RESUMO
Increasing evidence shows that dysregulated epidermal growth factor receptor (EGFR) signalling plays an important part in neoplasia. When over expressed or mutated, EGFR is frequently associated with more aggressive tumour growth, poor patient prognosis and resistance of tumours to cytotoxic agents, including radiation. The present studies with murine carcinomas showed that there is an inverse correlation between the level of EGFR and tumour radiocurability. Likewise, the present clinical study in patients with head and neck cancer shows that EGFR over expression correlates with poorer tumour response to radiotherapy. Adding EGFR to tumour cells in vitro protected cells against the cytotoxic action of radiation, whereas blocking EGFR with anti-EGFR antibodies enhanced cell radiosensitivity. A casual relationship between EGFR and increased cellular resistance to radiation was established by transferring the EGFR gene into low EGFR-expressing radiosensitive tumour cells, which then become radioresistant. Radiation activated EGFR and its downstream signalling pathways in radioresistant but not in radiosensitive tumours, and this effect was associated with increased resistance to radiation, and enhanced repopulation in irradiated tumours. Increasing evidence shows that blockage of EGFR or interference with any of the steps in its signal transduction cascade can counteract negative outcomes of EGFR signalling, which has recently been explored as a therapeutic strategy in cancer treatment. The present findings demonstrate that treatment of human tumour xenografts with C225, an anti-EGFR monoclonal antibody, dramatically enhanced tumour response to radiation. Overall, the findings show that over expression of EGFR may serve as a predictor of tumour treatment outcome by radiotherapy and as a therapeutic target to enhance the efficacy of radiotherapy.
Assuntos
Receptores ErbB/antagonistas & inibidores , Neoplasias/radioterapia , Animais , Receptores ErbB/análise , Receptores ErbB/efeitos da radiação , Humanos , Neoplasias/patologia , Antígeno Nuclear de Célula em Proliferação/análise , Tolerância a Radiação , Transdução de SinaisRESUMO
A prospective randomized study was conducted to determine whether amifostine (Ethyol) reduces the rate of severe esophagitis and hematologic and pulmonary toxicity associated with chemoradiation or improves control of non-small cell lung cancer (NSCLC). Sixty patients with inoperable stage II or III NSCLC were treated with concurrent chemoradiotherapy. Both groups received thoracic radiation therapy (TRT) with 1.2 Gy/fraction, 2 fraction per day, 5 days per week for a total dose 69.6 Gy. All patients received oral etoposide (VP-16), 50 mg Bid, 30 minutes before TRT beginning day 1 for 10 days, repeated on day 29, and cisplatin 50 mg/m(2) intravenously on days 1, 8, 29, and 36. Patients in the study group received amifostine, 500 mg intravenously, twice weekly before chemoradiation (arm 1); patients in the control group received chemoradiation without amifostine (arm 2). Patient and tumor characteristics were distributed equally in both groups. Of the 60 patients enrolled, 53 were evaluable (27 in arm 1, 26 in arm 2) with a median follow-up of 6 months. Median survival times were 26 months for arm 1 and 15 months for arm 2, not statistically significantly different. Morphine intake to reduce severe esophagitis was significantly lower in arm 1 (2 of 27, 7.4%) than arm 2 (8 of 26, 31%; P =.03). Acute pneumonitis was significantly lower in arm 1 (1 of 27, 3.7%) than in arm 2 (6 of 26, 23%; P =.037). Hypotension (20 mm Hg decrease from baseline blood pressure) was significantly more frequent in arm 1 (19 of 27, 70%) than arm 2 (1 of 26, 3.8%; P =.0001). Only 1 patient discontinued treatment because of hypotension. These preliminary results showed that amifostine significantly reduced acute severe esophagitis and pneumonitis. Further observation is required to assess long-term efficacy.
