Chemotherapeutic Management Research Articles

Regulation of mitochondrial metabolism: yet another facet in the biology of the oncoprotein Bcl-2

The Bcl-2 (Bcl is B-cell lymphocytic-leukaemia proto-oncogene) family comprises two groups of proteins with distinct functional biology in cell-fate signalling. Bcl-2 protein was the first member to be discovered and associated with drug resistance in human lymphomas. Since then a host of other proteins such as Bcl-xL, Bcl-2A1 and Mcl-1 with similar anti-apoptotic functions have been identified. In contrast, the pro-apoptotic Bcl-2 proteins contain prototypic effector proteins such as Bax and Bak, and the BH3 (Bcl-2 homology)-only proteins comprising Bak, Bid, Bim, Puma and Noxa. A complex interplay between the association of pro-apoptotic and anti-apoptotic proteins with each other determines the sensitivity of cancer cells to drug-induced apoptosis. The canonical functional of Bcl-2 in terms of apoptosis inhibition is its ability to prevent mitochondrial permeabilization via inhibiting the translocation and oligomerization of pro-apoptotic proteins such as Bax; however, more recent evidence points to a novel mechanism of the anti-apoptotic activity of Bcl-2. Overexpression of Bcl-2 increases mitochondrial oxygen consumption and in doing so generates a slight pro-oxidant intracellular milieu, which promotes genomic instability and blocks death signalling. However, in the wake of overt oxidative stress, Bcl-2 regulates cellular redox status thereby preventing excessive build-up of ROS (reactive oxygen species), which is detrimental to cells and tissues. Taken together, the canonical and non-canonical activities of Bcl-2 imply a critical involvement of this protein in the processes of tumour initiation and progression. In the present paper we review these functionally distinct outcomes of Bcl-2 expression with implications for the chemotherapeutic management of cancers.

Second generation benzofuranone ring substituted noscapine analogs: Synthesis and biological evaluation

Microtubules, composed of α/β tubulin heterodimers, represent a validated target for cancer chemotherapy. Thus, tubulin- and microtubule-binding antimitotic drugs such as taxanes and vincas are widely employed for the chemotherapeutic management of various malignancies. Although quite successful in the clinic, these drugs are associated with severe toxicity and drug resistance problems. Noscapinoids represent an emerging class of microtubule-modulating anticancer agents based upon the parent molecule noscapine, a naturally occurring non-toxic cough-suppressant opium alkaloid. Here we report in silico molecular modeling, chemical synthesis and biological evaluation of novel analogs derived by modification at position-7 of the benzofuranone ring system of noscapine. The synthesized analogs were evaluated for their tubulin polymerization activity and their biological activity was examined by their antiproliferative potential using representative cancer cell lines from varying tissue-origin [A549 (lung), CEM (lymphoma), MIA PaCa-2 (pancreatic), MCF-7 (breast) and PC-3 (prostate)]. Cell-cycle studies were performed to explore their ability to halt the cell-cycle and induce subsequent apoptosis. The varying biological activity of these analogs that differ in the nature and bulk of substituent at position-7 was rationalized utilizing predictive in silico molecular modeling.

Drugs for the treatment of neuroendocrine tumours

Neuroendocrine tumours are heterogeneous and rare malignancies arising from endocrine cells located in various anatomical locations. Neuroendocrine tumours can be functional and may produce a wide variety of mediators, however, the majority of neuroendocrine tumours do not produce biologically active hormones (non-functioning tumours). On the basis of their pathological and biological characteristics they can be well differentiated as low malignant and poorly differentiated highly malignant tumours. In the case of the advanced low malignant tumours the application of somatostatin analogues not only may control symptoms but they also have direct anti-tumour effect. The use of higher doses of somatostatin analogues or new subtype selective agonists, and chimeric or pan-somatostatin analogues will probably improve the clinical management of the patients who fail to respond to standard somatostatin analogue treatment. Data show that somatostatin analogues and interferon have a synergistic effect. The currently used chemotherapy in progressive neuroendocrine tumors is mainly devoted to poorly differentiated tumours, but also to well differentiated carcinomas which are either not eligible or resistant to other therapies. However, the new anti-tumoural agents, could eventually replace these old recipes in the near future. Clinical trials show that telozomide with capecitabine result in more favorable toxic profile and higher and longer response rate in the case of well-differentiated tumours. Targeted therapy became a new possibility in neuroendocrine tumours too. The monoclonal antibody bevacizumab, which affects the vascular endothelial growth factor receptors, has beneficial effects both in monotherapies and in combination with somatostatin analogues or with oxaliplatine and capecitabine. Recently, the low molecular multikinase inhibitor, sunitinib has demonstrated efficacy in pancreas neuroendocrine tumors, which was proven in a phase 3 trial. The mammalian target of the rapamycin inhibitor everolimus, currently investigated in phase 3 trials, was also efficient in the same subtype. Further trials are needed to determine that in the case of other types of neuroendocrine tumours which targeted therapy could be efficient. Radioisotope-labeled peptide receptor therapy with131I-MIBG,90Y-DOTA-TOC or177Lu-DOTA-TOC may offer a highly effective option for patients with progressive and advanced stage of neuroendocrine tumours. The purpose of this review is to review and analyze data available regarding contemporary chemotherapeutic management of neuroendocrine tumours in order to determine which therapy should be applied in the therapeutic arsenal. Orv. Hetil., 2011, 152, 379–391.

