肿瘤治疗策略及其局限性

本文简单回顾了肿瘤治疗策略的新进展,并对肿瘤治疗策略的前景及其局限性进行了预测和探讨。     

肿瘤基因治疗的研究进展

基因治疗作为一种新的治疗手段,给许多绝症患者带来希望。基因治疗的范围已从最初的单基因疾病扩展到恶性肿瘤、心脑血管及自身免疫等诸多领域,其中以恶性肿瘤为主要对象。本文综述了肿瘤基因治疗中的基因转移方法、基因治疗策略、导向基因治疗及其在应用上的问题与展望。     

Metabolic effects of anti-angiogenic therapy in tumors

Anti-angiogenic therapy has recently been added to the panel of cancer therapeutics, but predictive biomarkers of response are still not available. In animal models, anti-angiogenic therapy causes tumor starvation by increasing hypoxia and impairing nutrients supply. It is thus conceivable that angiogenesis inhibition causes remarkable metabolic perturbations in tumors, although they remain largely uncharted. We review here recent acquisitions about metabolic effects of angiogenesis blockade in tumors and discuss the possibility that some metabolic features of tumor cells - i.e. their dependency from glucose as primary energy substrate - might affect tumor responses to anti-VEGF treatment.     

Nutrient restriction preserves calcium cycling and mitochondrial function in cardiac myocytes during ischemia and reperfusion

Nutrient restriction (NR) prolongs longevity via enhanced mitochondrial function. We tested the hypothesis that NR enhances resistance to ischemia/reperfusion (IR) arrhythmias via preserved calcium (Ca) cycling and mitochondrial function. We examined the protective effects of NR on regional IR in cultured neonatal rat ventricular myocyte monolayers. Optical mapping of intracellular Ca and mitochondrial membrane potential Δψ(m) was performed using Rhod 2-AM and TMRE, respectively. Regional ischemia was mimicked by covering a portion of monolayer with a glass coverslip until loss of Ca propagation, and reperfusion was mimicked by removing the coverslip. NR was mimicked by culture in serum- and glucose-free medium for 24 h. Relative to controls, NR monolayers: (1) sustained Ca oscillations during longer periods of ischemia (19.2 ± 1.8 min vs 10.4 ± 1.4 min, p<0.001); (2) had attenuated increases in Ca transient duration (CaD) and time decay constant (Tau) during ischemia; (3) had preserved conduction velocity (CV) during early reperfusion, leading to protection against reperfusion arrhythmias; (4) had minimal "rebound" decreased CaD and Tau during reperfusion; and (5) had no depolarization of Δψ(m) during IR. NR attenuates IR arrhythmias via (1) stable calcium cycling and (2) prevention of Δψ(m) depolarization during IR. Enhanced mitochondrial resistance to IR arrhythmias may play a role in NR-induced longevity prolongation.     

Overcoming resistance to rapalogs in gliomas by combinatory therapies

Glioblastoma is the most common and aggressive brain tumor type, with a mean patient survival of approximately 1 year. Many previous analyses of the glioma kinome have identified key deregulated pathways that converge and activate mammalian target of rapamycin (mTOR). Following the identification and characterization of mTOR-promoting activity in gliomagenesis, data from preclinical studies suggested the targeting of mTOR by rapamycin or its analogs (rapalogs) as a promising therapeutic approach. However, clinical trials with rapalogs have shown very limited efficacy on glioma due to the development of resistance mechanisms. Analysis of rapalog-insensitive glioma cells has revealed increased activity of growth and survival pathways compensating for mTOR inhibition by rapalogs that are suitable for therapeutic intervention. In addition, recently developed mTOR inhibitors show high anti-glioma activity. In this review, we recapitulate the regulation of mTOR signaling and its involvement in gliomagenesis, discuss mechanisms resulting in resistance to rapalogs, and speculate on strategies to overcome resistance. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).     

Bortezomib-induced enzyme-targeted radiation therapy in herpesvirus-associated tumors

We investigated the possibility of using a pharmacologic agent to modulate viral gene expression to target radiotherapy to tumor tissue. In a mouse xenograft model, we had previously shown targeting of [(125)I]2'-fluoro-2'-deoxy-beta-D-5-iodouracil-arabinofuranoside ([(125)I]FIAU) to tumors engineered to express the Epstein-Barr virus thymidine kinase (EBV-TK). Here we extend those results to targeting of a therapeutic radiopharmaceutical [(131)I]FIAU to slow or stop tumor growth or to achieve tumor regression. These outcomes were achieved in xenografts with tumors that constitutively expressed the EBV-TK. With naturally infected EBV tumor cell lines (Burkitt's lymphoma and gastric carcinoma), activation of viral gene expression by pretreatment with bortezomib was required. Marked changes in tumor growth could also be achieved in naturally infected Kaposi's sarcoma herpesvirus tumors after pretreatment with bortezomib. Bortezomib-induced enzyme-targeted radiation therapy illustrates the possibility of pharmacologically modulating tumor gene expression to result in targeted radiotherapy.     

