Approach For Colorectal Cancer Research Articles

Genotype-based therapeutic approach for colorectal cancer: state of the art and future perspectives

Background: There is a considerable need to increase efforts in maximizing clinical outcome in the treatment of colorectal cancer, and the identification of genetic factors underlying drug response seems to be one of the most promising areas in this research field. Methods: Clinical trials and pharmacogenetic association studies were reviewed to offer an overview of the most commonly reported polymorphisms in candidate genes critically involved in the response to the chemotherapeutics used at present in the management of colorectal cancer. Results: Several studies investigating the association between genotype and therapeutic results show contrasting data, thus determining increasing uncertainty in the identification of reliable predictive genetic markers of drug response. However, some of the genetic variations identified in genes encoding thymidylate synthase, dihydropyrimidine dehydrogenase, glutathione S-transferase pi, and uridine diphosphate glucosyltransferase 1A1 seem to be promising predictors of drug efficacy and/or toxicity. Conclusion: Additional investigation is needed to validate fully the clinical relevance of individual genetic differences in the variability of drug response. It is hoped that this knowledge base will offer, in the not too distant future, the opportunity to overcome the empirical trial-and-error method in favor of therapeutic drug optimization based on individual genetic make-up.

Assessment of Colorectal Cancer Prognosis Through Nuclear Morphometry

Due to the fact that different biological parameters play a key role in colonic malignant behavior, with nuclear morphometry being a prognostic marker in many malignancies, then predictive approaches in colorectal cancer (CRC) carried out on histologically well-defined groups may prevent interpretative errors. Subsequently, in the present study, CRC patients were screened according to the morphometric features of tumor cell nuclei, using an accurate histotechnical approach, to analyze their clinical evolution according to Dukes' stratification. A total of 66 cases were grouped according to Dukes' classification (5 y of follow-up). The perimeter, nuclear area, and shape factor of 50 interphase carcinoma nuclei were recorded through microphotographs obtained from each subject. Nuclei boundaries were drawn by an electronic pencil and examined by a computerized system. Data were submitted to a variance analysis, and a multi-regression model compared results. The sample was made up of 44 males (66.67%) and 22 females (33.33%) aged 59.7 +/- 6 y old. Forty-nine patients (74.24%) were classified as stage B, and 17 (25.76%) as stage C. Nuclear homogeneity was confirmed by analysis of variance. The nuclear parameters were (mean +/- SD): area (3.17 +/- 1.74), perimeter (6.72 +/- 1.83), and shape factor (0.82 +/- 0.03). A multiple logistic regression model showed that stage C subjects had a higher risk of developing a worse clinical evolution than those at stage B (P < 0.02), independent of sex and age. Dukes' classification remains the best predictor of evolution. Although nucleomorphometric suitability is still controversial, this technique has become an additional tool to establish CRC prognosis.

Laparoscopic gastrectomy: advances enable wide clinical application

The current trend is toward laparoscopic gastrectomy. Although no level 1 randomized evidence or cost-effective analysis exists to show the superiority of laparoscopic gastrectomy over open gastrectomy, the indications and use of laparoscopic gastrectomy in clinical practice have been expanded beyond the carefully selected older patients described in the report by Singh et al. [1] in a recent issue of this journal. A current published report shows the clinical use of laparoscopic gastrectomy for early-stage gastric cancer with a trend also toward locally advanced carcinoma [2] and for carriers of CDH1 mutations to prevent hereditary diffuse gastric cancer (HDGC) syndrome [3, 4]. As laparoscopic gastrectomy currently is being applied in an environment of strong competition within various countries and among specialized institutions worldwide to attract patients, what are the benefits and risks of the laparoscopic approach? Laparoscopic gastrectomy is unlikely to improve survival or cure rates for gastric cancer patients, but evidence supports its superiority over open gastrectomy in improving quality of life (QOL). Singh et al. [1] report on a series of 20 elderly patients who underwent laparoscopic gastrectomy procedures. These patients were at risk for high morbidity and mortality with the use of conventional gastric surgery. There were no perioperative deaths. Four patients experienced significant complications, with two patients requiring reoperation. Extended D2 lymphadenectomy should be considered for patients with gastric cancer. Lee et al. [2] recently reported on laparoscopically assisted distal gastrectomy (LADG) with extended D2 lymphadenectomy for patients with early-stages gastric cancer. Two surgeons performed the procedure for 64 patients over an 8-month period, with a postoperative complication rate of only 3% and no deaths. The high-volume surgeons who performed the procedures are the key for these excellent results. The D2 lymphadenectomy compliance rate for the LADG was similar to that for open gastrectomy. Should D2 gastrectomy be the standard procedure for localized gastric cancer? Despite a long-term debate in the West [5–8], D2 surgery is a standard approach in Eastern countries [9, 10]. High cure rates have been reported with D2 surgery for early-stage gastric malignant tumors [9, 11, 12], but there still is no level 1 evidence in favor of D2 surgery [13]. The current status of the treatment for localized gastric cancer [14] includes either D2 surgery performed by experienced surgeons [15, 16] or, if this criterion is not met, limited D1 surgery plus chemoradiotherapy [17, 18]. With the randomized evidence for the safety and efficacy of the laparoscopic approach for colorectal cancer, laparoscopic gastrectomy has been growing rapidly. The advantages of laparoscopic over open gastrectomy include quicker return of gastrointestinal function, faster ambulation, and earlier discharge from the hospital, although the operating time is longer than for open gastrectomy [19]. Another important field of laparoscopic approach is the primary prevention of gastric cancer for individuals with familial susceptibility to the disease. This patient-friendly technique may increase the number of health individuals who are carriers of germ-line mutations in the CDH1 (Ecadherin) gene. For these carriers, who face a very high T. Liakakos (&) Third Surgical Department, University of Athens, Athens, Greece e-mail: theodlia@otenet.gr