Assuntos
Amifostina/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Etoposídeo/uso terapêutico , Neoplasias Pulmonares/radioterapia , Lesões por Radiação/prevenção & controle , Protetores contra Radiação/uso terapêutico , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Terapia Combinada , Esofagite/etiologia , Esofagite/prevenção & controle , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Pneumonite por Radiação/prevenção & controleRESUMO
Cyclooxygenase-2 (COX-2) is an enzyme induced by a variety of factors including tumor promoters, cytokines, growth factors and hypoxia. It is involved in the metabolic conversion of arachidonic acid to prostanoids, primarily in inflammatory states and tumors. In normal tissues, prostanoids are synthesized by COX-1, and they exert numerous homeostatic physiologic functions. COX-2 overexpression is linked to carcinogenesis, maintenance of progressive tumor growth and facilitation of metastatic spread. COX-2 and its products may act as protectors against cell damage by ionizing radiation. I describe findings showing that inhibition of COX-2 or prostanoids by selective COX-2 inhibitors or commonly used nonsteroidal antiinflammatory drugs (NSAIDs) has antitumor activity and may improve tumor response to radiation without significantly affecting normal tissue radioresponse. COX-2 inhibitors and radiation interact in multiple complex ways, with the enzyme inhibitor directly or indirectly augmenting tumor cell destruction by radiation. COX-2 represents a potential molecular target for improvement of cancer radiotherapy.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Anticarcinógenos/farmacologia , Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Isoenzimas/fisiologia , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Prostaglandina-Endoperóxido Sintases/fisiologia , Terapia Combinada , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Humanos , Proteínas de Membrana , Neovascularização Patológica/prevenção & controleRESUMO
BACKGROUND: The nucleoside analog gemcitabine is a potent radiosensitizer of both tumor and normal mucosa, so severe toxic reactions have resulted from its combination with radiation in some clinical treatment schedules for pancreatic cancer. WR-2721 (amifostine) has been shown to reduce normal tissue toxicity produced from both radiation treatment and some chemotherapeutics. The aim of this study was to determine if WR-2721 can protect the gastrointestinal mucosa from injury by concurrent gemcitabine and radiation treatment. METHODS AND MATERIALS: Gemcitabine was injected ip into C3Hf/Kam mice at a concentration of 33 mg/kg 24 h before whole-body irradiation. A single dose (200 mg/kg) of WR-2721 was given 30 min before the radiation treatment or 30 min before gemcitabine or at both times. A quantitative assessment of the chemotherapy/radiation-induced damage was carried out using the mouse microcolony assay for stem cell survival in the intestinal crypts. RESULTS: WR-2721 given 30 min before gemcitabine followed 24 h later by radiation did not confer any protection to the jejunum (DMF 0.95). However, WR-2721 administered 30 min before radiation without or with prior gemcitabine produced protection factors (PF) of 1.35 and 1.42 CONCLUSIONS: WR-2721 did not directly protect the gastrointestinal mucosa from gemcitabine toxicity, but it did protect the gemcitabine-radiosensitized mucosa from acute radiation damage by a factor of 1.42. Therefore, in clinical treatment protocols using concurrent chemoradiation with gemcitabine, WR-2721 may have clinical utility in protecting against radiation-induced mucosal toxicity.
