RESUMO
Compelling evidence indicates that radiotherapy (RT) has a systemic inhibitory effect on nonirradiated lesions (abscopal effect) in addition to the ablation of irradiated tumors. However, this effect occurs only in rare circumstances in clinical practice, and mechanisms underlying the abscopal effect of RT are neither fully understood nor therapeutically utilized. Here we identified that intercellular adhesion molecule-1 (ICAM-1), an inducible glycoprotein of the immunoglobulin superfamily, is up-regulated in nonirradiated tumors responsive to RT. ICAM-1 expression in preclinical animal models can be noninvasively detected by optical imaging and positron emission tomography (PET) using near-infrared fluorescence dye- and 64Cu-labeled imaging probes that we synthesized, respectively. Importantly, the expression levels of ICAM-1 determined by quantitative PET imaging showed a strong negative linear correlation with the growth of nonirradiated tumors. Moreover, genetic or pharmacologic up-regulation of ICAM-1 expression by either an intratumoral injection of engineered recombinant adenovirus or systemic administration of a Toll-like receptor 7 agonist-capsulated nanodrug could induce markedly increased abscopal responses to local RT in animal models. Mechanistic investigation revealed that ICAM-1 expression can enhance both the activation and tumor infiltration of CD8+ T cells to improve the responses of the nonirradiated tumors to RT. Together, our findings suggest that noninvasive PET imaging of ICAM-1 expression could be a powerful means to predict the responses of nonirradiated tumors to RT, which could facilitate the exploration of new combination RT strategies for effective ablation of primary and disseminated lesions.
Assuntos
Antineoplásicos/administração & dosagem , Imiquimode/administração & dosagem , Molécula 1 de Adesão Intercelular/metabolismo , Neoplasias Experimentais/radioterapia , Adenoviridae , Animais , Biomarcadores/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Avaliação Pré-Clínica de Medicamentos , Molécula 1 de Adesão Intercelular/administração & dosagem , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/metabolismo , Camundongos Endogâmicos BALB C , Nanopartículas , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Tomografia por Emissão de PósitronsRESUMO
PURPOSE: Increased angiogenesis is a marker of aggressiveness in many cancers. Targeted radionuclide therapy of these cancers with angiogenesis-targeting agents may curtail this increased blood vessel formation and slow the growth of tumors, both primary and metastatic. CD105, or endoglin, has a primary role in angiogenesis in a number of cancers, making this a widely applicable target for targeted radioimmunotherapy. METHODS: The anti-CD105 antibody, TRC105 (TRACON Pharmaceuticals), was conjugated with DTPA for radiolabeling with 177Lu (t 1/2 6.65 days). Balb/c mice were implanted with 4T1 mammary carcinoma cells, and five study groups were used: 177Lu only, TRC105 only, 177Lu-DTPA-IgG (a nonspecific antibody), 177Lu-DTPA-TRC105 low-dose, and 177Lu-DTPA-TRC105 high-dose. Toxicity of the agent was monitored by body weight measurements and analysis of blood markers. Biodistribution studies of 177Lu-DTPA-TRC105 were also performed at 1 and 7 days after injection. Ex vivo histology studies of various tissues were conducted at 1, 7, and 30 days after injection of high-dose 177Lu-DTPA-TRC105. RESULTS: Biodistribution studies indicated steady uptake of 177Lu-DTPA-TRC105 in 4T1 tumors between 1 and 7 days after injection (14.3 ± 2.3%ID/g and 11.6 ± 6.1%ID/g, respectively; n = 3) and gradual clearance from other organs. Significant inhibition of tumor growth was observed in the high-dose group, with a corresponding significant increase in survival (p < 0.001, all groups). In most study groups (all except the nonspecific IgG group), the body weights of the mice did not decrease by more than 10%, indicating the safety of the injected agents. Serum alanine transaminase levels remained nearly constant indicating no damage to the liver (a primary clearance organ of the agent), and this was confirmed by ex vivo histological analyses. CONCLUSION: 177Lu-DTPA-TRC105, when administered at a sufficient dose, is able to curtail tumor growth and provide a significant survival benefit without off-target toxicity. Thus, this targeted agent could be used in combination with other treatment options to slow tumor growth allowing the other agents to be more effective.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Lutécio/química , Neoplasias Experimentais/radioterapia , Neovascularização Patológica/radioterapia , Radioimunoterapia/métodos , Radioisótopos/química , Compostos Radiofarmacêuticos/uso terapêutico , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Linhagem Celular Tumoral , Endoglina/imunologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/patologia , Ácido Pentético/química , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Distribuição TecidualRESUMO