The immunology of colorectal cancer

Despite the fact that the vast majority of differentiated colorectal cancers express tumour-associated antigens (TAA's) such as Carcinoembryonic antigen (CEA) and Ep-CAM, the immune response particularly in advanced disease is often attenuated. This may result from clonal immunocyte energy to oncofetal antigens normally expressed during cell development, immune complex disease where the TAA is repeatedly shed into the circulation and tumour-induced impairments in T cell receptor recognition and stimulation. Commonly used monoclonal anti-TAA antibody therapy is also hampered by human anti-xenogeneic antibody production and by the physical distribution of the antibody into the center of tumour deposits where blood flow is limited and where tumour neovasculature is hyperpermeable. Moreover, animal models of colorectal cancer should be assessed carefully since CEA is not normally expressed, requiring the transduction of CEA cDNA into tumour xenografts or the creation of transgenic species where the mechanisms of tumour rejection are still governed by non-human antigenic histoincompatibility. All of this has resulted in the generation of novel immune constructs designed to enhance the inherent immunogenicity of colorectal cancer, using antigenic viral genomes or cytokine transduction methodology as well as the ex vivo stimulation of dendritic antigen-presenting cells or autologous tumour-infiltrating lymphocytes. Even these powerful strategies may be foiled by intratumoural mechanisms which result in excessive apoptosis of infused cells even when they have been shown in vitro to be immunocompetent and tumour-specific. This review discusses these immune approaches in colorectal cancer and their inherent limitations.

Microvessels in oropharyngeal squamous carcinomas

Despite the fact that the vast majority of differentiated colorectal cancers express tumour-associated antigens (TAA's) such as Carcinoembryonic antigen (CEA) and Ep-CAM, the immune response particularly in advanced disease is often attenuated. This may result from clonal immunocyte energy to oncofetal antigens normally expressed during cell development, immune complex disease where the TAA is repeatedly shed into the circulation and tumour-induced impairments in T cell receptor recognition and stimulation. Commonly used monoclonal anti-TAA antibody therapy is also hampered by human anti-xenogeneic antibody production and by the physical distribution of the antibody into the center of tumour deposits where blood flow is limited and where tumour neovasculature is hyperpermeable. Moreover, animal models of colorectal cancer should be assessed carefully since CEA is not normally expressed, requiring the transduction of CEA cDNA into tumour xenografts or the creation of transgenic species where the mechanisms of tumour rejection are still governed by non-human antigenic histoincompatibility. All of this has resulted in the generation of novel immune constructs designed to enhance the inherent immunogenicity of colorectal cancer, using antigenic viral genomes or cytokine transduction methodology as well as the ex vivo stimulation of dendritic antigen-presenting cells or autologous tumour-infiltrating lymphocytes. Even these powerful strategies may be foiled by intratumoural mechanisms which result in excessive apoptosis of infused cells even when they have been shown in vitro to be immunocompetent and tumour-specific. This review discusses these immune approaches in colorectal cancer and their inherent limitations.