Phase IIb randomized trial of adjunct immunotherapy in patients with first-diagnosed tuberculosis, relapsed and multi-drug-resistant (MDR) TB

Placebo-controlled, randomized, phase 2b trial was conducted in 34 adults comprising 18 first-diagnosed (52.9%), 6 relapsed (17.6%), and 10 MDR-TB (29.4%) cases to investigate the safety and efficacy of an oral immune adjunct (V5). The immunotherapy (N = 24) and placebo (N = 10) arms received once-daily tablet of V5 or placebo for one month in addition to conventional anti-TB therapy (ATT) administered under directly observed therapy (DOT).The enlarged liver, total bilirubin, erythrocyte sedimentation rate, lymphocyte and leukocyte counts improved significantly in V5 recipients (P = 0.002; 0.03; 8.3E-007; 2.8E-005; and 0.002) but remained statistically unchanged in the placebo group (P = 0.68; 0.96; 0.61; 0.91; and 0.43 respectively). The changes in hemoglobin and ALT levels in both treatment arms were not significant. The body weight increased in all V5-treated patients by an average 3.5 ± 1.8 kg (P = 2.3E-009), while 6 out of 10 patients on placebo gained mean 0.9 ± 0.9 kg (P = 0.01). Mycobacterial clearance in sputum smears was observed in 78.3% and 0% of patients on V5 and placebo (P = 0.009). The conversion rate in V5-receiving subjects with MDR-TB (87.5%) seemed to be higher than in first-diagnosed TB (61.5%) but the difference was not significant (P = 0.62). Scoring of sputum bacillary load (range 3-0) at baseline and post-treatment revealed score reduction in 23 out of 24 (95.8%) V5 recipients (from mean/median 2.2/3 to 0.3/0; P = 6E-010) but only in 1 out of 10 (10%) patients on placebo (1.9/1.5 vs. 1.8/1; P = 0.34). No adverse effects or TB reactivation were seen at any time during follow-up. V5 is safe as an immune adjunct to chemotherapeutic management of TB and can shorten substantially the duration of treatment.

Fifth Alon Dembo Memorial Workshop: Case 3

OVO5/EORTC 55855, a study punitively refuting the value of CA-125 in the follow-up of ovarian cancer patients, has many deficiencies, including a heterogeneous ovarian cancer patient population, no control of initial treatment regimens, and no control of subsequent surgery or chemotherapeutic management for recurrence. Recent studies suggest a role for prompt surgery in selected cases of recurrent ovarian cancer with CA-125 elevations, a role for tamoxifen in managing rising CA-125 levels in patients without evidence of disease and the use of platinum doublets for treating recurrent platinum-sensitive disease, none of which were incorporated into OVo5/EORTC 55955. A patient with advanced stage ovarian cancer presenting with a CA-125 level of 2000 U/mL, who is initially treated with surgery followed by chemotherapy and has a normal CT scan and normal CA-125 at completion of her initial chemotherapy. This patient remains at a very high risk for recurrence. I would continue to monitor this patient with serial CA-125 levels to identify recurrent cancer and consider initiating treatment before it is clinically obvious.

Evidence-based chemotherapeutic management of potentially platinum-sensitive recurrent ovarian cancer

The results of several excellent Phase III randomized trials have helped establish appropriate management of patients with recurrent (potentially platinum sensitive) epithelial ovarian cancer. Data suggest that combination platinum-based chemotherapy is superior to single-agent platinum treatment, but the overall utility of a combination regimen versus the planned sequential administration of a platinum agent plus a second (or third) drug known to be biologically active in ovarian cancer remains to be determined. Future studies will hopefully define optimal treatment in this clinical setting more critically, including the role of therapy based on unique molecular profiles demonstrated in individual patients’ tumors.