Assuntos
Amifostina/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/efeitos adversos , Jejuno/efeitos dos fármacos , Jejuno/efeitos da radiação , Protetores contra Radiação/uso terapêutico , Radiossensibilizantes/efeitos adversos , Irradiação Corporal Total/efeitos adversos , Amifostina/administração & dosagem , Animais , Esquema de Medicação , Feminino , Camundongos , Camundongos Endogâmicos C3H , Protetores contra Radiação/administração & dosagem , GencitabinaRESUMO
BACKGROUND: Gemcitabine and radiotherapy are a potent combination. A clinical assessment of the therapeutic ratio for locally advanced pancreatic cancer patients has not yet been reported. AIM OF STUDY: To assess the toxicity, survival, and pattern of failure of locally advanced pancreatic cancer patients treated with concurrent gemcitabine-based chemoradiation. Patients and Methods. Between the dates of December 1996 and August 2000 51 patients with locally advanced unresectable adenocarcinoma of the pancreas were treated with concurrent gemcitabine and radiotherapy at MDACC. Patients received 250-500 mg/m2 of gemcitabine weekly x7 over 30 min and 30-33 Gy in 10-11 fractions over two weeks to the primary tumor and regional lymphatics. Severe toxicity was defined as admission > 5 d, mucosal ulceration, > 3 dose deletions of gemcitabine or toxicity resulting in surgical intervention or that resulted in death. RESULTS: The median survival was 11 mo. Overall, 37 of 51 patients had objective evidence of local progression. The actuarial rate of local progression rate at 9 mo was 70%. The 9-mo distant metastasis rate was 52%. Tumors > or = 10 cm2 had worse local control, distant control, and overall survival. Six patients underwent pancreaticoduodenectomy after therapy. After review of the imaging, only four of these patients had minimal arterial involvement, one was incorrectly staged, and one had initial inflammatory change on CT that resolved. Twelve of 51 (24%) patients suffered severe acute toxicity, and 17 of 51 (33%) patients were admitted for supportive care. CONCLUSION: Concurrent gemcitabine and radiotherapy can be a very difficult combination to administer safely. Our results do not suggest a prolongation of median survival for patients with localized pancreatic cancer treated with this therapy. It is possible that gemcitabine-based chemoradiation contributes to the margin-negative resectability of a small number of patients with minimal arterial involvement, but this benefit is obscured by the frequent toxicity encountered in most patients. Locally advanced pancreatic cancer patients should continue to be enrolled on prospective studies investigating novel combinations of cytotoxic and/or biologic agents with concurrent radiotherapy.
Assuntos
Adenocarcinoma/radioterapia , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Neoplasias Pancreáticas/radioterapia , Radiossensibilizantes , Adenocarcinoma/patologia , Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Adulto , Idoso , Desoxicitidina/efeitos adversos , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia , Radiossensibilizantes/efeitos adversos , Radioterapia/efeitos adversos , Análise de Sobrevida , GencitabinaRESUMO
PURPOSE: Overexpression of epidermal growth factor receptor (EGFR) has been correlated with tumor resistance to radiation. Blockade of EGFR with C225 anti-EGFR antibody was previously shown to synergistically enhance radiation-induced tumor growth delay. The purpose of this study was to assess whether C225 can increase tumor cure by radiation. METHODS AND MATERIALS: Nude mice bearing 8-mm-diameter A431 tumor xenografts in the hind leg were treated with C225 antibody, graded single doses of local tumor irradiation, or both. C225 was given i.p. at a dose of 1 mg/mouse 6 h before irradiation or 6 h before and 3 plus 6 days after irradiation. Tumor cure was the treatment endpoint assessed by the TCD(50) assay 120 days after treatment. The onset of recurrences of tumors not cured was also determined. RESULTS: C225 antibody increased the antitumor effects of radiation by reducing TCD(50) values and delaying tumor recurrences. Tumor radiocurability was enhanced by a factor of 1.18 by a single dose and by a factor of 1.92 by three doses of C225. Likewise, the appearance of tumor recurrences was delayed by a factor of 1.37 by a single dose and by a factor of 2.13 by three doses of C225. CONCLUSION: The data presented here demonstrate that C225 can increase tumor radiocurability and delay the appearance of recurrences of tumors not cured by radiation treatment.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/radioterapia , Animais , Anticorpos Monoclonais Humanizados , Cetuximab , Relação Dose-Resposta à Radiação , Humanos , Masculino , Camundongos , Camundongos Nus , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias/química , Radiobiologia , Dosagem Radioterapêutica , Transplante HeterólogoRESUMO