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The peripheral benzodiazepine receptor (PBR) has been implicated in growth control of various tumour models. Although colorectal cancers were found to overexpress PBR, the functional role of PBR in colorectal cancer growth has not been addressed to date. Using primary cell cultures of human colorectal cancers and the human colorectal carcinoma cell lines HT29, LS174T, and Colo320 DM we studied the involvement of PBR in the growth control and apoptosis of colorectal cancers. Both mRNA and protein expression of PBR were detected by RT-PCR and flow cytometry. Using confocal laser scanning microscopy and immunohistochemistry the PBR was localized in the mitochondria. The specific PBR ligands FGIN-1-27, PK 11195, or Ro5-4864 inhibited cell proliferation dose-dependently. FGIN-1-27 decreased the mitochondrial membrane potential, which indicates an early event in apoptosis. Furthermore, FGIN-1-27, PK 11195 or Ro5-4864 increased caspase-3 activity. In addition to their apoptosis-inducing effects, PBR ligands induced cell cycle arrest in the G1/G0-phase. Thus, our data demonstrate a functional involvement of PBR in colorectal cancer growth and qualify the PBR as a possible target for innovative therapeutic approaches in colorectal cancer. © 2001 Cancer Research Campaign http://www.bjcancer.com

Specific ligands of the peripheral benzodiazepine receptor induce apoptosis and cell cycle arrest in human colorectal cancer cells.

The peripheral benzodiazepine receptor (PBR) has been implicated in growth control of various tumour models. Although colorectal cancers were found to overexpress PBR, the functional role of PBR in colorectal cancer growth has not been addressed to date. Using primary cell cultures of human colorectal cancers and the human colorectal carcinoma cell lines HT29, LS174T, and Colo320 DM we studied the involvement of PBR in the growth control and apoptosis of colorectal cancers. Both mRNA and protein expression of PBR were detected by RT-PCR and flow cytometry. Using confocal laser scanning microscopy and immunohistochemistry the PBR was localized in the mitochondria. The specific PBR ligands FGIN-1-27, PK 11195, or Ro5-4864 inhibited cell proliferation dose-dependently. FGIN-1-27 decreased the mitochondrial membrane potential, which indicates an early event in apoptosis. Furthermore, FGIN-1-27, PK 11195 or Ro5-4864 increased caspase-3 activity. In addition to their apoptosis-inducing effects, PBR ligands induced cell cycle arrest in the G 1/G 0-phase. Thus, our data demonstrate a functional involvement of PBR in colorectal cancer growth and qualify the PBR as a possible target for innovative therapeutic approaches in colorectal cancer. © 2001 Cancer Research Campaign http://www.bjcancer.com

New chemotherapy approaches in colorectal cancer.

Colorectal cancer is one of the leading causes of cancer deaths in the Western world, with approximately 50% of all patients dying from metastatic disease. Until recently, therapeutic options for advanced colorectal cancer were mainly confined to chemotherapy with 5-fluorouracil in various schedules, with or without biochemical modulation with leucovorin. The development of new cytotoxic drugs with substantial activity in this tumor during the past 2 years has dramatically changed treatment strategies and therapeutic goals in metastatic colorectal cancer and has introduced neoadjuvant chemotherapy followed by secondary surgery with the intent of long-term survival. Among these new drugs, oral fluoropyrimidines (tegafur/uracil and capecitabine), irinotecan, and oxaliplatin have already established themselves as part of various treatment approaches. Other novel therapeutics including agents designed to act on molecular targets already show promising activity and will become part of combination protocols with current standard chemotherapy.

Policy emanating from epidemiologic data: what is the proper forum?

While some of my research over the years has had no clear application to disease prevention, another portion has had direct implications for clinical and public health decisions. Not surprisingly, the latter type of research has been (and continues to be) the most rewarding. Mining cancer surveillance data to explore demographic correlates of cancer incidence,1,2 for example, gives me some satisfaction, but not nearly as much as being able to document an effect of certain hormonal regimens on the risk of endometrial cancer.3,4 Or as much as estimat? ing the potential reduction in mortality from colorectal or prostate cancer with screening.5,6 However, having identified a way of using hormones that appears to raise the risk of endometrial cancer, or a screening approach for colorectal cancer that seems to be effective, my articles reporting these findings somehow never go on to recommend avoidance of those hormones, or to recommend establishment of a screen? ing program. What would it take for me to include a policy recommendation in an article that reports re? search results? The short answer to the above question: A lot. The longer answer: All of the following conditions would have to be fulfilled.

Biological therapy: approaches in colorectal cancer. Strategies to enhance carcinoembryonic antigen (CEA) as an immunogenic target.

Biological therapy: approaches in colorectal cancer. Strategies to enhance carcinoembryonic antigen (CEA) as an immunogenic target.