PURPOSE: To determine the role of Molsidomine in preventing radiation-induced retinopathy after head and neck region irradiation of rats with a single radiation dose of 15 Gy. MATERIALS AND METHODS: Male Wistar albino rats were randomly grouped into five as follows: (1) control group rats, which were applied through an intraperitoneal (i.p.) vehicle without radiotherapy (RT); (2) RT group rats received a single dose of 15 Gy irradiation and after daily 0.1 ml vehicle i.p. for 5 consecutive days; (3) molsidomine (MOL) group rats were treated for 5 consecutive days by i.p. with 4 mg/kg/day MOL; (4) irradiation plus MOL group (RT+MOL) rats received irradiation and after 10 days single daily i.p. dose of MOL for 5 consecutive days; and (5) MOL+RT group rats were treated for 5 consecutive days by i.p. with MOL before RT. At the end of the work the rats were sacrificed under high-dose anesthesia on the 16th day and then eye tissues were taken for histopathological, immunohistochemical (caspase-3), and biochemical analyses (superoxide dismutase [SOD], glutathione peroxidase [GSH], and malondialdehyde [MDA]). RESULTS: RT significantly decreased both the content of GSH and the activity of SOD, and significantly increased the production of MDA level in the rat eyes. MOL treatment significantly increased the SOD and GSH levels and significantly decreased the MDA production (p < 0.0001). In addition, RT significantly increased the number of ganglion cells (GCs; p = 0.001), whereas especially pretreatment with MOL improved (p = 0.013). RT led to significant retinopathy formation, and MOL therapy protected the retina from radiation-induced retinopathy (p < 0.0001). CONCLUSIONS: We suggest that MOL is a powerful antioxidant and free radical scavenger that prevents the rat eyes from radiation-induced retinopathy and oxidative stress.
Assuntos
Molsidomina/farmacologia , Neoplasias Experimentais/radioterapia , Estresse Oxidativo , Lesões Experimentais por Radiação/prevenção & controle , Doenças Retinianas/prevenção & controle , Animais , Glutationa Peroxidase/metabolismo , Imuno-Histoquímica , Peroxidação de Lipídeos , Masculino , Malondialdeído/metabolismo , Doadores de Óxido Nítrico/farmacologia , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia , Ratos , Ratos Wistar , Doenças Retinianas/etiologia , Doenças Retinianas/metabolismo , Superóxido Dismutase/metabolismoRESUMO
PURPOSE: To investigate an enhancement of DNA double-strand break (DSB) induction and cell killing effect by K-shell ionization of phosphorus atoms and Auger electrons on human cell lines. MATERIALS AND METHODS: Induction of DSB, DNA damage responses, cell cycle distributions, and cell killing effects were investigated after exposures of the cells with monochromatic synchrotron radiation soft X-rays of 2153 and 2147 eV, which were the resonance peak and off peak, respectively, of the K-shell photoabsorption of phosphorus. RESULTS: Higher biological effects in the cells irradiated with soft X-rays at 2153 eV than at 2147 eV were observed in (i) the efficiency of 53BP1/γ-H2AX co-localized foci formation per dose and residual number of foci, (ii) prolonged phosphorylation levels of DSB repair and/or cell cycle checkpoint related proteins and G2 arrest, (iii) the cell killing effects at the 10% survival level of normal human fibroblasts, HeLa cells, and human glioblastoma M059K cells (1.2-1.5 times higher) and that of human ataxia telangiectasia mutated (ATM)-defective cells and glioblastoma DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-defective cells (1.2 times). CONCLUSION: The yield of DSB and partly less-reparable complex DNA damage induction in human cells was enhanced by K-shell photoabsorption of phosphorus and low-energy Auger electrons.
Assuntos
Apoptose/efeitos dos fármacos , Apoptose/genética , Dano ao DNA/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/radioterapia , Fósforo/efeitos da radiação , Absorção de Radiação , Linhagem Celular Tumoral , Relação Dose-Resposta à Radiação , Elétrons/uso terapêutico , Humanos , Neoplasias Experimentais/patologia , Dosagem Radioterapêutica , Resultado do TratamentoRESUMO
PURPOSE: A more immediate impact for therapeutic approaches of current clinical research efforts is of major interest, which might be obtained by developing a noninvasive radiation dose-escalation strategy, and neutron capture therapy represents one such novel approach. Furthermore, some recent researches on neutron capture therapy have focused on using gadolinium as an alternative or complementary for currently used boron, taking into account several advantages that gadolinium offers. Therefore, in this study, we carried out feasibility evaluation for both single and multiple injections of gadolinium-based MRI contrast agent incorporated in calcium phosphate nanoparticles as neutron capture therapy agent. METHODS: In vivo evaluation was performed on colon carcinoma Col-26 tumor-bearing mice irradiated at nuclear reactor facility of Kyoto University Research Reactor Institute with average neutron fluence of 1.8 × 10(12) n/cm(2). Antitumor effectivity was evaluated based on tumor growth suppression assessed until 27 days after neutron irradiation, followed by histopathological analysis on tumor slice. RESULTS: The experimental results showed that the tumor growth of irradiated mice injected beforehand with Gd-DTPA-incorporating calcium phosphate-based nanoparticles was suppressed up to four times higher compared to the non-treated group, supported by the results of histopathological analysis. CONCLUSION: The results of antitumor effectivity observed on tumor-bearing mice after neutron irradiation indicated possible effectivity of gadolinium-based neutron capture therapy treatment.