We compared and evaluated available laboratory and clinical data on the use of concurrent gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and radiation in pancreatic cancer to provide guidance for subsequent prospective research initiatives. Preclinical data suggest that the timing of administration of gemcitabine with respect to radiotherapy is important, but this issue has not yet been confirmed by clinical data. Phase I clinical data indicate that the amount of acute toxicity from the combination of gemcitabine and radiotherapy is strongly related to the dose and schedule of administration of gemcitabine, as well as to the radiation field size. There also appears to be an inverse linear relationship between the maximum tolerated gemcitabine dose and radiation dose. Also important, but less clear, is the infusion rate of gemcitabine as it relates to the systemic efficacy of the drug. The combination of additional agents with gemcitabine and radiation appears to be feasible. Finally, the addition of radioprotectors may enable chemotherapy dose escalation, but safe escalation of the radiotherapy dose with newer techniques has not been established. Semin Oncol 28 (suppl 10):25-33.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/radioterapia , Radiossensibilizantes/uso terapêutico , Antimetabólitos Antineoplásicos/administração & dosagem , Ensaios Clínicos como Assunto , Terapia Combinada , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Esquema de Medicação , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Radiossensibilizantes/administração & dosagem , Dosagem Radioterapêutica , GencitabinaRESUMO
Although combined chemotherapy and radiotherapy has produced significantly improved response and survival rates among cancer patients, there is still a compelling need to establish the most effective way to deliver these agents. We hypothesize that the radiosensitizing effect of a chemotherapeutic agent can be further enhanced if the drug is delivered at an optimal concentration and is maintained in the tumor for a prolonged period. Using a water-soluble poly(L-glutamic acid)-conjugated paclitaxel (PG-TXL) as a model compound, we investigated whether paclitaxel delivered by means of polymeric carrier could increase the tumor's response to radiation. Mice bearing 8-mm syngeneic ovarian carcinoma OCa-1 tumors implanted intramuscularly were treated with i.v. injected PG-TXL alone or in combination with single doses of local radiation. The enhancement factors at 24 h interval, as measured by incremental tumor growth delay compared with radiation alone, ranged from 2.48 to 4.28. The values varied as a function of radiation dose. The enhancement of radioresponse is also a function of time interval between injection of PG-TXL and tumor irradiation. The enhancement factor increased with decreasing interval, suggesting that radiation may in turn mediate the sensitivity of tumor toward PG-TXL. Thus, the mechanism of PG-TXL's radiopotentiation activity is probably multifactorial. Remarkably, while combined radiation and TXL produced additive or even sub-additive interaction when radiation preceded TXL injection, combined radiation and PG-TXL produced synergistic interaction in a mammary MCa-4 tumor model. Radiation significantly increased tumor uptake of PG-TXL, suggesting a potential role of radiation-modulated antitumor activity of polymeric drugs. Our data support a treatment strategy combining radiation and polymeric chemotherapy that may have important clinical implications in terms of scheduling and optimization of the therapeutic ratio.
Assuntos
Radiossensibilizantes/administração & dosagem , Radiossensibilizantes/farmacologia , Animais , Sistemas de Liberação de Medicamentos , Feminino , Citometria de Fluxo , Camundongos , Modelos Biológicos , Neoplasias Ovarianas/radioterapia , Polímeros , Radiossensibilizantes/farmacocinética , Distribuição Tecidual , Células Tumorais CultivadasRESUMO
PURPOSE: The purpose of this workshop summary is to provide an overview of preclinical and clinical data on combined-modality radiotherapy. METHODS AND MATERIALS: The 8th Annual Radiation Workshop at Round Top was held April 13-16, 2000 at the International Festival Institute (Round Top, TX). RESULTS: Presentations by 30 speakers (from Germany, Netherlands, Australia, England, and France along with U.S. participants and M. D. Anderson Cancer Center faculty) formed the framework for discussions on the current status and future perspectives of biology-based combined-modality radiotherapy. CONCLUSION: Cellular and molecular pathways available for radiation modification by chemical and biologic agents are numerous, providing new opportunities for translational research in radiation oncology and for more effective combined-modality treatment of cancer.
Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Radiossensibilizantes/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Terapia Combinada , Inibidores de Ciclo-Oxigenase/uso terapêutico , Citocinas/fisiologia , Inibidores Enzimáticos/uso terapêutico , Genes ras/efeitos dos fármacos , Substâncias de Crescimento/fisiologia , Humanos , Protetores contra Radiação/uso terapêutico , RadiobiologiaRESUMO
Docetaxel, a potent chemotherapeutic drug and a strong enhancer of tumor radioresponse, possesses immunomodulating properties. We previously reported that 40% of murine tumors responding to docetaxel by growth delay showed heavy infiltration with macrophages or lymphocytes. The present study explored the effect of whole body irradiation on antitumor action of docetaxel alone or docetaxel plus tumor irradiation. Mice bearing 8-mm MCa-K mammary carcinoma in the leg received 33 mg/kg docetaxel i.v., 5 to 65 Gy tumor irradiation, or both (radiation given 24 h after docetaxel). Docetaxel delayed tumor growth and enhanced the efficacy of radiation: it dramatically reduced TCD50 (radiation dose yielding 50% tumor cure) from the control value of 38.6 Gy to 11.8 Gy, for an enhancement factor of 3.27. In addition to enhancing tumor radioresponse, docetaxel decreased the lung metastatic rate in mice with local tumor control from 26% in mice receiving radiation alone to 11% in mice receiving docetaxel plus radiation. Docetaxel induced heavy infiltration of tumors with lymphocytes, determined 2-4 days after treatment: the percentage of lymphocytes increased from the control value of <2% to 27% in mice that received docetaxel 3 days earlier. This increase was due to the influx of helper/inducer T-lymphocytes and natural killer cells. Immunosuppression of tumor-bearing mice with 6 Gy whole-body irradiation prior to tumor isotransplantation reduced docetaxel-induced lymphocyte infiltration of tumors, antitumor and anti-metastatic action of docetaxel, and docetaxel-induced enhancement of tumor radioresponse. Thus, our results showed that docetaxel stimulates tumor infiltration with immune cells, which then participate in antitumor action of docetaxel alone or when combined with radiotherapy.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Sistema Imunitário/fisiologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Musculares/imunologia , Paclitaxel/análogos & derivados , Paclitaxel/uso terapêutico , Radiossensibilizantes/uso terapêutico , Taxoides , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Terapia Combinada , Docetaxel , Tolerância Imunológica , Imunocompetência , Células Matadoras Naturais/imunologia , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/radioterapia , Camundongos , Camundongos Endogâmicos C3H , Neoplasias Musculares/patologia , Neoplasias Musculares/radioterapia , Linfócitos T Auxiliares-Indutores/imunologia , Irradiação Corporal TotalRESUMO
Gemcitabine has been demonstrated to be a potentradiosensitizer in the laboratory and in the clinic (1-7)and has proven clinical systemic activity to pancreaticcancer. Responses to systemic gemcitabine inpatients with metastatic pancreatic adenocarcinomahave been documented in phase I, phase II, and phaseIII clinical settings (8,9). Moreover, a recent randomizedtrial of gemcitabine vs 5-FU as first-linetherapy in patients with advanced pancreatic adenocarcinomademonstrated a modest median survivalbenefit (4.41 vs 5.65 mo,p= 0.0025) for those patientswho received gemcitabine compared to those whoreceived 5-FU (10). In addition, gemcitabine wasshown to improve cancer-related symptoms and performancestatus as assessed by a quantitative clinicalbenefit scale in both untreated and previouslytreated patients with metastatic adenocarcinoma ofthe pancreas (10,11). Based on these data, the FDAapproved gemcitabine as a first-line agent for patientswith advanced adenocarcinoma of the pancreas.
