Denileukin diftitox as novel targeted therapy for lymphoid malignancies

Denileukin diftitox (DAB₃₈₉IL-2; Ontak) is a cytotoxic fusion protein designed to target cells expressing the receptor for interleukin-2 (IL-2). It has been approved for treatment of patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL) whose malignant cells express the CD25 component of the IL-2 receptor, but more recent data indicate activity in the setting of not only T-cell but also B-cell malignancies. This review will update the experience to date of denileukin diftitox in T- and B-cell malignancies.     

Toxic epidermal necrolysis associated with denileukin diftitox (DAB389IL-2) administration in a patient with follicular large cell lymphoma

Denileukin diftitox (DAB₃₈₉IL-2 or Ontak®) is a synthetic fusion protein with demonstrated efficacy in a number of lymphoproliferative disorders, including non-Hodgkin's lymphoma. We report the case of a 45-year-old man with progressive follicular large cell lymphoma following an autologous stem cell transplant treated with denileukin diftitox who developed a fatal skin rash associated with extensive erythema, edema and large bullae involving his entire body. The clinical features and pathology were compatible with toxic epidermal necrolysis. This is the first reported case of toxic epidermal necrolysis in the literature associated with denileukin diftitox.     

Bexarotene: a clinical review

Bexarotene (Targretin^®, Ligand Pharmaceuticals Inc.) is a synthetic retinoid analog with specific affinity for the retinoid X receptor and belongs to a group of compounds called rexinoids. Early clinical trials of this drug demonstrated activity in cutaneous T-cell lymphoma. Subsequent Phase II/III trials have demonstrated a greater than 50% response rate in patients with all stages of cutaneous T-cell lymphoma who were refractory or intolerant to the previous therapy. The principal toxicities of bexarotene include central hypothyroidism, xeroderma and elevation of cholesterol and triglycerides. These toxicities can be managed with dose attenuation or addition of atorvastatin (Lipitor^®, Pfizer) or fenofibrate (TriCor?, Abbott Laboratories). Since bexarotene has little bone marrow toxicity, it is an excellent candidate for combination therapy with other modalities useful in the treatment of cutaneous T-cell lymphoma. These include ultraviolet B irradiation, psoralen and ultraviolet A photochemotherapy, interferons, denileukin diftitox (Ontak^®, Ligand Pharmaceuticals Inc.) and cytotoxic chemotherapy. Bexarotene has also been investigated in the treatment of breast cancer and non-small cell carcinoma of the lung with promising early results.     

Biosimilar monoclonal antibodies in lymphoma: a critical appraisal

Rituximab, an anti-CD20 monoclonal antibody, revolutionized the treatment of lymphoma. Although newer generation anti-CD20 monoclonal antibodies are being examined, patent expiries and patient demand have fueled the development of rituximab biosimilars. The development of such agents is both an important and difficult undertaking. By definition, although they aim to have safety and efficacy comparable with their reference agents, biosimilars are not exact replicas of those agents, and small changes in nonclinical and preclinical properties may ultimately affect in vivo activity. Consideration must be given to the complex mechanisms of action, sensitive patient populations that may be treated, and appropriate clinical trial endpoints. Furthermore, extrapolation of indications is multifaceted, deserving close examination. This review represents a critical look at biosimilars in lymphoma and their safety, efficacy and long-term effects on patient outcomes.     