Assuntos
Fosfatos de Cálcio/administração & dosagem , Neoplasias do Colo/patologia , Neoplasias do Colo/radioterapia , Meios de Contraste/administração & dosagem , Gadolínio DTPA/administração & dosagem , Imageamento por Ressonância Magnética/métodos , Nanopartículas/administração & dosagem , Terapia por Captura de Nêutron/métodos , Animais , Estudos de Viabilidade , Feminino , Humanos , Injeções , Japão , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/radioterapia , Dosagem Radioterapêutica , Distribuição Tecidual , Resultado do TratamentoRESUMO
Nanocarriers play an important role in improving the photo- and thermal-stability of photosensitizers to gain better pharmacokinetics behavior in tumor photothermal therapy. Herein, PEGylated chitosan (CG-PEG; PEG: polyethylene glycol) nanoparticles with ultrasmall size (â¼5 nm) were prepared through a water-in-oil reverse microemulsion method using genipin as a cross-linker. Particle size and zeta-potential can be tuned by varying the molar ratio between chitosan amino groups and genipin. CG-PEG-ICG (ICG: indocyanine green) nanoparticles were fabricated by adding ICG to CG-PEG aqueous solution through a self-assembly method via electrostatic interaction. The resultant CG-PEG-ICG nanoparticles exhibited improved photo- and thermal-stability, good biocompatibility, and low toxicity. When irradiated with a laser, the cells incubated with CG-PEG-ICG nanoparticles showed very low cell viability (15%), indicating the CG-PEG-ICG nanoparticles possess high in vitro photothermal toxicity. Moreover, the CG-PEG nanocarriers can significantly alter the biodistribution and prolong the retention time of ICG in the mice body after intravenous injection. In vivo photothermal study of tumors injected with CG-PEG-ICG nanoparticles containing ICG at a concentration greater than 100 µg·mL(-1) (100 µL) induced irreversible tissue damage. The growth of U87 tumors was dramatically inhibited by CG-PEG-ICG nanoparticles, demonstrating that the CG-PEG nanoparticles may act as potential ICG nanocarriers for effective in vivo tumor photothermal therapy.
Assuntos
Portadores de Fármacos/síntese química , Nanopartículas/química , Neoplasias Experimentais/radioterapia , Fármacos Fotossensibilizantes/síntese química , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Quitosana , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Iridoides , Terapia com Luz de Baixa Intensidade , Camundongos , Tamanho da Partícula , Fármacos Fotossensibilizantes/farmacologiaRESUMO
This study was designed to investigate the impact of ultra-filtration extract mixture from Astragals mongholicus (UEMAM) o radiosensitivity of H22 ascitic tumor in mice to 12C6+ ions radiation. The H22 ascitic tumor model was established in mice by intraperitoneal injection of 0.2 mL H22 ascitic cells. The animals were subsequently divided into 4 groups randomly, treated with normal saline, UEMAM, heavy ion beam radiotherapy and UEMAM plus heavy ion beam radiotherapy, respectively. The body weights, abdomen circumference of the mice were measured and the mouse behavior was monitored every day; survival time was recorded to evaluate life extension effect; flow cytometry technique was used to detect H22 cell apoptosis and cell cycle; protein levels of p53, Bax, Bcl-2 and cleaved Caspase-3 were analyzed by Western blot; the single cell gel electrophoresis was used to detect the level of deoxyribonucleic acid damage (DNA damage). The results suggest that UEMAM significantly increased survival time, and decreased body weights and abdomen circumference over the saline control group. The treatment increased cell apoptosis, cycle arrest and DNA damage compared to the saline control group. UEMAM significantly enhanced the therapeutic effect of heavy ion beam radiation in survival time, and decreased body weights and abdomen circumference in the tumor-baring mice. The combination increased cell apoptosis, cycle arrest and DNA damage compared to the radiotherapy group. The results of Western blot suggest that the treatment significantly enhanced p53-induced apoptotic signals. The experiment discovered that UEMAM could improve radiosensitivity of H22 ascitic tumor through activation of p53-mediated apoptotic signal pathway.
