Antisense and nonantisense effects of antisense Bcl-2 on multiple roles of Bcl-2 as a chemosensitizer in cancer therapy

Bcl-2 is an oncoprotein that plays a critical role in inhibiting apoptotic cell death in the mitochondria-dependent pathway in cancer chemotherapy. As a strategy for blocking Bcl-2 for enhancement of the chemotherapeutic effect, antisense Bcl-2 (AS Bcl-2; G3139, oblimersen sodium, Genasense) has shown promise, and there are several ongoing clinical studies with hematological malignancies as well as solid tumors. Although several preclinical and clinical studies have shown the therapeutic efficacy of Bcl-2 in combination with an anticancer drug as a chemosensitizer, in clinical trials the downregulation of Bcl-2 has not been observed with a high frequency in tumor cells. Nevertheless, previous studies showed nonantisense effects such as production of reactive oxygen species and immunostimulatory action through cytosine-phosphate-guanosine-motif in the antisense oligodeoxynucleotides. Further, Bcl-2 is able to inhibit Beclin 1-dependent autophagic cell death, which is a nonapoptotic cell death. The current status and future directions of AS Bcl-2 and the potential mechanisms for multiple roles that Bcl-2 has in cancer therapy are reviewed.     

Regulatory considerations for preclinical development of anticancer drugs

The entry of new anticancer treatments into phase I clinical trials is ordinarily based on relatively modest preclinical data. This report defines the battery of preclinical tests important for assessing safety under an Investigational New Drug application (IND) and outlines a basis for extrapolating starting doses of investigational anticancer drugs in phase I clinical trials from animal toxicity studies. Types of preclinical studies for the support of marketing of a new anticancer drug are also discussed. This report addresses differences and similarities in the preclinical development of cytotoxic drugs (including photosensitizers and targeted delivery products), drugs used chronically (chemopreventive drugs, hormonal drugs, immunomodulators), and drugs intended to enhance the efficacy (MDR-reversing agents and radiation/chemotherapy sensitizers) or diminish the toxicity of currently used anticancer therapies. Factors to consider in the design of preclinical studies of combination therapies, alternative therapies, and adjuvant therapies in the treatment of cancer, and to support changes in clinical formulations or route of administration, are also discussed. Received: 19 December 1996 / Accepted: 2 June 1997     

Oblimersen sodium (G3139 Bcl-2 antisense oligonucleotide) therapy in Waldenstrom's macroglobulinemia: a targeted approach to enhance apoptosis

The components of the apoptotic pathway are targets for anticancer therapy. Bcl-2 protein inhibits apoptosis and confers resistance to treatment with traditional cytotoxic chemotherapy, radiotherapy, and monoclonal antibodies. Oblimersen sodium (G3139, Genasense, Genta Inc, Berkeley Heights, NJ) is an antisense oligonucleotide compound designed to specifically bind to the first six codons of the human bcl-2 mRNA sequence, resulting in degradation of bcl-2 mRNA and subsequent decrease in Bcl-2 protein translation. Oblimersen is the first oligonucleotide to demonstrate proof of principle of an antisense effect in human tumors by the documented downregulation of the target Bcl-2 protein. A growing body of preclinical and clinical evidence suggests that oblimersen synergizes with many cytotoxic and biologic/immunotherapeutic agents against a variety of hematologic malignancies and solid tumors. Randomized clinical trials are currently underway to evaluate the efficacy and tolerability of oblimersen in combination with cytotoxic chemotherapy in chronic lymphocytic leukemia (CLL), multiple myeloma (MM), malignant melanoma, and non-small cell lung cancer. In addition, nonrandomized trials are underway to evaluate oblimersen in non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), and hormone-refractory prostate cancer. Preclinical data support the clinical evaluation of oblimersen in additional tumor types, including chronic myelogenous leukemia, and breast, small cell lung, gastric, colon, bladder (CML), and Merkel cell cancers. Enhancement of the efficacy of anticancer treatments with oblimersen Bcl-2 antisense therapy represents a promising new apoptosis-modulating strategy, and ongoing clinical trials will test this therapeutic approach.     

