigilância Sanitária (ANVISA) para o tratamento de primeira linha do melanoma avançado não cirúrgico e metastático. PERGUNTA: O uso de terapia-alvo ou imunoterapia é mais eficaz, seguro e custo-efetivo do que a quimioterapia com dacarbazina para o tratamento de primeira linha do melanoma avançado não-cirúrgico e metastático? TECNOLOGIAS: terapia-alvo (vemurafenibe, dabrafenibe, cobimetinibe, trametinibe) e imunoterapia (ipilimumabe, nivolumabe, pembrolizumabe). EVIDÊNCIAS CIENTÍFICAS: Quando comparadas ao tratamento padrão com dacarbazina, todas as terapias demonstraram superioridade estatisticamente significativa, tanto no desfecho de sobrevida livre de progressão (SLP) quanto em sobrevida global (SG), exceto dabrafenibe isolado. Em relação à SG, as estimativas pontuais demonstram maior benefício na redução do risco de morte com a combinação de nivolumabe/ipilimumabe (67%; 23% no pior cenário) seguida das imunoterapias isoladas com nivolumabe ou pembrolizumabe (54%; 41% no pior cenário), terapias-alvo combinadas (44-46%; 23-27% no pior cenário), imunoterapia isolada com ipilimumabe (32%; 7% no pior cenário) e terapia-alvo isolada com vemurafenibe (20%; 3% no pior cenário). Os eventos adversos graus 3/4 foram avaliados entre as classes terapêuticas de terapia-alvo, imunoterapia e quimioterapia. Os estudos reportaram menor risco de eventos adversos para a imunoterapia isolada anti-PD-1 (nivolumabe e pembrolizumabe) em relação à dacarbazina. As classes terapêuticas que apresentaram maior risco de eventos adversos foram: terapia-alvo isolada, terapia-alvo combinada, imunoterapia isolada com anti-CTLA-4 e imunoterapia combinada, todas com estimativa pontual de risco relativo acima de 1,40. AVALIAÇÃO ECONÔMICA: A avaliação de custo-efetividade demonstrou o ipilimumabe como a alternativa com menor razão de custo-efetividade incremental (ICER) em relação à dacarbazina. O nivolumabe e a sua associação com ipilimumabe tiveram melhores resultados em efetividade, porém com maior custo. Uma redução do preço do nivolumabe em 8 vezes tornaria seu ICER menor que 1 PIB per capita em relação à dacarbazina. A análise de sensibilidade probabilística revelou incertezas sobre a análise e o nivolumabe + ipilimumabe teve maior probabilidade que a dacarbazina de ser custo-efetivo em limiares próximos a R$322.000/QALY. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: O impacto orçamentário incremental em 5 anos variou de R$ 617.226.282,43 a R$ 2.880.924.401,13 para o ipilimumabe e sua associação com nivolumabe, respectivamente. As associações com terapia-alvo resultaram em impacto orçamentário menor que o nivolumabe, pois nessas estratégias apenas metade da população que tem a mutação BRAF seria tratada. O modelo buscou considerar além dos custos com os medicamentos, os custos diretos relacionados aos tratamentos. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Plenário da CONITEC presentes na 84ª reunião ordinária, no dia 05 de dezembro de 2019, definiram que o tema deve ser submetido à consulta pública com recomendação preliminar desfavorável à incorporação no SUS de terapia-alvo e da imunoterapia para o tratamento de primeira linha de pacientes com melanoma avançado não-cirúrgico e metastático. Apesar destas terapias apresentarem maior eficácia em relação à dacarbazina, o elevado custo do tratamento produziu uma relação de custo-efetividade e um impacto orçamentário incrementais que inviabilizam a sua incorporação. CONSULTA PÚBLICA: A Consulta Pública nº 85/2019, ocorreu entre os dias 02/01/2020 e 21/01/2020. Foram recebidas 2.300 contribuições, das quais 1.995 (mil novecentos e noventa e cinco) foram do formulário de experiência ou opinião e 305 (trezentos e cinco) do formulário técnico científico. Das contribuições de experiência ou opinião, 92% discordaram da recomendação preliminar e entre as contribuições técnico-científicas, 95% discordaram da recomendação preliminar e a maior parte das contribuições foram relacionadas à eficácia da terapia-alvo e da imunoterapia quando comparadas à dacarbazina. Os principais argumentos foram relacionados ao direito ao acesso ao tratamento de alto custo, eficácia dos tratamentos avaliados, e obsolescência do medicamento mais amplamente utilizado atualmente do SUS (dacarbazina). Foram recebidas contribuições de 4 (quatro) empresas fabricantes das tecnologias. Algumas contribuições levaram à atualização do modelo econômico, mas mostraram que o nivolumabe e a combinação nivolumabe com ipilimumabe permaneceram sendo as estratégias não dominadas. Outras terapias passaram a ter dominância extendida, mas não passaram a ser dominantes. Na discussão do tema, os membros do Plenário destacaram que a utilização do desfecho "cura dos pacientes com melanoma metastático", conforme apresentado pelo fabricante, não