RESUMO
PURPOSE: It has been shown that paclitaxel (TXL) can strongly enhance tumor cells' sensitivity to radiation. We examined whether the radiosensitizing effect of paclitaxel can be further enhanced when it is delivered systemically as a polymer-drug conjugate that provides enhanced tumor uptake and prolonged release of TXL in the tumor. METHODS AND MATERIALS: C3Hf/Kam mice bearing 8-mm murine ovarian OCa-1 tumors were treated with i.v.-injected Poly(L-glutamic acid)-paclitaxel (PG-TXL) at an equivalent TXL dose of 80 mg/kg, followed 24 h later by single doses of local radiation ranging from 5 to 15 Gy. To determine how long the radiopotentiation persisted at extended times after PG-TXL administration, mice with OCa-1 tumors were given i.v. PG-TXL and 4, 24, 48, 72, 120, or 168 h later their tumors were irradiated at a dose of 10 Gy. Antitumor activity was determined by delay in tumor growth. Cell cycle distribution was assayed using flow cytometry. Tumor vascular volume was estimated using Tc-99 m-labeled red blood cells. RESULTS: PG-TXL strongly potentiated the radioresponse of the OCa-1 tumor. The enhancement factors ranged from 2.79 to 4.28, depending on radiation dose, when PG-TXL preceded radiation by 24 h. The enhancement factor derived from radiation dose-response curves was as high as 5.13. The radiosensitizing effect of PG-TXL was also dependent on the interval between PG-TXL administration and radiation delivery, with greater enhancement been observed when the interval was decreased. The percentage of G2/M cells was significantly increased to 21.4% 48 h after PG-TXL but declined to a preinjection level of 14.8% 72 h after PG-TXL. PG-TXL only moderately increased the tumor vascular volume by 37% 24 h after PG-TXL administration. CONCLUSION: PG-TXL markedly potentiated response of OCa-1 tumor to radiation. When compared to literature data obtained from the same tumor model used here, PG-TXL exhibited stronger radiosensitization effect than TXL. Although its action is possibly mediated by arrest of cells in G2/M phases of cell cycle and by increased tumor blood supply, PG-TXL may exert its radiopotentiation activity through increased tumor uptake of PG-TXL and sustained release of TXL in the tumor. Our results show that conjugation of TXL to a polymer has the potential to further enhance its radiosensitizing activity and that clinical trials of PG-TXL in combination with radiation is warranted.
Assuntos
Ácido Glutâmico/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/radioterapia , Paclitaxel/farmacologia , Radiossensibilizantes/farmacologia , Animais , Relação Dose-Resposta à Radiação , Combinação de Medicamentos , Feminino , Camundongos , Radiobiologia , Dosagem Radioterapêutica , Fatores de Tempo , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/efeitos da radiaçãoRESUMO
There are increasing requests for delivering a second course of radiation to patients who develop second primary tumors within or close to previous radiotherapy portal or late in-field recurrences. Rational treatment decisions demand rather precise knowledge on long-term recovery of occult radiation injury in various organs. This article summarizes available experimental and clinical data on the effects of reirradiation to the skin, mucosa, gut, lung, spinal cord, brain, heart, bladder, and kidney. The data reveal that, in general, acutely responding tissues recover radiation injury within a few months and, therefore, can tolerate another full course of radiation. For late toxicity endpoints, however, tissues vary considerably in their capacity to recover from occult radiation damage. The heart, bladder, and kidney do not exhibit long-term recovery at all. In contrast, the skin, mucosa, lung, and spinal cord do recover subclinical injury partially to a magnitude dependent on the organ type, size of the initial dose, and, to a lesser extent, the interval between radiation courses. The available clinical data have inspired many radiation oncologists to undertake systematic studies addressing the efficacy and toxicity of reirradiation in various clinical settings. Hopefully, systematic scoring, collection, and analysis of patient outcome will produce quantitative data useful for clinical practice.