二甲双胍在乳腺癌中抗肿瘤作用研究进展

临床前研究表明降糖药二甲双胍对乳腺癌有抗肿瘤作用,能降低糖尿病患者乳腺癌发病风险和死亡风险,也能提高乳腺癌患者新辅助化疗后病理完全缓解率。体内外实验表明二甲双胍有效抑制各种乳腺癌细胞和移植瘤,并和化疗药物、HER2靶向药物、新型抗肿瘤药物有良好协同作用。主要分子机制包括全身性下调胰岛素及相关信号通路、肿瘤细胞内激活LKBl／AMPK、抑制下游mTOR通路等。目前各国开展了多个临床试验评估--sp双胍在乳腺癌防治中的应用价值。     

A pitfall in the survival benefit of adjuvant chemotherapy for node- and hormone receptor-positive patients with breast cancer: the paradoxical role of Bcl-2 oncoprotein (review)

The survival benefit of adjuvant chemotherapy in node-positive patients with breast cancer compared with surgery alone has been established. The survival benefit differs considerably between hormone receptor-positive and -negative patients, and it is believed that the effectiveness of adjuvant chemotherapy can be increased by hormonal therapy with tamoxifen. In the present review, we discuss the rationale behind the effectiveness of combination treatment with anticancer drugs and tamoxifen in terms of the paradoxical role of Bcl-2 in apoptosis in breast cancer. The survival benefit between receptor-positive and -negative patients was assessed using previous reports of randomized controlled studies for postoperative adjuvant chemotherapy in node-positive breast cancer. Tamoxifen induces the anti-apoptotic gene, Bcl-2, by its effect on estradiol (E2), via an E2-response element in the promotor region of Bcl-2. The efficicacy of chemoendocrine therapy was assessed in terms of the influence of tamoxifen on the effect of anticancer drugs. Adjuvant chemotherapy, including anthracycline and non-anthracycline based regimens, has an overall survival benefit in node-positive breast cancer, with a 23.5% reduction in the annual odds of recurrence and a 15% reduction in mortality (P<0.00001). A comparison of the reduction of the relative risk indicates that the survival benefit in receptor-negative patients is superior to that in receptor-positive patients by approximately 3-fold. Further, in contrast to receptor-negative patients, there is no additional benefit from paclitaxel over doxorubicin and cyclophosphamide (AC) in receptor-positive patients. The possible reasons that the chemotherapy benefit in receptor-positive patients is small and marginal are the following: i) concurrent treatment or pretreatment with tamoxifen can increase plasma E2 levels in premenopausal patients, thereby inducing Bcl-2 in residual cancer cells, which might decrease drug-sensitivity in combination with chemotherapy; ii) induction of Bcl-2 might be involved predominantly in the resistance to taxanes, the cytotoxic action of which targets Bcl-2. Co-treatment or pretreatment with tamoxifen for adjuvant therapy might decrease the efficacy of anticancer drugs, an effect that is mediated by induction of Bcl-2, especially in premenopausal patients with node-positive breast cancer. Treatment with anticancer drugs should be followed by treatment with tamoxifen to produce a survival benefit from combination therapy in receptor-positive patients.     

Potential roles of antisense therapy in the molecular targeting of genes involved in cancer (review)

Recent advances in antisense methods targeting genes involved in cell proliferation, angiogenesis, and apoptosis provide a potential anticancer effect alone as well as in combination with drugs, and antisense therapy may be useful in overcoming drug resistance and increasing survival in patients with advanced cancer including those with solid tumors. In particular, antisense to Bcl-2 comprises a most promising therapy and is being tested in combination with anticancer drugs in randomized phase III trials for chronic lymphocytic leukemia, multiple myeloma, and malignant melanoma. The targeting of apoptosis-related proteins is promising for enhancing the effect of cancer chemotherapy. The molecular mechanism by which anticancer drugs induce apoptosis has been identified as mitochondrial dysfunction mediated by the release of cytochrome c. Modulation of multiple antiapoptotic signaling pathways involving Bcl-2 and Akt, which are related to growth factor-stimulated signal transduction in cell survival, is essential for enhancement of the cytotoxic effect of anticancer drugs. Herein, we review the current status of antisense therapy and its potential for enhancing anticancer drug-induced apoptosis.     