Impact of pomalidomide therapy in multiple myeloma: a recent survey

Abstract

Pomalidomide (Pomalyst^®) is a synthetic compound derived by modifying the chemical structure of thalidomide to improve its potency and reduce its side effects and third drug in the class of immunomodulatory drugs. Pomalidomide is under global development with Celgene Corporation, was approved by the U.S. Food and Drug Administration on February 8, 2013 to treat patients with relapsed and refractory multiple myeloma (MM) who have received at least two prior therapies including bortezomib and lenalidomide. In October 2009, it has found orphan designation for the treatment of relapsed and refractory MM by the EMA, and on August 2013, marketing authorization has issued in Europe by gaining a positive response. It inhibits myeloma cell growth and angiogenesis directly. Pomalidomide is the latest myeloma cell growth inhibitor to be approved in both USA and EU. The predominant side effects are thrombocytopenia, neuropathy, and deep vein thrombosis. Pomalidomide is also being investigated in patients with amyloidosis, prostate cancer, small cell lung cancer, pancreatic cancer, graft-versus-host disease, and Waldenstrom’s macroglobulinemia. This article reviews the available information on pomalidomide with respect to its clinical pharmacology, mechanism of action, pharmacokinetics, pharmacodynamics, metabolism, pre-clinical studies, and clinical trials.     

Challenges in the diagnosis of marginal zone lymphoma with symptoms of small intestinal disease: a case report and scoping review of the literature

BackgroundMarginal zone lymphoma can be accompanied by symptoms of small intestinal disease including abdominal pain and malabsorption. However, the best diagnostic approach for suspected marginal zone lymphoma is unknown and intestinal biopsies are frequently negative. We describe the case of a patient with symptoms of small bowel involvement where marginal zone lymphoma could only be detected upon peripheral lymph node resection. To assess the clinical variability of intestinal marginal zone lymphoma as a rare clinical entity, a scoping review with systematic literature research was performed.MethodsA 57-year-old man presented with a 10-year history of postprandial abdominal pain, systemic inflammation and recent weight loss. Endoscopies and a surgical small bowel specimen revealed non-specific findings. Flow cytometry from the bone marrow was highly suspicious for marginal zone lymphoma. A 2-¹⁸F-fluorodeoxyglucose-positron emission tomography/computed tomography (2-¹⁸F-FDG-PET/CT) showed hypermetabolic lymph nodes on both sides of the diaphragm. Cervical lymph node dissection finally confirmed marginal zone lymphoma. Immunochemotherapy yielded lasting oncological remission and resolved symptoms. We searched PubMed, Embase and Ovid MEDLINE^® for additional case reports limited to the last 25 years. Five primary search terms combined using “AND” were used freely and as controlled vocabulary. Additional studies were identified by reviewing the reference lists of included articles.ResultsOur review revealed 52 cases of marginal zone lymphoma with small intestinal manifestation. Patients presented with abdominal pain, bowel obstruction, weight loss or gastrointestinal bleeding. Diagnosis was mainly established by surgery (73%). The most frequent endoscopic findings were mucosal erosions and ulcerations. A 2-¹⁸F-FDG-PET/CT was positive in 9/15 patients. Treatment included rituximab, chemotherapy, surgery and/or radiation resulting in clinical remission in 82% of cases.ConclusionsDiagnostic workup for suspected small intestinal marginal zone lymphoma is challenging, necessitating a multidisciplinary approach. Endoscopy, imaging including 2-¹⁸F-FDG-PET/CT and small bowel resection or dissection of hypermetabolic lymph nodes can be useful. If marginal zone lymphoma is suspected vigorous diagnostic efforts are justified since remission can be achieved in most patients. Our review highlights the variable clinical presentation of this underdiagnosed disease and adds systematic data to the literature.     

Potent antitumor effects of bevacizumab in a microenvironment-dependent human lymphoma mouse model

We established a mouse model of microenvironment-dependent human lymphoma, and assessed the therapeutic potential of bevacizumab, an antitumor agent acting on the microenvironment. NOD/Shi-scid, IL-2Rγ(null) (NOG) mice were used as recipients of primary tumor cells from a patient with diffuse large B-cell lymphoma (DLBCL), which engraft and proliferate in a microenvironment-dependent manner. The lymphoma cells could be serially transplanted in NOG mice, but could not be maintained in in vitro cultures. Injection of bevacizumab together with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) significantly increased necrosis and decreased vascularization in the tumor, compared with CHOP alone. Levels of human soluble interleukin-2 receptor (sIL2R) in the serum of bevacizumab+CHOP-treated mice (reflecting the DLBCL tumor burden) were significantly lower than in CHOP recipients. Mice receiving bevacizumab monotherapy also showed significant benefit in terms of tumor necrosis and vascularization, as well as decreased serum sIL2R concentrations. The present DLBCL model reflects the human DLBCL in vivo environment more appropriately than current mouse models using established tumor cell lines. This is the first report to evaluate the efficacy of bevacizumab in such a tumor microenvironment-dependent model. Bevacizumab may be a potential treatment strategy for DLBCL patients.     