Recent studies that influence the chemotherapeutic paradigm in the management of advanced ovarian cancer

Several recently reported evidence-based phase 3 trials that focus on the role of cytotoxic chemotherapy have the potential to strongly influence the care of women with advanced epithelial ovarian cancer. Particular areas of interest include: (a) neoadjuvant chemotherapy; (b) chemotherapy of recurrent platinum-sensitive ovarian cancer; and (c) the relevance of paclitaxel scheduling in the primary chemotherapeutic management of the malignancy. This report will briefly discuss the results of these studies and the potential implications of the findings for routine care of patients in these clinical settings.

O-Methylguanine-DNA Methyltransferase Immunoexpression in a Double Pituitary Adenoma

Double pituitary adenomas in surgical cases are rarely reported. The incidence in published surgical specimens ranges from 0.4% to 1.3%. We present a treatment dilemma of a double adenoma that had differential O-methylguanine-DNA methyltransferase (MGMT) reactivity. A 48-year-old man presented with acromegaly and a recurrent pituitary adenoma. He had elevated growth hormone (GH) and elevated insulin-like growth factor blood levels and hyperprolactinemia. Subtotal transsphenoidal resection was performed. Morphologic examination disclosed 2 histologically distinct tumors, including a GH adenoma and a prolactin adenoma. Immunohistochemistry revealed Ki-67 labeling indices of 1% and 2%, respectively. Of significant note was MGMT immunopositivity in the GH adenoma and lack of staining in the prolactin adenoma. This is the first clinical instance in which MGMT was assessed in double adenomas of the pituitary. The 2 tumors showed significant differences in reactivity that could impact chemotherapeutic management. The adenomas underwent recurrence, a feature that reflects their invasive nature and the possibility that chemotherapeutic intervention may be required in the future. Response to temozolomide use is anticipated with respect to the prolactin adenoma but would likely not benefit the GH cell adenoma of our patient.

Epithelial Ovarian Cancer: Focus on Targeted Therapy

Over the past five decades ovarian cancer has been of considerable interest to clinical cancer investigators due to the fact that it is among the most chemosensitive of all solid tumors [1]. Unfortunately, despite the advances in the chemotherapeutic management of this malignancy, the large majority of patients ultimately recur, progress, and ultimately die as a direct result of complications of the disease process. Thus, there is a critical need to find novel agents that may favorably impact the natural history of ovarian cancer. In recent years there has been a particular focus in the cancer research community to discover and subsequently develop clinically active drugs that are capable of specifically targeting biological pathways relevant in a particular tumor type (e.g., ovarian cancer) and even within a specific patient with that type of cancer (so-called, “personalized medicine”). Research in this arena in ovarian cancer remains in its early stages although a number of quite exciting developments have recently been reported in the peer-reviewed medical literature that suggest the realistic potential that this novel general class of drugs will soon become important components of “standard-of-care” in the management of this difficult malignancy. In this special issue, investigators from around the world have contributed to this literature by summarizing a number of important developments. In the papers of this special issue, an initial discussion of the role of surgical cytoreduction in the malignancy is followed by an overview of the management of recurrent ovarian cancer and the relevance of molecular abnormalities in specific ovarian cancer subtypes. This is followed by several excellent and comprehensive overviews of the possible roles of targeted therapy in ovarian cancer, the potential impact of antiangiogenic drugs, epidermal growth factor and PARP inhibitors, disruption of insulin and glucose pathways, and novel treatments affecting histone deacetylase and metastatic colonization, as well as an innovative approach to immunotherapy in the malignancy. The peer-reviewed papers in this special issue provide important insight into both the current and future management of epithelial ovarian cancer. M.Markman Jalid Sehouli Charles F. Levenback Dennis S. Chi

Development of sulforaphane-encapsulated microspheres for cancer epigenetic therapy

Even though conventional chemotherapeutic management of cancer has reduced morbidity and mortality to a great extent, virtually all chemotherapeutic agents cause damage to healthy cells, necessitating exploration of novel anticancer agents that exert their effects through an alternate mode of action. Objectives of our research were twofold. First, we explored the promising potential of histone deacetylase inhibitor sulforaphane for epigenetic therapy for cancer as this therapeutic approach aims to reverse aberrant epigenetic modifications that affect gene expression. In vitro cell culture studies performed using B16 and S91 melanoma cells showed that sulforaphane inhibited growth and proliferation of cancer cells by downregulating deacetylation enzymes. The second part of our research investigated polymeric drug delivery systems to increase therapeutic efficacy and to minimize potential side effects of R,S-sulforaphane. Albumin microspheres encapsulating sulforaphane were developed by spray drying. Microspheres were characterized for their morphology, size and zeta potential. Cell culture studies using melanoma cells and in vivo studies in melanoma tumor-bearing C57BL/6 mice demonstrated that albumin based polymeric delivery system was efficacious and has the potential to enhance the therapeutic effect and anticancer activity of sulforaphane.