Comparative clinical trials

The therapeutic advantages of a newly developed cancer chemotherapy should be evaluated in comparison with the standard (or control) treatment. Therefore the comparative clinical trials should be designed so that the only differences observed among treatment groups are directly made by treatment program. This requires comparability of patients throughout the trial. The preferred method of evaluation is randomized controlled trials which can eliminate conscious or unconscious bias in assigning treatment. Before patients are randomized into the treatments of the trial, it is advisable to stratify patients according to known prognostic factors (stratified randomization) in an attempt to achieve equal distribution of these factors within each stratum. There are many difficulties with historical control study in the conduct of the comparative clinical trials, and its use may be acceptable only when randomized controlled trials are not feasible. The method of administration of anticancer drugs, patient eligibility, response parameters, toxicity of anticancer drugs, size and duration of the study, and advantages and disadvantages of multi-institution trials were also discussed within the framework of the comparative clinical trials.     

Biologic agents as modifiers of chemotherapeutic effects.

Recent papers dealing with the effect of biologic response modifiers on the therapeutic activity of anticancer drugs are reviewed. Preclinical findings indicate that both interferons and tumor necrosis factor-alpha are able to synergize with different cytotoxic drugs in increasing both tumor cytotoxicity or cytostasis in vitro and the therapeutic effect in animal models in vivo. The mechanism of such a synergy, however, has not been definitively worked out. Several clinical phase I and II trials have assessed the interactions of biologic response modifiers (mainly interferons and interleukin-2) with anticancer drugs, particularly in melanoma and renal cancer patients. Evidence of a therapeutic synergism is limited with most of the studies, indicating a lack of synergic or additive effects of the combination compared with single agents. Few phase III studies provided conflicting results. It is concluded that further studies on the combination of biologic response modifiers and chemotherapy both at preclinical and clinical levels are necessary to establish the possible synergistic or additive therapeutic effect of such a therapeutic approach.     

Bcl-2 antisense therapy in B-cell malignant proliferative disorders

Opinion statement Overexpression of Bcl-2 oncogene has been clinically associated with an aggressive clinical course, chemotherapy and radiotherapy resistance, and poor survival in patients with malignant B-cell disorders. Patients with relapsed or refractory chronic lymphocytic leukemia, multiple myeloma, or non-Hodgkin’s lymphoma have limited therapeutic options. Preclinical and early clinical data have shown that Bcl-2 oncoprotein can be decreased by Bcl-2 antisense therapy. Also, downregulation of Bcl-2 protein can result in reversal of chemotherapy resistance and improved antitumor activity of biologic agents. Various clinical trials are evaluating the role of targeting Bcl-2 as a mechanism to enhance the antitumor potential of chemotherapy and immunotherapy. Early results from these clinical studies are encouraging and confirm the proof of principle for antisense therapy. As current data mature, these trials will hopefully validate preliminary results and establish Bcl-2 antisense as an important addition to the current armamentarium used in the treatment of patients with B-cell neoplasms.v     

Antiemetics and its clinical evaluations]

Nausea and vomiting induced by anticancer agents are common problems associated with chemotherapy for cancer. Recent trials have examined a variety of antiemetics, representing several different classes of drugs. High dose metoclopramide provided the impetus for many of the current studies because of its effect against cisplatin induced vomiting. However, current regimens are not yet entirely effective in many patients receiving cisplatin or other highly emetogenic anticancer agents. A promising new class of antiemetics, 5-hydroxytryptamine receptor antagonists are undergoing clinical evaluations. Members of this class are easily and safely administered to patients receiving cisplatin or other emetogenic anticancer agents. These are highly active antiemetics, both prophylactic and interventional treatment. Lack of extrapyramidal reaction and other adverse effects associated with its use makes the drug a very attractive one. However, studies of antiemetics require consideration of methodologic issues that may not be of concern in trials of anticancer agents. The results of these studies can be affected by the patient population, the sample size, pharmacologic variables, the trial design, the method of analysis, etc. Recently, developments both in new-antiemetics and better ways of using the existing ones, lead us to cautious thought that nausea and vomiting due to cancer chemotherapy can be controlled substantially with benefit to the patients.     