Identifying afterloading PDR and HDR brachytherapy errors using real-time fiber-coupled Al2O3:C dosimetry and a novel statistical error decision criterion

Background and purpose

The feasibility of a real-time in vivo dosimeter to detect errors has previously been demonstrated. The purpose of this study was to: (1) quantify the sensitivity of the dosimeter to detect imposed treatment errors under well controlled and clinically relevant experimental conditions, and (2) test a new statistical error decision concept based on full uncertainty analysis.

Materials and methods

Phantom studies of two gynecological cancer PDR and one prostate cancer HDR patient treatment plans were performed using tandem ring applicators or interstitial needles. Imposed treatment errors, including interchanged pairs of afterloader guide tubes and 2-20 mm source displacements, were monitored using a real-time fiber-coupled carbon doped aluminum oxide (Al₂O₃:C) crystal dosimeter that was positioned in the reconstructed tumor region. The error detection capacity was evaluated at three dose levels: dwell position, source channel, and fraction. The error criterion incorporated the correlated source position uncertainties and other sources of uncertainty, and it was applied both for the specific phantom patient plans and for a general case (source-detector distance 5-90 mm and position uncertainty 1-4 mm).

Results

Out of 20 interchanged guide tube errors, time-resolved analysis identified 17 while fraction level analysis identified two. Channel and fraction level comparisons could leave 10 mm dosimeter displacement errors unidentified. Dwell position dose rate comparisons correctly identified displacements ?5 mm.

Conclusion

This phantom study demonstrates that Al₂O₃:C real-time dosimetry can identify applicator displacements ?5 mm and interchanged guide tube errors during PDR and HDR brachytherapy. The study demonstrates the shortcoming of a constant error criterion and the advantage of a statistical error criterion.     

ALK-1-negative anaplastic large cell lymphoma associated with breast implants: a new clinical entity

Concerns have been raised recently regarding the increasing number of reports of non-Hodgkin lymphoma (NHL) that developed in close proximity to silicone or saline breast implants. In particular, an increased risk of anaplastic large cell lymphoma (ALCL) in patients with breast prostheses has been proposed. We reviewed clinical and pathologic findings in 40 women who received a diagnosis of breast NHL arising in association with breast implants and of 27 patients who had a diagnosis of ALCL with breast involvement reported in the published literature. Among the 40 reported cases of prosthesis-associated breast lymphomas, 28 were anaplastic lymphoma kinase-1–negative (ALK-1^–) ALCLs, whereas of 27 ALCLs in patients without implants found in the literature, only 10 were ALK-1^–. The finding of 28 cases of breast ALK-1^– ALCL occurring in patients with implants compared with 10 cases in women without implants is in favor of an association between silicone breast prostheses and ALK-1^– ALCL. Although the incidence of this type of lymphoma remains remarkably low given that breast prostheses have been widely used for decades, clinical and pathologic evidence for a causative role is becoming dramatically strong. The histologic, phenomenologic, and clinical similarities of the majority of implant-related ALK-1^– ALCLs suggest a common mechanism, especially when compared with the counterpart of patients without implants in which very few and highly dishomogeneous cases of the same malignancy were detected. There is convincing evidence that primary implant-related ALK-1^– ALCL represents a distinct clinicopathologic entity that has been inappropriately fitted into the category of systemic ALK-1^– ALCL. Thus it should be recognized as a separate category and classified on its own.     