Assuntos
Astrágalo/química , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/radioterapia , Extratos Vegetais/farmacologia , Tolerância a Radiação , Animais , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Dano ao DNA , Íons , Camundongos , Transdução de SinaisRESUMO
Targeted radionuclide therapy has shown impressive results for the palliative treatment of several types of cancer diseases. The folate receptor has been identified as specifically associated with a variety of frequent tumor types. Therefore, it is an attractive target for the development of new radionuclide therapies using folate-based radioconjugates. Previously, we found that pemetrexed (PMX) has a favorable effect in reducing undesired renal uptake of radiofolates. Moreover, PMX also acts as a chemotherapeutic and radiosensitizing agent on tumors. Thus, the aim of our study was to investigate the combined application of PMX and the therapeutic radiofolate (177)Lu-EC0800. Determination of the combination index (CI) revealed a synergistic inhibitory effect of (177)Lu-EC0800 and PMX on the viability of folate receptor-positive cervical (KB) and ovarian (IGROV-1) cancer cells in vitro (CI < 0.8). In an in vivo study, tumor-bearing mice were treated with (177)Lu-EC0800 (20 MBq) and a subtherapeutic (0.4 mg) or therapeutic amount (1.6 mg) of PMX. Application of (177)Lu-EC0800 with PMXther resulted in a two- to four-fold enhanced tumor growth delay and a prolonged survival of KB and IGROV-1 tumor-bearing mice, as compared to the combination with PMXsubther or untreated control mice. PMXsubther protected the kidneys from undesired side effects of (177)Lu-EC0800 (20 MBq) by reducing the absorbed radiation dose. Intact kidney function was shown by determination of plasma parameters and quantitative single-photon emission computed tomography using (99m)Tc-DMSA. Our results confirmed the anticipated dual role of PMX. Its unique features resulted in an improved antitumor effect of folate-based radionuclide therapy and prevented undesired radio-nephrotoxicity.
Assuntos
Complexos de Coordenação/uso terapêutico , Receptores de Folato com Âncoras de GPI/antagonistas & inibidores , Antagonistas do Ácido Fólico/administração & dosagem , Ácido Fólico/uso terapêutico , Glutamatos/administração & dosagem , Guanina/análogos & derivados , Lutécio/administração & dosagem , Neoplasias Experimentais/radioterapia , Compostos Radiofarmacêuticos/administração & dosagem , Animais , Linhagem Celular Tumoral , Terapia Combinada , Avaliação Pré-Clínica de Medicamentos , Feminino , Guanina/administração & dosagem , Humanos , Células KB , Masculino , Camundongos , Camundongos Nus , Neoplasias Experimentais/patologia , Pemetrexede , Projetos Piloto , Radioisótopos/administração & dosagem , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Clofarabine, an approved anticancer drug, was evaluated in combination with radiation in six subcutaneously implanted human tumor xenograft models. Clofarabine had no effect on the growth of SF-295 glioblastoma, which was not enhanced by radiation. There was no difference between clofarabine with and without radiation in the DU-145 prostate model. The combined effect on NCI-H460 lung tumors appeared to be additive. SR475 head and neck, PANC-1 pancreatic, and HCT-116 colon tumors were radiomodified by clofarabine. The radiomodifying capacity of clofarabine was superior to that for gemcitabine in two models (PANC-1 and HCT-116) and was comparable in the other four models.
Assuntos
Nucleotídeos de Adenina/uso terapêutico , Antineoplásicos/uso terapêutico , Arabinonucleosídeos/uso terapêutico , Neoplasias Experimentais/terapia , Nucleotídeos de Adenina/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Arabinonucleosídeos/administração & dosagem , Linhagem Celular Tumoral , Clofarabina , Terapia Combinada , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/radioterapia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , GencitabinaRESUMO
BACKGROUND AND PURPOSE: The relevance of Mitogen Activated Protein Kinase (MAPK) inhibitors as co-treatments for radiation therapy is investigated, with special focus on a potential link between the MAPK pathway and tumor hypoxia, which is a critical determinant for response to therapy. MATERIALS AND METHODS: The effects of two MAPK inhibitors, Sorafenib and PD0325901, were monitored daily using in vivo EPR (Electron Paramagnetic Resonance) oximetry in FSaII and TLT tumor models in order to identify a window of reoxygenation, during which tumor blood flow, oxygen consumption and radiation sensitivity were assessed. RESULTS: Reoxygenation was shown after two days of treatments with Sorafenib or PD0325901 in two tumor models, which was further successfully exploited with Sorafenib for improving the radiation response of FSaII tumors by a factor of 1.5. The increase in tumor oxygenation was shown to be the result of two major factors: (i) an increase in blood flow for Sorafenib, that might be linked to its anti-angiogenic effect (vascular normalization), and (ii) a decrease in oxygen consumption for Sorafenib and PD0325901, due to an alteration of the mitochondrial activity. CONCLUSION: We evidenced tumor reoxygenation in vivo following MAPK inhibition and suggest a rationale for the combination of radiation therapy with Sorafenib.