Rationale for sequential tamoxifen and anticancer drugs in adjuvant setting for patients with node- and receptor-positive breast cancer

Since the survival benefit of tamoxifen (TAM) combined with anticancer drugs in treating node- and receptor-positive breast cancer is small, appropriate treatment schedules and the rationale for the combination remains unclear. We examined the effect of estradiol (E2) on sensitivity to anticancer drugs to clarify the survival benefit of tamoxifen combined with anticancer drugs. We used the MTT assay to assess the effect of E2 on sensitivity to anticancer drugs in the E2 receptor-positive and -negative breast cancer cell lines, MCF-7 and MDA-MB-231, respectively. We assessed the expression of apoptosis-related proteins by Western blotting, and evaluated apoptosis using the TUNEL method. Serum levels of E2 were measured using an enzyme-labeled radioimmunoassay in patients with premenopausal breast cancer before and during treatment with tamoxifen. Estrogen administration decreased sensitivity in MCF-7 cells to the anticancer drugs, adriamycin (ADM), mitomycin C (MMC), and paclitaxel (TXL), evaluated as increases in the IC50 values for ADM (4.1-fold), MMC (1.9-fold) and TXL (13.0-fold), compared with those of each drug alone. Estradiol in MDA-MB-231 cells similarly increased the IC50 values for ADM (9.5-fold), MMC (15.6-fold), and TXL (2.4-fold). The decreased sensitivity to these anticancer drugs was associated with the attenuation of apoptosis. Estrogen dose-dependently increased the expression of Bcl-2 protein in MCF-7, but not in MDA-MB-231 cells, and suppressed the expression of Bax and cytochrome c induced by anticancer drugs in association with decreased apoptosis compared with the effect of each drug alone. Phosphorylation of the Bcl-2 protein induced by TXL was decreased in the presence of E2 in MCF-7 cells. Serum levels of E2 were increased in 5 patients without amenorrhea and in 1 patient with amenorrhea after treatment with TAM alone in adjuvant therapy, compared with levels before treatment. Estradiol decreased sensitivity to ADM, MMC, and TXL in MCF-7 and MDA-MB-231 breast cancer cells, and this was associated in part with an increase in the amount of Bcl-2 protein, and decreases in levels of Bax and cytochrome c leading to apoptosis. These results suggest that therapy with TAM and anticancer drugs should be sequentially scheduled with anticancer drugs followed by TAM in an adjuvant setting to treat patients with breast cancer for a potentially improved survival benefit.     

Bcl-2 antisense therapy in hematologic malignancies

PURPOSE OF REVIEW: Overexpression of the Bcl-2 oncoprotein is noted in various malignant disorders. In patients with hematologic malignancies, increased production of the Bcl-2 oncoprotein is associated with chemotherapy resistance, aggressive clinical course, and poor survival. Bcl-2 is an important molecular target. Downregulating Bcl-2 can potentially reverse inherent tumor resistance to, and possibly improve response to therapy. This review focuses on the preclinical data, as well as the current clinical information available on oblimersen, a novel antisense approach targeting Bcl-2 in malignant hematologic disorders. RECENT FINDINGS: Early clinical trials have shown single-agent activity of oblimersen in patients with chronic lymphocytic leukemia and non-Hodgkin lymphoma, and thus, provide proof of principle for antisense therapy. Phase I and phase II studies using oblimersen in combination with conventional chemotherapy have shown encouraging results in patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, and acute myeloid leukemia. Phase III studies in patients with multiple myeloma and chronic lymphocytic leukemia have completed accrual and results are awaited. SUMMARY: Bcl-2 is a clinically meaningful target in patients with hematologic malignancies. Downregulation of the Bcl-2 oncoprotein can be achieved with oblimersen (antisense molecule specific for Bcl-2). Early clinical results suggest a possible role of this antisense approach in targeting Bcl-2. Ongoing clinical trials will establish the clinical utility of oblimersen in patients with hematologic malignancies.     