Accessing radiation response using hypoxia PET imaging and oxygen sensitive electrodes: A preclinical study

Purpose

Tumor hypoxia is a known cause of resistance to radiotherapy. The aim of this study was to investigate the prognostic value of hypoxia measured by ¹⁸F-fluoroazomycin arabinoside (¹⁸F-FAZA) PET or the Eppendorf oxygen electrode in a pre-clinical tumor model.

Material/methods

Pretreatment ¹⁸F-FAZA PET scans and blood sampling was conducted in 92 Female CDF1 mice with subcutaneous C3H mammary carcinomas grown in the right foot. Similarly, oxygenation status of 80 equivalent tumors was assessed using an invasive oxygen sensitive electrode. Tumors were then irradiated with a single dose of 55 Gy and local tumor control up to 90 days after the treatment was determined.

Results

A significant difference in local tumor control between “more hypoxic” or “less hypoxic” groups separated either by a median ¹⁸F-FAZA PET determined tumor-to-blood ratio (P = 0.007; hazard ratio, HR = 0.21 [95% CI: 0.06-0.74]), or the fraction of oxygen partial pressure (pO₂) values ?2.5 mmHg (P = 0.018; HR = 0.31 [95% CI: 0.11-0.87]), was found. Both assays showed that the more hypoxic tumors had significantly lower tumor control.

Conclusion

¹⁸F-FAZA PET analysis showed that pre treatment tumor hypoxia was prognostic of radiation response. Similar results were obtained when oxygenation status was assessed by the Eppendorf pO₂ Histograph. The results of this study support the role of ¹⁸F-FAZA as a non-invasive prognostic marker for tumor hypoxia.     

Proliferative and metabolic markers in incompletely excised pediatric pilocytic astrocytomas--an assessment of 3 new variables in predicting clinical outcome

Although pilocytic astrocytoma (PA) is the most common brain tumor diagnosed in children, few prognostic variables have been delineated that stratify the risk of clinical progression in patients with this tumor. In this study, the MIB-1 labeling index was compared with 2 other immunohistochemical markers of cell proliferation, phospho-histone H3 (PHH3) and mini-chromosomal maintenance protein 2 (MCM2) in 80 incompletely resected PAs to see which was best able to identify patients at risk for tumor progression. 0(6)-Methylguanine-DNA methyltransferase (MGMT) protein expression, which has been predictive of progression-free survival (PFS) in high-grade gliomas in children, was also evaluated in these cases. The mean follow-up period was 7.81 ± 3.9 years, and 42.8% of tumors have shown progression at the time of censoring. A MIB-1 labeling index ≥2.0 was associated with shortened PFS as a grouped variable by log-ranked analysis (P = .03) and by Cox regression analysis as a continuous variable (P = .007). None of the other potential biomarkers was significantly predictive of PFS. Although the amount of MCM2 staining correlated with the MIB-1 labeling index (P < .001), MCM2 reactivity was not independently associated with outcome. We conclude that MIB-1 labeling remains the best predictor of PFS in pediatric PAs.     

Activation of kinin B1 receptor increases the release of metalloproteases-2 and -9 from both estrogen-sensitive and -insensitive breast cancer cells

The kinin B(1) receptor (B(1)R) agonist Lys-des[Arg(9)]-bradykinin (LDBK) increases proliferation of estrogen-sensitive breast cancer cells by a process involving activation of the epidermal growth factor receptor (EGFR) and downstream signaling via the ERK1/2 mitogen-activated protein kinase pathway. Here, we investigated whether B(1)R stimulation induced release of the extracellular matrix metalloproteases MMP-2 and MMP-9 via ERK-dependent pathway in both estrogen-sensitive MCF-7 and -insensitive MDA-MB-231 breast cancer cells. Cells were stimulated with 1-100nM of the B(1)R agonist for variable time-points. Western blotting and gelatin zymography were used to evaluate the presence of MMP-2 and MMP-9 in the extracellular medium. Stimulation of B(1)R with as little as 1 nM LDBK induced the accumulation of these metalloproteases in the medium within 5-30min of stimulation. In parallel, immunocytochemistry revealed that metalloprotease levels in the breast cancer cells declined after stimulation. This effect was blocked either by pre-treating the cells with a B(1)R antagonist or by transfecting with B(1)R-specific siRNA. Activation of the ERK1/2 pathway and EGFR transactivation was required for release of metalloproteases because both the MEK1 inhibitor, PD98059, and AG1478, an inhibitor of the EGFR-tyrosine kinase activity, blocked this event. The importance of EGFR-dependent signaling was additionally confirmed since transfection of cells with the dominant negative EGFR mutant HERCD533 blocked the release of metalloproteases. Thus, activation of B(1)R is likely to enhance breast cancer cells invasiveness by releasing enzymes that degrade the extracellular matrix and thereby favor metastasis.     