Assuntos
Neoplasias Experimentais/radioterapia , Consumo de Oxigênio/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Tolerância a Radiação/fisiologia , Indutores da Angiogênese , Animais , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Western Blotting , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Espectroscopia de Ressonância de Spin Eletrônica , Fibrossarcoma/metabolismo , Fibrossarcoma/radioterapia , Glutationa/análise , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/radioterapia , Camundongos , Neoplasias Experimentais/metabolismo , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos de Fenilureia/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/efeitos da radiação , SorafenibeRESUMO
The purpose of this study is to test the hypothesis that gold nanoparticle (AuNP, nanogold)-enhanced radiation therapy (nanogold radiation therapy, NRT) is efficacious when treating the radiation resistant and highly aggressive mouse head and neck squamous cell carcinoma model, SCCVII, and to identify parameters influencing the efficacy of NRT. Subcutaneous (sc) SCCVII leg tumors in mice were irradiated with x-rays at the Brookhaven National Laboratory (BNL) National Synchrotron Light Source (NSLS) with and without prior intravenous (iv) administration of AuNPs. Variables studied included radiation dose, beam energy, temporal fractionation and hyperthermia. AuNP-mediated NRT was shown to be effective for the sc SCCVII model. AuNPs were more effective at 42 Gy than at 30 Gy (both at 68 keV median beam energy) compared to controls without gold. Similarly, at 157 keV median beam energy, 50.6 Gy NRT was more effective than 44 Gy NRT. At the same radiation dose ( approximately 42 Gy), 68 keV was more effective than 157 keV. Hyperthermia and radiation therapy (RT) were synergistic and AuNPs enhanced this synergy, thereby further reducing TCD50 s (tumor control dose 50%) and increasing long-term survivals. It is concluded that gold nanoparticles enhance the radiation therapy of a radioresistant mouse squamous cell carcinoma. The data show that radiation dose, energy and hyperthermia influence efficacy and better define the potential utility of gold nanoparticles for cancer x-ray therapy.
Assuntos
Carcinoma de Células Escamosas/radioterapia , Ouro/química , Neoplasias de Cabeça e Pescoço/radioterapia , Nanopartículas Metálicas/química , Nanotecnologia/métodos , Neoplasias Experimentais/radioterapia , Animais , Relação Dose-Resposta à Radiação , Hipertermia Induzida , Camundongos , Modelos Estatísticos , Radioterapia/métodos , Resultado do Tratamento , Raios XRESUMO
Our analysis failed to establish any antitumor effect of treatment of rats with transplantable glioma-35 with iron-containing mineral drinking water (ICMW). The latter treatment combined with irradiation (15 Gy) was followed by enhanced genotoxic effect in white blood cells. Post-irradiation administration of ICMW did not influence glioma growth significantly as compared with radiation alone. Pre- and post-iradiation drinking of ICMW resulted in marked leukopenia 24 hrs after exposure as well as to significant decrease in tumor size (20-40 days after of experiment) as compared with control.
Assuntos
Neoplasias Encefálicas/radioterapia , Glioma/radioterapia , Ferro da Dieta/administração & dosagem , Animais , Terapia Combinada , Modelos Animais de Doenças , Íons/administração & dosagem , Masculino , Neoplasias Experimentais/radioterapia , Dosagem Radioterapêutica , Radioterapia Adjuvante/efeitos adversos , Ratos , Fatores de Tempo , Falha de Tratamento , ÁguaRESUMO
Current therapeutic approaches to treatment of patients with bulky cervical cancer are based on conventional in situ ablative modalities including cisplatin-based chemotherapy and radiation therapy. The 5-year survival of patients with nonresectable disease is dismal. Because over 99% of squamous cervical cancer is caused by persistent infection with an oncogenic strain of human papillomavirus (HPV), particularly type 16 and viral oncoproteins E6 and E7 are functionally required for disease initiation and persistence, HPV-targeted immune strategies present a compelling opportunity in which to demonstrate proof of principle. Sublethal doses of radiation and chemotherapeutic agents have been shown to have synergistic effect in combination with either vaccination against cancer-specific antigens, or with passive transfer of tumor-specific cytotoxic T lymphocytes (CTLs). Here, we explored the combination of low-dose radiation therapy with DNA vaccination with calreticulin (CRT) linked to the mutated form of HPV-16 E7 antigen (E7(detox)), CRT/E7(detox) in the treatment of E7-expressing TC-1 tumors. We observed that TC-1 tumor-bearing mice treated with radiotherapy combined with CRT/E7(detox) DNA vaccination generated significant therapeutic antitumor effects and the highest frequency of E7-specific CD8(+) T cells in the tumors and spleens of treated mice. Furthermore, treatment with radiotherapy was shown to render the TC-1 tumor cells more susceptible to lysis by E7-specific CTLs. In addition, we observed that treatment with radiotherapy during the second DNA vaccination generated the highest frequency of E7-specific CD8(+) T cells in the tumors and spleens of TC-1 tumor-bearing mice. Finally, TC-1 tumor-bearing mice treated with the chemotherapy in combination with radiation and CRT/E7(detox) DNA vaccination generate significantly enhanced therapeutic antitumor effects. The clinical implications of the study are discussed.