Bcl-2 Family of Proteins as Therapeutic Targets in Genitourinary Neoplasms

IntroductionOverexpression of antiapoptotic B-cell lymphoma (Bcl-2) proteins confers the dysregulation of apoptosis and results in drug resistance in a variety of cancers, including those of the genitourinary tract. Inhibitors that target prosurvival Bcl-2 proteins are in preclinical and clinical development. The objective of this review is to assess the involvement of Bcl-2 proteins as well as the preclinical and clinical activity of Bcl-2 inhibitors under evaluation for genitourinary neoplasms.Materials and MethodsPubMed was used with both medical subject heading terms and free search to identify the relevant literature. Information on clinical trials was obtained using http://Clincaltrials.gov, EU Clinical Trials Register, and meeting abstracts of the American Society of Clinical Oncology.ResultsTo date, 2 Bcl-2 inhibitors have been evaluated in clinical trials for genitourinary tumors (oblimersen and AT-101 (R-(–)-gossypol)). Both agents demonstrated some success in early stages of development, but their clinical activity did not meet expectations. Preclinical studies are under way for other Bcl-2 inhibitors including ABT-737, HA14-1, and Bcl-2 homology 3 inhibitors.ConclusionAntiapoptotic Bcl-2 proteins are potential molecular targets in genitourinary cancers. Bcl-2 inhibitors might be effective as single agents or in combination with conventional therapies. However, the biology of the Bcl-2 family in genitourinary cancers remains poorly understood and robust preclinical studies are needed to inform clinical development. Such studies should aim to identify: (1) pharmacodynamic markers that could help guide patient selection for treatment with Bcl-2 inhibitors, and (2) optimal combinations of Bcl-2 inhibitors with other anticancer agents for future clinical investigation.     

Current status and perspectives in cancer chemotherapy

New anticancer drugs with novel structures including paclitaxel, docetaxel, ilinotecan and gemcitabine have shown significant activity against various solid tumors in phase II trials. Phase II trials of combination regimens containing these drugs are currently in progress. Some combinations such as paclitaxel plus cisplatin in ovarian cancer have shown superiority over the past standard regimen. Not surprisingly, several analogues of these drugs have been developed and currently phase II trials are in progress. ET-743 may has some hope to become the first anticancer drug from a marine product. Oral chemotherapy is useful for treatment of outpatients. A combination regimen of UFT plus oral leucovorin has shown equivalent activity to 5-fluorouracil and leucovorin in advanced colorectal cancer, and capecitabine has shown superior activity and less toxicity than 5-fluorouracil and leucovorin in advanced colorectal cancer. Monoclonal antibody therapy has been successful in patients with breast cancer overexpressing HER2 and in patients with B-cell lymphoma. Currently clinical trials of 17-1A for colorectal cancer and HUM195 for acute myelogeneous leukemia are in progress. Recently presented results of angiogenesis inhibitors are discussed.     

Combination of antiangiogenic therapy with other anticancer therapies: results, challenges, and open questions.