Hydroxyglutaric aciduria and malignant brain tumor: a case report and literature review

l-2-Hydroxyglutaric aciduria (l-2-OHGA) is a rare autosomal recessive inherited encephalopathy. This inborn error, characterized by psychomotor retardation, progressive ataxia and typical magnetic resonance imaging findings, presents in early infancy. To make a definitive diagnosis, an anomalous accumulation of l-2-hydroxyglutaric acid must be detected in body fluids. Here, we present a 17-year-old boy with l-2-OHGA who developed an anaplastic ependymoma during the course of this disease. We also present a literature review including seven other patients who developed malignant brain tumors during the course of l-2-OHGA. This correlation may indicate a possible increased risk of brain tumors among patients with l-2-hydroxyglutaric aciduria.     

Nasal natural killer (NK)/T-cell lymphoma: clinical, histological, virological, and genetic features

Nasal natural killer (NK)/T-cell lymphoma (NNKTL) is a clinical illness characterized by progressive unrelenting ulceration and necrosis of the nasal cavity and midline facial tissues. Histological features of the lymphoma include angiocentric and polymorphous lymphoreticular infiltrates, called polymorphic reticulosis. Surface antigens and the NK-cell marker, CD56, as well as pan-T antigen CD2, cytoplasmic CD3 (CD3ɛ), and CD45 are expressed in the lymphoma cells. The origin of the lymphoma is thought to be either NK-cell linkage without T-cell receptor (TCR) rearrangement or γδT-cell linkage with γδTCR rearrangement. Since the authors of this study first demonstrated the presence of Epstein Barr virus (EBV)-DNA and EBV oncogenic proteins in NNKTL, the lymphoma has been classified as one of the EBV-associated malignancies. The NNKTL cells produce interleukin (IL)-9, IL-10, and interferon-γ-inducible protein-10 (IP-10), possibly due to EBV-oncogenic proteins in the lymphoma cells, and such cytokines take an important part in the cell proliferation and invasion, acting in an autocrine manner. Clinically, the serum EBV-DNA copy number is useful as a specific tumor marker and a predictive prognostic factor. Even in early clinical stages, the lymphoma shows poor prognosis caused by the rapid progression of the lesion into distinct organs. Our newly designed arterial infusion chemotherapy, from the superficial temporal artery, in combination with radiotherapy, has shown a favorable outcome in patients with NNKTL. In this article, the clinical, pathological, and virological characteristics of the lymphoma are reviewed, along with a report of our investigations.     

Vascular-targeted photodynamic therapy with BF2-chelated Tetraaryl-Azadipyrromethene agents: a multi-modality molecular imaging approach to therapeutic assessment

Background:

Photodynamic therapy (PDT) is a treatment modality for a range of diseases including cancer. The BF₂-chelated tetraaryl-azadipyrromethenes (ADPMs) are an emerging class of non-porphyrin PDT agent, which have previously shown excellent photochemical and photophysical properties for therapeutic application. Herein, in vivo efficacy and mechanism of action studies have been completed for the lead agent, ADMP06.

Methods:

A multi-modality imaging approach was employed to assess efficacy of treatment, as well as probe the mechanism of action of ADPM06-mediated PDT.