é adequado, por se tratar de uma avaliação indireta por meio de dados da literatura sobre respostas completas sustentadas em um período determinado de tempo. Foi ressaltado, em termos gerais, que as terapias avaliadas, principalmente imunoterapias anti-PD1, mudam inteiramente o contexto atual do melanoma metastático, representando uma evolução no tratamento. Porém, o custo das terapias permanece muito elevado. Houve novas propostas de preços pelas empresas fabricantes dos medicamentos anti-PD1 avaliados (nivolumabe e pembrolizumabe) que apresentaram satisfatórios perfis de eficácia e segurança. Com as informações adicionais a avaliação econômica foi atualizada com a alteração da duração de tratamento do pembrolizumabe e com novos preços propostos pelas empresas. Para o nivolumabe houve a proposta de redução do preço que era de R$27.882,36 para R$20.939,69, com duração de tratamento até a progressão da doença ou morte. Para o pembrolizumabe houve a proposta de redução do preço que era de R$28.954,80 para R$23.724 (ICMS 17%) ou R$19.690,02 (ICMS 0%), com duração de tratamento até progressão da doença ou morte ou até vinte e quatro meses em pacientes sem progressão. RECOMENDAÇÃO FINAL: Os membros da Conitec presentes na 88ª reunião ordinária, no dia 08 de julho de 2020, deliberaram, por unanimidade, por recomendar a incorporação no Sistema Único de Saúde da classe anti-PD1 (nivolumabe ou pembrolizumabe), para tratamento de primeira linha do melanoma avançado não cirúrgico e metastático, conforme modelo da assistência oncológica no SUS. Foram levadas em consideração as novas propostas de preços apresentadas pelas empresas fabricantes dos medicamentos anti-PD1 avaliados (nivolumabe e pembrolizumabe) além dos satisfatórios perfis de eficácia e segurança demonstrado pelos dois medicamentos. Discutiu-se que o custo mensal do tratamento de ambos os medicamentos deveriam ainda ser reduzidos conforme valor de referência de 3 PIB/per capita para uma razão de custo-efetividade incremental favorável. Foi discutida também a possibilidade de criação de um valor máximo para o procedimento na tabela SIGTAP com a recomendação da classe terapêutica. Foi assinado o Registro de Deliberação nº 533/2020. DECISÃO: incorporar a classe anti-PD1 (nivolumabe e pembrolizumabe) para o tratamento de primeira linha do melanoma avançado não-cirúrgico e metastático, conforme o modelo da assistência oncológica, no âmbito do Sistema Único de Saúde - SUS, conforme a Portaria nº 23, publicada no Diário Oficial da União nº 149, seção 1, página 91, em 05 de agosto de 2020.
Asunto(s)
Humanos , Neoplasias Cutáneas/tratamiento farmacológico , Dacarbazina/uso terapéutico , Ipilimumab/uso terapéutico , Vemurafenib/uso terapéutico , Nivolumab/uso terapéutico , Melanoma/tratamiento farmacológico , Metástasis de la Neoplasia , Evaluación de la Tecnología Biomédica , Sistema Único de Salud , Brasil , Análisis Costo-Beneficio/economíaRESUMEN
Antineoplastic therapy has been associated with pain syndrome development characterized by acute and chronic pain. The chemotherapeutic agent dacarbazine, used mainly to treat metastatic melanoma, is reported to cause painful symptoms, compromising patient quality of life. Evidence has proposed that transient receptor potential ankyrin 1 (TRPA1) plays a critical role in chemotherapy-induced pain syndrome. Here, we investigated whether dacarbazine causes painful hypersensitivity in naive or melanoma-bearing mice and the involvement of TRPA1 in these models. Mouse dorsal root ganglion (DRG) neurons and human TRPA1-transfected HEK293 (hTRPA1-HEK293) cells were used to evaluate the TRPA1-mediated calcium response evoked by dacarbazine. Mechanical and cold allodynia were evaluated after acute or repeated dacarbazine administration in naive mice or after inoculation of B16-F10 melanoma cells in C57BL/6 mice. TRPA1 involvement was investigated by using pharmacological and genetic tools (selective antagonist or antisense oligonucleotide treatment and Trpa1 knockout mice). Dacarbazine directly activated TRPA1 in hTRPA1-HEK293 cells and mouse DRG neurons and appears to sensitize TRPA1 indirectly by generating oxidative stress products. Moreover, dacarbazine caused mechanical and cold allodynia in naive but not Trpa1 knockout mice. Also, dacarbazine-induced nociception was reduced by the pharmacological TRPA1 blockade (antagonism), antioxidants, and by ablation of TRPA1 expression. TRPA1 pharmacological blockade also reduced dacarbazine-induced nociception in a tumor-associated pain model. Thus, dacarbazine causes nociception by TRPA1 activation, indicating that this receptor may represent a pharmacological target for treating chemotherapy-induced pain syndrome in cancer patients submitted to antineoplastic treatment with dacarbazine.