Angiogenesis is necessary for tumor growth. Drug discovery efforts have identified several potential therapeutic targets on endothelial cells and selective inhibitors capable of slowing tumor growth or producing tumor regression by blocking angiogenesis in in vivo tumor models. Certain antiangiogenic therapeutics increase the activity of cytotoxic anticancer treatments in preclinical models. More than 75 antiangiogenic compounds have entered clinical trials. Most of the early clinical testing was conducted in patients with advanced disease resistant to standard therapies. Several phase III trials have been undertaken to compare the efficacy of standard chemotherapy versus the same in combination with an experimental angiogenesis inhibitor. Preliminary results of the clinical studies suggest that single-agent antiangiogenic therapy is poorly active in advanced tumors. Although some of the results of combination trials are controversial, recent positive outcomes with an antivascular endothelial growth factor antibody combined with chemotherapy as front-line therapy of metastatic colorectal cancer have renewed enthusiasm for this therapeutic strategy. This article presents an overview of experimental and clinical studies of combined therapy with antiangiogenic agents and highlights the challenges related to the appropriate strategies for selection of the patients, study design, and choice of proper end points for preclinical and clinical studies using these agents.     

Bcl-2 and apoptosis in chronic lymphocytic leukemia

Opinion statement The Bcl-2 family of pro- and antiapoptotic proteins are key regulators of the apoptosis cascade and the mitochondrial-mediated pathway of caspase activation. Of this family, Bcl-2 was the first identified and remains the best characterized. Aberrant expression of Bcl-2 is common in chronic lymphocytic leukemia (CLL) and is associated with poor response to chemotherapy and decreased overall survival. Bcl-2 is an attractive target for novel therapeutic agents. Antisense oligonucleotides directed against Bcl-2 are effective in vitro and are being evaluated in clinical trials in CLL. Small molecule Bcl-2 inhibitors are in preclinical development and should be ready for clinical evaluation in the next few years. Strategies that induce apoptosis and bypass Bcl-2 may also be therapeutically useful in CLL. Thus, over the next decade, one can envision incorporating measurements of apoptotic proteins such as Bcl-2 into the risk assessment and treatment algorithms for individual patients. In addition, we anticipate that in the next decade, rationally designed therapies targeting specific molecular defects in the malignant CLL lymphocytes will be introduced into the clinic.     

Preclinical evaluation of antisense bcl-2 as a chemosensitizer for patients with gastric carcinoma

BACKGROUND: Because bcl-2 is a critical factor for anticancer drug-induced apoptosis, the authors conducted a preclinical evaluation of antisense (AS) bcl-2 as an enhancer of the chemotherapeutic effect in the treatment of patietns with gastric carcinoma. METHODS: AS bcl-2 was used with 18-mer phosphorothiated oligonucleotides in the MKN-45 gastric carcinoma cell line. Drug sensitivity in vitro was evaluated using the methyl-thiazoldiphenyl tetrazolium assay, and antitumor effects in vivo were evaluated using the nude mouse xenograft. Apoptosis was determined with the terminal deoxyuridine triphosphate nick-end labeling assay. AS bcl-2 in vitro was treated with lipofectin, whereas it was administered intraperitoneally for 6 consecutive days twice every 2 weeks in vivo. Anticancer drugs were administered intraperitoneally four times per week. RESULTS: bcl-2 was down-regulated to 60% of its initial value after treatment with 1.0 muM AS bcl-2 compared with the controls of random and mismatched oligonucleotides. Drug sensitivity to doxorubicin, cisplatin, and paclitaxel (TXL) was increased 3-4-fold when used in combination with AS bcl-2, which was determined with 50% inhibitory concentration values, compared with the control group. Increased drug sensitivity was associated with apoptosis, which increased in Bax and poly-adenosine diphosphate (ADP-ribose) polymerase and decreased in phosphorylated Akt (pAkt). The antitumor effect of cisplatin and TXL in vivo was enhanced significantly in combination with AS bcl-2. Down-regulation of bcl-2 was observed on Day 4 after the treatment with AS bcl-2. CONCLUSIONS: Combination treatment with AS bcl-2 and anticancer drugs, including cisplatin and TXL, may be a new strategy for enhancing chemotherapeutic effects in the treatment of gastric carcinoma.     