Results:

Tumour ablation in 71% of animals bearing mammary tumours was achieved after delivery of 2 mg kg⁻¹ of ADPM06 followed immediately by light irradiation with 150 J cm⁻². The inherent fluorescence of ADPM06 was utilised to monitor organ biodistribution patterns, with fluorescence reaching baseline levels in all organs within 24 h. Mechanism of action studies were carried out using dynamic positron emission tomography and magnetic resonance imaging techniques, which, when taken together, indicated a decrease in tumour vascular perfusion and concomitant reduction in tumour metabolism over time after treatment.

Conclusion:

The encouraging treatment responses in vivo and vascular-targeting mechanism of action continue to indicate therapeutic benefit for this new class of photosensitiser.     

HER2/neu in systemic therapy for women with breast cancer: a systematic review

BACKGROUND: Amplification and/or overexpression of the HER2/neu gene is associated with a poor prognosis in breast cancer. Many studies have suggested that this gene may be associated with the relative efficacy of chemotherapy and endocrine therapy options. METHODS: A systematic review of the evidence was conducted. MEDLINE, EMBASE, the Cochrane Library, the American Society of Clinical Oncology annual meeting proceedings, and the San Antonio Breast Cancer Symposia proceedings were all searched to November 2006 for reports of analysis by HER2/neu status of the relative efficacy of the treatment arms in randomized controlled trials. RESULTS: Thirty-five trials were identified. A meta-analysis of trials of tamoxifen versus observation found no significant interaction between treatment and HER2/neu status, although one trial not included in the meta-analysis did find interaction. A meta-analysis of adjuvant anthracycline-based chemotherapy trials found a significant interaction (difference in disease-free survival log-hazard ratios -0.31, 95% confidence interval -0.50 to -0.13; difference in overall survival log-hazard ratios -0.34, 95% confidence interval -0.53 to -0.14). Significant interaction was also found in a meta-analysis of disease-free survival in trials of adjuvant taxane therapy versus non-taxane therapy (difference in disease-free survival log-hazard ratios -0.36, 95% confidence interval -0.68 to -0.04). HER2/neu overexpression and/or amplification was associated with greater efficacy of the anthracycline or taxane regimen. CONCLUSIONS: Current evidence supports the conclusion that the benefit of both anthracycline-based and taxane-based adjuvant chemotherapy is associated on HER2/neu status, with patients with HER2/neu-positive cancers benefiting more from these therapies than those with HER2/neu-negative cancers.     

Calcium, calcium-sensing receptor and colon cancer

There is much evidence that dietary Ca(2+) loading reduces colon cell proliferation and carcinogenesis in humans and rodents, but during carcinogenesis it becomes ineffective or even tumor-promoting. We are beginning to see how Ca(2+) balances the continuous massive cell production in colon crypts by driving the terminal differentiation and eventually the apoptosis of the cells mainly on the mucosal surface, and how this Ca(2+) control is lost during colon carcinogenesis. The rapid proliferation of the transit-amplifying (TA) progeny of the colon stem cells is driven by the so-called "Wnt" signaling mechanism, which involves the stimulation of proliferogenic genes such as those for c-Myc and cyclin D1 and the silencing of the gene for the cell cycle-stopping p21(Cip1/WAF1) protein by nuclear beta-catenin*Tcf-4 complexes. TA cells avoid mitotic damage and premature apoptosis by expressing the protein survivin. It appears that TA cell cycling stops and terminal differentiation starts when the cells reach a higher level in the crypt where there is enough lumenal Ca(2+) to stimulate the expression and activation of CaSRs (Ca(2+)-sensing receptors), the signals from which stimulate the expression of E-cadherin. Along with this, the APC (adenomatous polyposis coli) protein appears and some of it enters the nucleus. There it makes the TA cells susceptible to the eventual apoptotic balancing by stopping survivin expression and the beta-catenin*Tcf-4 complex from driving further cell cycling by releasing beta-catenin from the nucleus, and delivering it to cytoplasmic APC*axin*GSK-3beta complexes for ultimate proteasomal destruction. Cytoplasmic beta-catenin is then prevented from returning to the nucleus by either being intercepted and destroyed by APC*axin*GSK-3beta complexes or locked by the emerging E-cadherin into membrane adherens junctions which tie the cell into the sheet of proliferatively shut-down cells with APC-dependent cytoskeletons moving to the mouth of the crypt and onto the flat mucosal surface. A common first step in sporadic colon carcinogenesis is the loss of functional APC which disorients upwardly directed migration and causes the retention of nuclear beta-catenin and proliferogenic beta-catenin*Tcf-4 complexes as well as genomic instability. Eventually the balance between cell proliferation and terminal differentiation and death is radically tipped in favour of proliferation by the appearance of apoptosis-resistant, survivin-expressing clones of Ca(2+)-insensitive cells which are locked into the proliferative, mutation-prone mode because of CaSR-disabling gene mutations which prevent the stimulation of E-cadherin expression and terminal differentiation.     