Assuntos
Imunoterapia Ativa , Neoplasias Experimentais/terapia , Vacinas contra Papillomavirus/uso terapêutico , Radioterapia Adjuvante/métodos , Linfócitos T Citotóxicos/imunologia , Vacinas de DNA/uso terapêutico , Animais , Apoptose , Calreticulina/genética , Calreticulina/imunologia , Linhagem Celular Transformada/imunologia , Linhagem Celular Transformada/transplante , Transformação Celular Viral , Terapia Combinada , Citocinas/análise , Modelos Animais de Doenças , Feminino , Pulmão , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/radioterapia , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/imunologia , Proteínas E7 de Papillomavirus , Dosagem Radioterapêutica , Proteínas Recombinantes de Fusão/imunologia , Neoplasias do Colo do ÚteroRESUMO
The efficacy of radiotherapy may be partly dependent on indirect effects, which can sterilise malignant cells that are not directly irradiated. However, little is known of the influence of these effects in targeted radionuclide treatment of cancer. We determined bystander responses generated by the uptake of radioiodinated iododeoxyuridine ([*I]IUdR) and radiohaloanalogues of meta-iodobenzylguanidine ([*I]MIBG) by noradrenaline transporter (NAT) gene-transfected tumour cells. NAT specifically accumulates MIBG. Multicellular spheroids that consisted of 5% of NAT-expressing cells, capable of the active uptake of radiopharmaceutical, were sterilised by treatment with 20 kBqmL(-1) of the alpha-emitter meta-[211At]astatobenzylguanidine ([211At]MABG). Similarly, in nude mice, retardation of the growth of tumour xenografts containing 5% NAT-positivity was observed after treatment with [131I]MIBG. To determine the effect of subcellular localisation of radiolabelled drugs, we compared the bystander effects resulting from the intracellular concentration of [131I]MIBG and [131I]IUdR (low linear energy transfer (LET) beta-emitters) as well as [123I]MIBG and [123I]IUdR (high LET Auger electron emitters). [*I]IUdR is incorporated in DNA whereas [*I]MIBG accumulates in extranuclear sites. Cells exposed to media from [131I]MIBG- or [131I]IUdR-treated cells demonstrated a dose-response relationship with respect to clonogenic cell death. In contrast, cells receiving media from cultures treated with [123I]MIBG or [123I]IUdR exhibited dose-dependent toxicity at low dose but elimination of cytotoxicity with increasing radiation dose (i.e. U-shaped survival curves). Therefore radionuclides emitting high LET radiation may elicit toxic or protective effects on neighbouring untargeted cells at low and high dose respectively. It is concluded that radiopharmaceutical-induced bystander effects may depend on LET of the decay particles but are independent of site of intracellular concentration of radionuclide.
Assuntos
3-Iodobenzilguanidina/farmacologia , Efeito Espectador , Idoxuridina/farmacologia , Neoplasias Experimentais/radioterapia , Compostos Radiofarmacêuticos/farmacologia , 3-Iodobenzilguanidina/análogos & derivados , 3-Iodobenzilguanidina/metabolismo , Animais , Morte Celular/efeitos da radiação , Linhagem Celular Tumoral , Meios de Cultivo Condicionados/metabolismo , Relação Dose-Resposta à Radiação , Humanos , Idoxuridina/metabolismo , Radioisótopos do Iodo , Camundongos , Camundongos Nus , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Doses de Radiação , Compostos Radiofarmacêuticos/metabolismo , Esferoides Celulares , Transfecção , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We have previously reported that buthionine sulfoximine (BSO) enhances sodium borocaptate (BSH) uptake by down regulating glutathione (GSH) synthesis in cultured cells. This study investigated the influence of BSO on tissue BSH uptake in vivo and the efficacy of BSH-BSO-mediated boron neutron capture therapy (BNCT) on tumor growth using a Fisher-344 rat subcutaneous tumor model. With BSO supplementation, boron uptake in subcutaneous tumor, blood, skin, muscle, liver, and kidney was significantly enhanced and maintained for 12h. Tumor growth was significantly delayed by using BSO. With further improvement in experimental conditions, radiation exposure time, together with radiation damage to normal tissues, could be reduced.