Tuberculosis of the knee

Extrapulmonary manifestations of tuberculosis are reported in less than one in five cases with the knee affected in 8% after the spine and hip. We report a case of isolated highly erosive tuberculosis of the knee presenting in a previously fit Vietnamese woman. The difficulties of diagnosis, modalities of chemotherapeutic management, and surgical treatment are discussed.

An Update on the Use of Intraperitoneal Chemotherapy in the Management of Ovarian Cancer

The intraperitoneal delivery of chemotherapy as a strategy to manage epithelial ovarian cancer has been extensively examined in both the preclinical and clinical settings. Several randomized phase 3 trials have documented improved survival associated with regional versus systemic delivery of cisplatin in the primary chemotherapeutic management of small volume residual advanced ovarian cancer. Unfortunately, despite the existence of these evidence-based data, this management strategy remains underutilized. Future research efforts are mandated to develop regimens which improve the toxicity profile of this novel method of treatment while maintaining the documented enhanced efficacy of the approach.

Cytotoxic chemotherapeutic management of newly diagnosed glioblastoma multiforme

Cytotoxic chemotherapeutic management of newly diagnosed glioblastoma multiforme

Latest progress in treatment of gynaecological cancers

The present report gives the scope of relevant contributions focusing on the treatment of gynaecologic malignancies presented at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO) held from May 30 to June 3, 2008 in Chicago, Illinois. Some new data will directly influence the routine in gynaecologic oncology, while other data have to await their confirmation in ongoing studies until their clinical impact can be definitively evaluated. Regarding the radiotherapeutic adjuvant management of intermediate-high-risk endometrial cancers, the PORTEC-2 trial clearly demonstrated the non-inferiority of vaginal brachytherapy (VBT) as compared with external beam radiotherapy (EBRT) of the whole pelvis with regard to disease-free and overall survival and revealed a higher rate of treatment-related complications and side-effects for EBRT and consequently a higher quality of life in patients treated with VBT. In chemotherapeutic management of advanced and recurrent cervical cancer the four-armed GOG 204 trial demonstrated the best therapeutic index for the cisplatin-paclitaxel regimen. Hence, the authors advocated that this doublet should be used as a control arm in further GOG protocols investigating this setting. Fundamental changes in the routine first-line chemotherapy for ovarian cancer should be expected from the outcome of the phase III Japanese Gynecologic Oncology Group trial that revealed a survival benefit for weekly dose-dense administration of paclitaxel as compared with standard three-weekly carboplatin-paclitaxel.

Treatment of Recurrent Metastatic Colon Cancer in the Age of Modern Adjuvant Therapy

The treatment of patients with metastatic colon cancer has evolved tremendously over the past 10 years, with improved overall survival (OS) rates as a result of the advent of several important agents. Following the results of important adjuvant trials, the incorporation of oxaliplatin into the adjuvant setting has significantly increased the disease-free survival and OS rates in patients who undergo curative resection. However, still a significant number of patients will present with recurrent disease after being treated with oxaliplatin-containing chemotherapy regimens. Herein, we present approaches to the chemotherapeutic management of such patients with a review of the literature.

Cytotoxic chemotherapeutic management of newly diagnosed glioblastoma multiforme

The addition of temozolomide to radiation therapy is an option for patients with newly diagnosed glioblastoma (GBM) who are older than 70 years with a Karnofsky performance status (KPS) above 50. For patients 70 years or older with newly diagnosed GBM, temozolomide alone is a well tolerated alternative to radiation therapy and its benefit might be comparable to that obtained with radiation therapy alone. Radiation therapy followed by one of the nitrosoureas is recommended for those patients who cannot receive temozolomide.