Spontaneous apoptosis in ovarian carcinomas: a positive association with p53 gene mutation is dependent on growth fraction

Changes in cell survival contribute to tumour development, influence tumour biology and its response to chemotherapy. p53 gene alterations should negatively affect apoptosis by impaired p53-dependent apoptotic response. We looked for associations between spontaneous apoptosis, p53 gene mutation, p53 protein accumulation, growth fraction, bcl-2 expression and histological parameters in 64 ovarian, four tubal and three peritoneal carcinomas. Apoptotic cells were detected with the TUNEL method. p53 gene variants were detected by the single-strand conformation polymorphism and were sequenced directly. P53, Ki-67 and bcl-2 protein expressions were detected immunohistochemically. A weighed multiple logistic regression model was applied. Apoptotic index (AI) ranged 0.02-0.18 (mean 0.11); proliferation index (PI) ranged 3-90% (mean 54%). p53 gene mutations were present in 51, p53 protein accumulation in 46, and diffuse bcl-2 expression in 29 of 71 tumours. The AI was positively associated with the presence of p53 gene mutation (P = 0.011). However, the PI included into the analysis did positively influence the AI (P = 0.02) and diminished the association with p53 gene mutation (P = 0.082). The AI was negatively associated with good histological differentiation (P = 0.0006), the serous tumour type (P = 0.002), and diffuse bcl-2 expression (P = 0.025). Strong bcl-2 expression was associated with endometrioid tumour type (P = 0.002). FIGO stage and p53 protein accumulation were the only parameters that influenced overall survival time. Thus, our results suggest that histological tumour type and grade are major determinants of spontaneous apoptosis in ovarian carcinomas; p53 alterations do not adversely but rather positively affect spontaneous apoptosis by increasing growth fraction. This, in turn, suggests p53-independency of spontaneous apoptosis in ovarian carcinomas.     

Resveratrol modulation of signal transduction in apoptosis and cell survival: a mini-review

BACKGROUND: There is mounting evidence in the literature that resveratrol is a promising natural compound for prevention and treatment of a variety of human cancers. This overview summarizes recent studies of the major apoptosis and survival pathways regulated by resveratrol. BIOLOGICAL MECHANISMS: Apoptosis or programmed cell death is a key regulator of tissue homeostasis during normal development and also in adult organism under various conditions including adaptive responses to cellular stress. For example, tissue homeostasis is maintained by tight control of signaling events regulating cell death and survival. Thus, uncontrolled proliferation or failure to undergo cell death is involved in pathogenesis and progression of many human diseases, for example in tumorigenesis or in cardiovascular disorders. Moreover, current cancer therapies primarily act by triggering apoptosis programs in cancer cells. THERAPEUTIC APPLICATIONS: Natural products such as resveratrol have gained considerable attention as cancer chemopreventive or cardioprotective agents and also because of their antitumor properties. Among its wide range of biological activities, resveratrol has been reported to interfere with many intracellular signaling pathways, which regulate cell survival or apoptosis. DISCUSSION: Further insights into the signaling network and interaction points modulated by resveratrol may provide the basis for novel drug discovery programs to exploit resveratrol for the prevention and treatment of human diseases.