The multipleparameter combinatory analysis of EEG rhythms in norm and at schizophrenia

On the base of EEG records of 38 healthy subjects and 17 schizophrenic patients the statistical structural analysis of 176 elementary characteristics in all 11 spectral ranges for each of 4 experimental conditions was carried out, employing "Kora-n" recognition algorithm, adopted for EEG analysis by Kaplan. The list of characteristics with a minimal error revealed statistically significant differences between spectral power of delta- and theta-ranges in healthy subjects and schizophrenic patients. Spectral power of these slow rhythms was always higher in the formers then in the latter. As a whole, in schizophrenic patients the decrease of delta-rhythm spectral power in the lower frontal area of right hemisphere and theta-rhythm - in the lower temporal area of left hemisphere most frequently is observed. These results are in agreement with hypofrontality and hypotemporality characteristic of schizophrenic patients and testify to the lack of "fundamental" brain base of cognitive functions. These facts are evidently connected with the significant neurochemical disturbances taking place in schizophrenia.     

131I]metaiodobenzylguanidine therapy in carcinoid tumors.

Our experience with [131I]metaiodobenzylguanidine (131I-MIBG) therapy in two patients with carcinoid tumor is described. These patients were selected because of multiple areas of uptake on 131I-MIBG scan, consistent with the extent of the disease. Both patients presented diarrhea and liver metastases. Para-aortical lymphonodes and skeletal metastases were present in the first and the second patient, respectively. Previous treatment involved r-alpha-interferon, surgery or radiotherapy. In both cases 131I-MIGB therapy was started in December 1990 and is still continuing. No haematologic or hepatic side-effects have been observed. Mild hypotension (90/60 mmHg) occurred in one patient during the first course of therapy and was resolved by corticoid treatment. A stabilization of disease and a progressive reduction of diarrhea have been observed in both patients. In the second patient an initial decrease in liver metastases was confirmed by ultrasonography 7 months after the beginning of therapy.     

Trophoblastic tumors of the uterus-problems of methotrexate therapy

Nineteen patients with trophoblastic tumors of the uterus were evaluated at the University of California San Francisco Medical Center. Eight patients, admitted before 1956, did not receive chemotherapy; the mortality rate was 87.5 per cent. Ten of the remaining 11 patients were given intermittent, intensive Methotrexate therapy; actinomycin D and vincristine were used in treating two patients in whom resistance to Methotrexate developed. The mortality was 10 per cent. Toxicity was a prominent factor but was completely reversible when chemotherapy was stopped.None of the patients showed recurrent disease during follow-up evaluation eight months to five years and eight months after therapy was completed.It is postulated that continuing chemotherapy four to six months after the chorionic gonadotropin titer becomes negative decreases recurrent disease.     

Results of combined therapy in patients with nonseminomatous testicular tumors

The results of multidrug therapy of 44 male patients with non-seminomatous testicular tumours are discussed. The diagnosed tumours were of all stages of the clinical advances and were treated with combined chemotherapy (surgery and PVP regimen). Thirty two patients (73%) are followed up between 7 and 103 months and survived, complete remission is noted in 29 patients (66%) including 6 patients who survived over 5 years. Symptoms of the tumour are found in 3 patients. Twelve patients (27%) died. The treatment did not produce life-threatening complications. The obtained results have been compared with those reported by other authors.     

PET for diagnosis and therapy of brain tumors

Main contribution of PET in the management of brain tumors is at the therapeutic level. Specific reasons explain this role of molecular imaging in the therapeutic management of brain tumors, especially gliomas. Gliomas are by nature infiltrating neoplasms and the interface between tumor and normal brain tissue may not be accurately defined on CT and MRI. Also, gliomas are often histologically heterogeneous with anaplastic areas evolving within a low-grade tumor, and the contrast-enhancement on CT or MRI does not represent a good marker for anaplastic tissue detection. Finally, assessment of tumor residue, recurrence or progression may be altered by different signals related to inflammation or adjuvant therapies, even on contrast-enhanced CT and MRI. These limitations of the conventional neuroimaging in delineating tumor and detecting anaplastic tissue lead to potential inaccuracy in lesion targeting at different steps of the management (diagnostic, surgical, and post-therapeutic stages). Molecular information provided by PET has proved helpful to supplement morphological imaging data in this context. ¹⁸F-FDG (FDG) and amino-acid tracers such as ¹¹C-methionine (MET), provides complementary metabolic data that are independent from the anatomical MR information. These tracers help in the definition of glioma extension, in the detection of anaplastic areas and in the postoperative follow-up. Additionally, PET data have an independent prognostic value. To take advantage of PET data in glioma treatment, PET might be integrated in the planning of image-guided biopsies, radiosurgery and resection.     