The diagnosis and management of rectal cancer: expert discussion and recommendations derived from the 9th World Congress on Gastrointestinal Cancer, Barcelona, 2007

Knowledge of the biology and management of rectal cancer continues to improve. A multidisciplinary approach to a patient with rectal cancer by an experienced expert team is mandatory, to assure optimal diagnosis and staging, surgery, selection of the appropriate neo-adjuvant and adjuvant strategy and chemotherapeutic management. Moreover, optimal symptom management also requires a dedicated team of health care professionals. The introduction of total mesorectal excision has been associated with a decrease in the rate of local failure after surgery. High quality surgery and the achievement of pathological measures of quality are a prerequisite to adequate locoregional control. There are now randomized data in favour of chemoradiotherapy or short course radiotherapy in the preoperative setting. Preoperative chemoradiotherapy is more beneficial and has less toxicity for patients with resectable rectal cancer than postoperative chemoradiotherapy. Furthermore chemoradiotherapy leads also to downsizing of locally advanced rectal cancer. New strategies that decrease the likelihood of distant metastases after initial treatment need be developed with high priority. Those involved in the care for patients with rectal cancer should be encouraged to participate in well-designed clinical trials, to increase the evidence-based knowledge and to make further progress. Health care workers involved in the care of rectal cancer patients should be encouraged to adopt quality control processes leading to increased expertise.

Outcome After Radical Cystectomy With Limited or Extended Pelvic Lymph Node Dissection

We compared recurrence patterns and survival of patients with urothelial bladder cancer undergoing radical cystectomy who either had limited or extended pelvic lymph node dissection at 2 institutions between 1987 and 2000. Two consecutive series of patients treated with radical cystectomy and limited pelvic lymph node dissection (336; Cleveland Clinic) and extended pelvic lymph node dissection (322; University of Bern) were analyzed. All cases were staged N0M0 prior to radical cystectomy, and none were treated with neoadjuvant radiotherapy or chemotherapy. Patients with PTis/pT1 and pT4 disease were excluded from analysis. Pathological characteristics based on the 1997 TNM system and recurrence patterns were determined. The overall lymph node positive rate was 13% for patients with limited and 26% for those who had extended pelvic lymph node dissection. The 5-year recurrence-free survival of patients with lymph node positive disease was 7% for limited and 35% for extended pelvic lymph node dissection. The 5-year recurrence-free survival for pT2pN0 cases was 67% for limited and 77% for extended pelvic lymph node dissection, and the respective percentages for pT3pN0 cases were 23% and 57% (p <0.0001). The 5-year recurrence-free survival for pT2pN0-2 cases was 63% for limited and 71% for extended pelvic lymph node dissection, and for pT3pN0-2 cases the respective figures were 19% and 49% (p <0.0001). Incidence of local and systemic failure correlated closely with pathological stage for both series. Our data suggest that limited pelvic lymph node dissection is associated with suboptimal staging, poorer outcome for patients with node positive and node negative disease, and a higher rate of local progression. Extended pelvic lymph node dissection allows for more accurate staging and improved survival of patients with nonorgan confined and lymph node positive disease.

Development of antiangiogenic agents for ovarian cancer

Epithelial ovarian cancer (EOC) remains a major source of cancer morbidity and mortality, despite advances in surgical and chemotherapeutic management. The molecular pathways that control angiogenesis have been demonstrated to be key to the pathogenesis of EOC, and have been shown to have prognostic significance. Increased understanding of the pathways and molecules involved in angiogenesis has allowed the identification of a number of targets for antiangiogenic therapies and the development of a variety of antiangiogenic drugs. There is now significant preclinical evidence, and a growing body of clinical data, demonstrating promising results with antiangiogenic drugs in the treatment of EOC. Single-agent VEGF inhibitor response rates in pretreated patients of between 15 and 20% have been reported, with much higher response rates when used in combination with chemotherapeutic agents. These benefits, however, must be balanced with the toxicities associated with these drugs, particularly the more serious ones, such as gastrointestinal perforation. The results of ongoing and future randomized clinical trials will confirm if, and how, antiangiogenic therapies should be integrated into the routine management of EOC. However, critical issues, such as the relative importance of combination remission induction regimens and maintenance therapy, remain poorly defined.

Quality-of-Life Issues in the Management of Epithelial Ovarian Cancer

The importance of quality-of-life (QOL) measurements in cancer management is being increasingly appreciated. This is especially important in patients with advanced cancers. Over 80% of women with epithelial ovarian cancer (EOC) will present with disease outside the ovary as there are no accurate screening tests, and symptoms usually do not develop until EOC has spread. Standard treatment includes debulking surgery followed by chemotherapy to which most women will have a complete response but only a minority of women with advanced disease will be cured. Fortunately, advances in surgical and chemotherapeutic management have improved overall survival with 45% of women of all stages living 5 years or longer. EOC may in many cases be considered a "chronic cancer," which highlights the importance of QOL in management decisions. QOL may be affected by the disease itself as well as by surgical and chemotherapeutic treatments. Future studies of the care and treatment of EOC patients should include well-designed QOL evaluations.