Assuntos
Neoplasias/radioterapia , Cuidados Paliativos , Lesões por Radiação , Animais , Humanos , Recidiva Local de Neoplasia/radioterapia , Segunda Neoplasia Primária/radioterapia , Doses de Radiação , Lesões Experimentais por Radiação , Tolerância a RadiaçãoRESUMO
Angiogenesis is known to be a critical process for the tumor growth and metastasis. There are many indigenous role-players in tumor angiogenesis and anti-angiogenesis, where tumor-host interaction may work. A lot of agents with anti-angiogenic activity have been developed for anti-cancer treatment. Several agents including Marimastat, Primostat, Neovastat, Bay-12-9566m, Interferon-alpha, SU101, retinoids, and IM862, are/were under phase-three study. There are still many future-promising results of basic or clinical studies on inhibitors of MMPs, and inhibitors of VEGF/R, Endostatin, somatostatin analogues, COX-2 inhibitors, and others. Most of the combination treatments of antiangiogenetic agent and conventional anticancer agents therapy, or radiation therapy as we reported, showed relatively small or minute increase in toxicity of these cytotoxic treatments.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias/terapia , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/uso terapêutico , Terapia Combinada , Inibidores de Ciclo-Oxigenase/uso terapêutico , Fatores de Crescimento Endotelial/antagonistas & inibidores , Fatores de Crescimento Endotelial/fisiologia , Humanos , Linfocinas/antagonistas & inibidores , Linfocinas/fisiologia , Inibidores de Metaloproteinases de Matriz , Metaloproteinases da Matriz/fisiologia , Neoplasias/irrigação sanguínea , Neovascularização Patológica , Pirazóis/uso terapêutico , Radioterapia , Sulfonamidas/uso terapêutico , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
The poly(L-glutamic acid)-paclitaxel (PG-TXL) conjugate has been shown to exhibit significantly greater antitumor activity than conventionally formulated paclitaxel (TXL) against solid tumors (Li et al., Cancer Res., 58: 2404-2409, 1998). Here we report that local tumor irradiation enhanced the distribution of PG-TXL given 24 h later to ovarian OCa-1 carcinoma implanted i.m. in C3Hf/Kam mice. Radiation significantly increased tumor uptake of PG-TXL and tumor vascular permeability, caused elevation of the serum concentration of vascular endothelial growth factor, and arrested OCa-1 cells in the G1 phase of cell cycle. The enhancement factors, as measured by incremental tumor growth delay compared with PG-TXL alone, ranged from 1.36-4.44. Complete tumor regression was also observed at a higher radiation dose (>10 Gy) and a higher PG-TXL dose (>80 mg equivalentTXL/kg). Furthermore, combined radiation and PG-TXL produced a significantly greater tumor growth delay than treatment with radiation and TXL when both drugs were given at the same equivalent TXL dose of 60 mg/kg 24 h after tumor irradiation (enhancement factors, 4.44 versus 1.50). These data suggest that conjugation of TXL to poly(L-glutamic acid) is necessary for improved response and that the supra-additive effect of combined radiation and PG-TXL therapy is due in part to modulation of the enhanced permeability and retention effect of macromolecules by radiation. We propose a treatment strategy combining radiation and macromolecular chemotherapy that may have important clinical implications in terms of scheduling and optimization of the therapeutic ratio.
Assuntos
Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/radioterapia , Paclitaxel/análogos & derivados , Paclitaxel/uso terapêutico , Taxoides , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Transporte Biológico , Permeabilidade Capilar , Terapia Combinada , Fatores de Crescimento Endotelial/sangue , Feminino , Linfocinas/sangue , Camundongos , Camundongos Endogâmicos C3H , Neoplasias Ovarianas/irrigação sanguínea , Paclitaxel/farmacocinética , Ácido Poliglutâmico/farmacocinética , Ácido Poliglutâmico/uso terapêutico , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
The antitumor effects of the selective cyclooxygenase (COX)-2 inhibitor SC-236 alone and in combination with radiation were investigated using the human glioma cell line U251 grown in monolayer culture and as tumor xenografts. On the basis of Western and Northern blot analyses, these cells express COX-2 protein and mRNA to levels similar to those in the human colon carcinoma cell line HT29. Treatment of U251 cells in monolayer culture with 50 microM SC-236 resulted in a time-dependent decrease in cell survival as determined by a clonogenic assay. The cell death induced by SC-236 was associated with apoptosis and the detachment of cells from the monolayer. After 2 days of drug treatment, the cells that remained attached were exposed