Assuntos
Boroidretos/farmacologia , Terapia por Captura de Nêutron de Boro/métodos , Boro/metabolismo , Butionina Sulfoximina/farmacologia , Neoplasias Experimentais/radioterapia , Compostos de Sulfidrila/farmacologia , Animais , Boroidretos/administração & dosagem , Butionina Sulfoximina/administração & dosagem , Isótopos/metabolismo , Masculino , Transplante de Neoplasias , Ratos , Ratos Endogâmicos F344 , Compostos de Sulfidrila/administração & dosagemRESUMO
AIM: To examine the effects of electromagnetic field with amplified magnetic component and local inductive hyperthermia (IH) on nonlinear dynamics of the growth of animal tumors. MATERIALS AND METHODS: Guerin carcinoma, Lewis lung carcinoma, sarcoma 45, Walker 256 carcinosarcoma and Pliss lymphosarcoma were studied. The animal tumors were exposed inside of loop aerial, 3 cm in diameter locally for 30 min. Parameters of electromagnetic irradiation (EI): frequency 40 MHz, magnetic intensity 72 A/m, electric intensity 200 V/m and the output power 50 W. The temperature measured by immersion of thermocouple inside the center of the tumor didn't exceed 38.5-39.5 degrees C. Nonlinear dynamics of the growth of animal tumors was analyzed by autocatalytic equation. The heterogeneity of ultrasonic image of the tumor was analyzed by Moran spatial autocorrelation. RESULTS: The strongest inhibition effect under the influence of EI was in Pliss lymphosarcoma and sarcoma 45. The growth stimulation of animal tumors after EI was recorded in Walker 256 carcinosarcoma. The use of mild IH increased the blood flow in the tumor of Guerin carcinoma. CONCLUSION: These results are important for clinical application because they testify the necessity of optimization of schemes for local EI during anticancer neoadjuvant therapy with the use of drugs or magnetic nanoparticles. The use of mild IH as a basis for the monotherapy of malignant tumors is not expedient.
Assuntos
Campos Eletromagnéticos , Hipertermia Induzida , Neoplasias Experimentais/radioterapia , Neoplasias Experimentais/terapia , Dinâmica não Linear , Animais , Carcinoma 256 de Walker/irrigação sanguínea , Carcinoma 256 de Walker/diagnóstico por imagem , Carcinoma 256 de Walker/patologia , Carcinoma 256 de Walker/radioterapia , Carcinoma 256 de Walker/terapia , Carcinoma Pulmonar de Lewis/irrigação sanguínea , Carcinoma Pulmonar de Lewis/diagnóstico por imagem , Carcinoma Pulmonar de Lewis/patologia , Carcinoma Pulmonar de Lewis/radioterapia , Carcinoma Pulmonar de Lewis/terapia , Catálise , Terapia Combinada , Linfoma não Hodgkin/diagnóstico por imagem , Linfoma não Hodgkin/patologia , Linfoma não Hodgkin/radioterapia , Linfoma não Hodgkin/terapia , Masculino , Camundongos , Camundongos Endogâmicos , Transplante de Neoplasias , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/patologia , Ratos , Ratos Endogâmicos , Sarcoma Experimental/irrigação sanguínea , Sarcoma Experimental/diagnóstico por imagem , Sarcoma Experimental/patologia , Sarcoma Experimental/radioterapia , Sarcoma Experimental/terapia , Especificidade da Espécie , UltrassonografiaRESUMO
PURPOSE: Molecular imaging and targeted radiotherapy are emerging fields in nuclear oncology. Five human somatostatin receptors (hsstr1-hsstr5) are known to be overexpressed to some degree on various tumors, sstr2 being the most important one. Clinically used somatostatin based radiopeptides target exclusively sstr2. The aim of this study was to develop novel analogues with a broader sstr profile for diagnostic (positron emission tomography and single-photon emission computed tomography) and radiotherapeutic applications. EXPERIMENTAL DESIGN: The following promising structures emerged from a parallel synthetic approach: [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA(0)),1-Nal(3),Thr(8)]-octreotide (1, DOTA-NOC-ATE) and [DOTA(0),BzThi(3),Thr(8)]-octreotide (2, DOTA-BOC-ATE). The conjugates were labeled with cold and radioactive (111)In. Pharmacologic properties were compared with [(111)In-DOTA,Tyr(3)]-octreotide ([(111)In-DOTA]-TOC). RESULTS: The receptor affinity profile showed high affinity of both peptides to hsstr2, hsstr3, and hsstr5 and some intermediate affinity to hsstr4, whereas [(111)In-DOTA]-TOC shows affinity only to sstr2. The internalization is fast in sstr2 expressing AR4-2J and in transfected sstr3 expressing human embryonic kidney 293 cells. Both radiopeptides internalize much more efficiently than [(111)In-DOTA]-TOC. Animal biodistribution studies showed very high and specific uptake of [(111)In]-1 and [(111)In]-2 in s.c. implanted AR4-2J tumors (Lewis rats) and in somatostatin receptor expressing normal tissues. The uptake was at least 2-fold higher in these tissues and in the tumor compared with [(111)In-DOTA]-TOC. In addition, the kidney uptake was significantly lower for both radiopeptides. CONCLUSIONS: These data suggest that the novel radiopeptides are superior to [(111)In/(90)Y-DOTA]-TOC and show great promise for the clinical application in the imaging of somatostatin receptor-positive tumors and their targeted radiotherapy.