On optimal delivery of combination therapy for tumors

A mathematical model for the scheduling of angiogenic inhibitors in combination with a chemotherapeutic agent is formulated. Conditions are given that allow tumor eradication under constant infusion therapies. Then the optimal scheduling of a vessel disruptive agent in combination with a cytotoxic drug is considered as an optimal control problem. Both theoretical and numerical results on the structure of optimal controls are presented.     

Dendritic cell therapy of primary brain tumors.

BACKGROUND: Although current treatment modalities for malignant gliomas, such as surgery, radiation and chemotherapy, have been improved markedly in the past two decades, the prognosis of these neoplasms remains poor, the two year survival rate being approximately 5%. Therefore, alternative treatment options, such as gene therapy and immunotherapy are rapidly gaining momentum. One of the most promising immunotherapeutic approaches for the treatment of cancer is the vaccination of cancer patients with dendritic cells (DC) pulsed with tumor antigens. Immunotherapy with DC seems to be able to overcome, at least partially, the immunosuppressive state associated with primary malignant gliomas. DC therapy proved to be safe in both animal models and clinical trials. No serious side effects and no evidence of autoimmune toxicity occurred. Most studies used DC pulsed with an array of tumor-associated antigens rather than single peptides, to allow for presentation of unknown tumor-specific antigens to DC. Routes of administration either were subcutaneous, intradermal or intraperitoneal, with multiple injections of DC to enhance antitumor immunity. DC therapy as an adjuvant treatment for patients with malignant glioma seems to be biologically safe. Further clinical studies are warranted.     

Eradication of established tumors in mice by a combination antibody-based therapy

Tumor-cell apoptosis is the basis of many cancer therapies, and tumor-specific T cells are the principal effectors of successful antitumor immunotherapies. Here we show that induction of tumor-cell apoptosis by an agonistic monoclonal antibody to DR5, the apoptosis-inducing receptor for TNF-related apoptosis-inducing ligand (TRAIL), combined with T-cell activation by agonistic monoclonal antibodies to the costimulatory molecules CD40 and CD137, potently and rapidly stimulated tumor-specific effector CD8+ T cells capable of eradicating preestablished tumors. Primary fibrosarcomas initiated with the carcinogen 3-methylcholanthrene (MCA), multiorgan metastases and a primary tumor containing as many as 90% tumor cells resistant to DR5-specific monoclonal antibody were rejected without apparent toxicity or induction of autoimmunity. This combination therapy of three monoclonal antibodies (trimAb) rapidly induced tumor-specific CD8+ T cells producing interferon (IFN)-gamma in the tumor-draining lymph node, consistent with a crucial requirement for CD8+ T cells and IFN-gamma in the tumor rejection process. These results in mice indicate that a rational monoclonal antibody-based therapy that both causes tumor-cell apoptosis through DR5 and activates T cells may be an effective strategy for cancer immunotherapy in humans.     

Gene therapy for mitochondrial disease by delivering restriction endonucleaseSmaI into mitochondria

The restriction endonucleaseSmaI has been used for the diagnosis of neurogenic muscle weakness, ataxia and retinitis pigmentosa disease or Leigh's disease, caused by the Mt8993TG mutation which results in a Leu156Arg replacement that blocks proton translocation activity of subunit a of F₀F₁-ATPase. Our ultimate goal is to applySmaI to gene therapy for this disease, because the mutant mitochondrial DNA (mtDNA) coexists with the wild-type mtDNA (heteroplasmy), and because only the mutant mtDNA, but not the wild-type mtDNA, is selectively restricted by the enzyme. For this purpose, we transiently expressed theSmaI gene fused to a mitochondrial targeting sequence in cybrids carrying the mutant mtDNA. Here, we demonstrate that mitochondria targeted by theSmaI enzyme showed specific elimination of the mutant mtDNA. This elimination was followed with repopulation by the wild-type mtDNA, resulting in restoration of both the normal intracellular ATP level and normal mitochondrial membrane potential. Furthermore, in vivo electroporation of the plasmids expressing mitochondrion-targetedEcoRI induced a decrease in cytochromec oxidase activity in hamster skeletal muscles while causing no degenerative changes in nuclei. Delivery of restriction enzymes into mitochondria is a novel strategy for gene therapy of a special form of mitochondrial diseases.