to graded doses of radiation, and the clonogenic assay was performed. Comparison of the survival curves for drug-treated and untreated cultures revealed that SC-236 enhanced radiation-induced cell death. In these combination studies, SC-236 treatment resulted in a dose-enhancement factor of 1.4 at a surviving fraction of 0.1, with the surviving fraction at 2 Gy (SF2) reduced from 0.61 to 0.31. These data indicate that in vitro SC-236 induces U251 apoptotic cell death and enhances the radiosensitivity of the surviving cells. To extend these investigations to an in vivo situation, U251 glioma cells were grown as tumor xenografts in the hind leg of nude mice, and SC-236 was administered in drinking water. SC-236 alone slowed tumor growth rate, and when administered in combination with local irradiation, SC-236 caused a greater than additive increase in tumor growth delay. These in vitro and in vivo results suggest that the selective inhibition of COX-2 combined with radiation has potential as a cancer treatment.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Glioma/tratamento farmacológico , Glioma/radioterapia , Pirazóis/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Sulfonamidas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Northern Blotting , Western Blotting , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Terapia Combinada , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/farmacologia , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Citometria de Fluxo , Humanos , Marcação In Situ das Extremidades Cortadas , Isoenzimas/biossíntese , Proteínas de Membrana , Camundongos , Camundongos Nus , Transplante de Neoplasias , Prostaglandina-Endoperóxido Sintases/biossíntese , RNA Mensageiro/metabolismo , Radiossensibilizantes/farmacologia , Fatores de Tempo , Células Tumorais CultivadasRESUMO
This study investigated P-glycoprotein (Pgp) expression by murine tumors with and without resistance to paclitaxel and the role of (99m)Tc-2-methoxyisobutylisonitrile (MIBI)/(201)Tl imaging in predicting the effect of paclitaxel. Antitumor effect of paclitaxel and biodistribution of the radiopharmaceuticals were evaluated in mice bearing four tumor types. Pgp expression did not correlate with the antitumor efficacy of paclitaxel. Although the absolute uptake of (99m)Tc-MIBI did not correlate with Pgp expression, (99m)Tc-MIBI could predict paclitaxel sensitivity by its higher uptake.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Experimentais/diagnóstico por imagem , Paclitaxel/farmacologia , Compostos Radiofarmacêuticos , Tecnécio Tc 99m Sestamibi , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Animais , Antineoplásicos Fitogênicos/farmacocinética , Resistencia a Medicamentos Antineoplásicos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C3H , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Paclitaxel/farmacocinética , Cintilografia , Radioisótopos de Tálio , Distribuição Tecidual , Contagem Corporal TotalRESUMO
Cyclooxygenase-2 (COX-2), an inducible isoform of cyclooxygenase, is overexpressed in many types of malignant tumors, where it mediates production of prostaglandins (PGs), which in turn may stimulate tumor growth and protect against damage by cytotoxic agents. This study investigated whether SC-'236, a selective inhibitor of COX-2, potentiates antitumor efficacy of radiation without increasing radiation injury to normal tissue. Mice bearing the sarcoma FSA in the hind legs were treated daily for 10 days with SC-'236 (6 mg/kg given in the drinking water) when tumors were 6 mm in diameter. When tumors reached 8 mm in diameter, the mice were given 11- to 50-Gy single-dose local tumor irradiation with or without SC-'236. SC-'236 inhibited tumor growth on its own, and it greatly enhanced the effect of tumor irradiation. The growth delay was increased from 14.8 days after 25-Gy single dose to 28.4 days after the combined treatment (P = 0.01). SC-'236 reduced TCD50 (radiation dose yielding 50% tumor cure) from 39.2 Gy to 20.9 Gy (enhancement factor = 1.87). SC-'236 did not appreciably alter radiation damage to jejunal crypt cells and tissue involved in the development of radiation-induced leg contractures. The SC-'236-induced enhancement of tumor radioresponse was associated with a decrease in PGE2 levels in FSA tumors. The drug had no effect on radiation-induced apoptosis. Neoangiogenesis was inhibited by SC-'236, which could account for some of the increase in tumor radioresponse. Overall, our findings demonstrated that treatment with a selective inhibitor of COX-2 greatly enhanced tumor radioresponse without markedly affecting normal tissue radioresponse. Thus, COX-2 inhibitors have a high potential for increasing the therapeutic ratio of radiotherapy.