Newly emerging standard chemotherapies for gastric cancer and clinical potential in elderly patients

With the increase in average life expectancy, the rate of occurrence of gastric cancer in elderly patients is also rising. While many clinical trials have been conducted to examine the effect of chemotherapy treatment on gastric cancer, age limits for eligible subjects have prevented the establishment of standards for chemotherapy in elderly patients with gastric cancer. As of March 2009, evidence-based standard chemotherapy regimens were established. In the Western world, debates centered on the ECF (Epirubicin/cisplatin/5-FU) or DCF (Docetaxel/cisplatin/5-FU) regimens based on the phase III randomized controlled trial at the Royal Marsden Hospital (RMH) or the V325 study, respectively. The JCOG9912 and SPIRITS trials emerged from Japan indicating attractive regimens that include S-1 for advanced gastric cancer patients. Using these active anticancer drugs, the trials that studied the efficacy of adjuvant therapies or surgical approaches, such as the Int-116/MAGIC/ACTS-GC trials, have actually succeeded in demonstrating the benefits of adjuvant therapies in gastric cancer patients. For cases of gastric cancer in elderly patients, treatment policies should consider these studies while analyzing not only the therapeutic effects but also drug toxicity, individual general health conditions, and social factors to select treatments that emphasize quality of life.     

Prognostic value of Bcl-2 in invasive breast cancer receiving chemotherapy and endocrine therapy

Apoptosis induced by anticancer agents is a mechanism of treatment activity, overexpression of antiapoptotic genes could produce drug resistant tumors. We have demonstrated that the susceptibility of Bcl-2-negative tumors to a series of anticancer drugs was significantly higher than that of Bcl-2-positive tumors. The purpose of this study was to examine if negative Bcl-2 expression has treatment benefit in breast cancer patients received chemotherapy and endocrine treatment. A cohort of 147 Japanese women with invasive ductal carcinoma was studied. All the patients received postoperative adjuvant therapy consisting of combination chemotherapy with cyclophosphamide, epirubicin, and fluorouracil, and tamoxifen therapy. The expression of Bcl-2, estrogen receptor (ER) and MIB-1 was evaluated in breast cancer surgical specimens. Bcl-2 immunostaining was inversely correlated with increasing histologic grade (p=0.0095) and MIB-1 (p=0.0128). Furthermore, a positive correlation between Bcl-2 and ER was observed (p<0.0001). Unexpectedly, survival curves determined by the Kaplan-Meier method and univariate analysis demonstrated that Bcl-2-positivity was associated with favorable prognosis (p=0.0430). Cox proportional hazard model demonstrated that positive Bcl-2 expression still has favorable survival (p=0.0242) after consideration of other prognostic factors. Our results imply that Bcl-2 is a significant favorable prognostic factor for breast cancer with chemotherapy and endocrine therapy.     

CIGB-300: A peptide-based drug that impairs the Protein Kinase CK2-mediated phosphorylation

Protein kinase CK2, formerly referred to as casein kinase II, is a serine/threonine kinase often found overexpressed in solid tumors and hematologic malignancies that phosphorylates many substrates integral to the hallmarks of cancer. CK2 has emerged as a viable oncology target having been experimentally validated with different kinase inhibitors, including small molecule ATP-competitors, synthetic peptides, and antisense oligonucleotides. To date only two CK2 inhibitors, CIGB-300 and CX-4945, have entered the clinic in phase 1-2 trials. This review provides information on CIGB-300, a cell-permeable cyclic peptide that inhibits CK2-mediated phosphorylation by targeting the substrate phosphoacceptor domain. We review data that support the concept of CK2 as an anticancer target, address the mechanism of action, and summarize preclinical studies showing antiangiogenic and antimetastatic effects as well as synergism with anticancer drugs in preclinical models. We also summarize early clinical research (phase 1/2 trials) of CIGB-300 in cervical cancer, including data in combination with chemoradiotherapy. The clinical data demonstrate the safety, tolerability, and clinical effects of intratumoral injections of CIGB-300 and provide the foundation for future phase 3 clinical trials in locally advanced cervical cancer in combination with standard chemoradiotherapy.