Assuntos
Antineoplásicos Hormonais/farmacocinética , Octreotida/farmacocinética , Compostos Organometálicos/farmacocinética , Animais , Antineoplásicos Hormonais/química , Antineoplásicos Hormonais/metabolismo , Ligação Competitiva , Células CHO , Linhagem Celular , Linhagem Celular Tumoral , Cricetinae , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Endocitose , Humanos , Radioisótopos de Índio/farmacocinética , Masculino , Estrutura Molecular , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/radioterapia , Octreotida/análogos & derivados , Octreotida/metabolismo , Compostos Organometálicos/metabolismo , Tomografia por Emissão de Pósitrons , Ratos , Ratos Endogâmicos Lew , Receptores de Somatostatina/metabolismo , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
Recent years have seen an increased effort in the development of peptide based radiopharmaceuticals for nuclear medicine applications in imaging and therapy. This field is of particular interest in the development of new cancer imaging and treatment strategies. Major developments in the molecular biology of cancer have brought forth the discovery of a number of receptor systems and other cell surface molecules that can be utilized as molecular targets for peptide based agents. Although such a strategy is very appealing and shows great potential for application in humans, there are as yet very few radiopharmaceuticals developed based on this scheme that have made it into clinical practice. Many different factors contribute to the generation of a successful radiopharmaceutical. Among these, a thorough and efficient pre-clinical evaluation process is necessary to single out those lead compounds that show more promise and are most likely to be winners in clinical applications. To maximize the efficacy of pre-clinical testing one must utilize currently available technology to the best extent possible. Expertise in different areas of drug development is indispensable for this type of research. This work will analyze currently available methods utilized to evaluate radiopharmaceuticals being developed, from compound design to evaluation in pre-clinical animal models.
Assuntos
Desenho de Fármacos , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/radioterapia , Fragmentos de Peptídeos , Compostos Radiofarmacêuticos , Animais , Avaliação Pré-Clínica de Medicamentos , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/uso terapêutico , Cintilografia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/uso terapêuticoRESUMO
The potential of increased antitumor effect of cyclophosphane used in conjunction with low-energy infra-red laser radiation was studied in sarcoma-45--bearing rats. Exposure to certain modes stimulated non-specific antitumor resistance and enhanced antitumor influence of the drug by reducing its damaging effect. Also, it inhibited refractory leukopenia and marked intoxication induced by antistressor reactions.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Ciclofosfamida/farmacologia , Raios Infravermelhos/uso terapêutico , Terapia com Luz de Baixa Intensidade , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/radioterapia , Animais , Antineoplásicos Alquilantes/efeitos adversos , Ciclofosfamida/efeitos adversos , Relação Dose-Resposta à Radiação , Masculino , RatosRESUMO
Peripheral blood was sampled for cytochemical assay of cationic proteins from three groups of animals--intact ones, those with tumor C45 and bearers of the same tumor treated with helium-laser radiation and chemotherapy. Radiotherapy involved such manifestations of enhanced nonspecific antitumor resistance and, in particular, mobilization of the cellular component, as increased number of neutrophils containing cationic protein granules and relatively high levels of such proteins in them. Cytochemical assay of cationic proteins in neutrophil granules may serve as a criterion of nonspecific antitumor resistance assessment.