Evidence for a new tumour suppressor gene locus for γ-radiation-induced thymic lymphoma located on the proximal part of mouse chromosome 18

Introduction

Five distinct thymic lymphoma suppressor regions have been identified on chromosome 4 (TLSR 1–5), and one on chromosome 19 (TLSR 8) through detection of loss of heterozygosity (LOH). Additionally, the involvement ofp16/INK4a, p15/INK4b, p73, Pten andFas had been reported in the most advanced stages of thymic lymphomagenesis.

Material and methods

Advanced thymic lymphomas (n=110) induced by gamma-irradiation in F1 hybrids from a BALB/c and C57BL/6J cross were analysed using micro-satellite markers on chromosomes 13, 14 and 18.

Results

Of the 110 tumours, 15 (14.5%) exhibited allelic losses on chromosome 18 atD18Mit21. Comparative analyses revealed significant differences (p<0.0001) for this marker and led us to define a new critical region of LOH on the proximal part of mouse chromosome 18, and named as TLSR9 according to the Mouse Nomenclature Committee.

Conclusions

The proposed TLSR9 region is orthologous with 18q11 region, which is affected in various types of human cancers (Mitelman Database of Chromosome Aberrations in cancer (2002) Mitelman F, Johansson B and Mertens F (eds), http://cgap.nci.nih.gov/Chromosomes/Mitelman), and containsN-cadherin as a possible candidate gene.     

Comparison of Two Diverse Populations, British Columbia, Canada, and Ardabil, Iran, Indicates Several Variables Associated with Gastric and Esophageal Cancer Survival

Background

Geographic variation and temporal trends in the epidemiology of esophageal and gastric cancers vary according to both tumor morphology and organ subsite. This study compares 1-year survival of gastric and esophageal cancers between two distinct populations: British Columbia (BC), Canada, and Ardabil, Iran.

Methods

Data for invasive primary esophageal and gastric cancer patients were obtained from the population-based cancer registries for BC and Ardabil. The relative survival rate was calculated using WHO Statistical Information System (WHOSIS) life-tables for each country. Chi-square and Fisher??s exact tests were used to compare survival differences between BC and Ardabil. T-tests, chi-square tests, and Fisher??s exact test were used to compare patient characteristics and tumor factors between the populations.

Results

The overall 1-year age-standardized relative survivals for gastric cancer were 48% and 21% in BC and Ardabil, respectively (p?p?Conclusion Findings of this study point to differences in disease characteristics and patient factors, not solely differences in healthcare systems, as being responsible for the survival difference in these populations.     

Oropharyngeal cancer related to Human Papilloma Virus: incidence and prognosis in Madrid,Spain

Purpose

To report the incidence of HPV-related oropharyngeal cancer (OC) in our region, and determine the influence of HPV status on survival among patients treated with chemoradiation (CRT).

Methods

A total of 102 patients with stage II–IV OC treated by CRT at four hospitals in Madrid, Spain were retrospectively reviewed. Immunohistochemistry analysis was performed to evaluate p16 expression in pretreatment tumor block samples obtained from these patients. HPV-positive and HPV-negative patients were compared to assess differences in overall survival (OS), loco-regional control and disease-free survival.

Results

Of the tumor samples evaluated, 26.7 % were p16 positive. HPV-positive patients were younger (median age, 56 vs 59 years; p = 0.052). No significant differences were observed in terms of tumor stage, gender, or smoking habit between HPV+ and HPV? patients. HPV+ patients showed a trend towards better OS (67.4, vs 49.7 %; hazard ratio, 0.55; p = 0.095).

Conclusions

Incidence of HPV-related OC in our region is similar to that reported in other regions in Europe, yet lower than in North America. We observed a trend for improved OS in patients with HPV+ oropharyngeal cancer.     

Rectal Versus Non-rectal Primary Signet Ring Cell Carcinoma of the Colorectum: a Retrospective Survival Analysis Controlled for Confounders

Purpose

Our objective was to compare the outcomes of rectal and non-rectal primary signet ring cell adenocarcinoma of the colorectum.

Methods

A retrospective survival analysis was performed using the Surveillance, Epidemiology, and End Results Program database between 2004 and 2009 on subjects who were diagnosed as having a primary signet ring cell carcinoma of the colorectum. Cox proportional hazard regression analysis controlled for confounders was used to assess overall survival comparing rectal and non-rectal cancers.

Results

Our population was composed of 1,484 patients: 200 affected by rectal cancer and 1,284 by non-rectal cancer. Unadjusted survival curves resulted to be almost superimposable (P?=?0.916). After controlling for age, gender, race, tumor stage, grade, and size, tumor location demonstrated a statistically significant impact on overall survival (P?=?0.032; 95 % confidence interval 0.640–0.980; hazard ratio 0.792).

Conclusion

On the basis of analysis of information from the SEER database, the signet ring cell carcinoma of the rectum was associated to a worse prognosis as compared to non-rectal cancer.     

Molecular and cytogenetic changes in multi-drug resistant cancer cells and their influence on new compounds testing

Purpose

Multi-drug resistance (MDR) is a major obstacle to successful cancer treatment. Therefore, in vitro models are necessary for the investigation of the phenotypic changes provoked by cytotoxic agents and more importantly for preclinical testing of new anticancer drugs.

Methods

We analyzed chromosomal, numerical, and structural changes after development of MDR, alterations in p53 and PTEN, single nucleotide polymorphisms (SNPs) in the mdr1 gene and corresponding protein expression of P-glycoprotein (P-gp) in three human MDR cancer cell lines: non-small cell lung carcinoma NCI-H460/R, colorectal carcinoma DLD1-TxR, and glioma U87-TxR. In addition, we explored how these molecular and phenotypic alterations influence the anticancer effect of new drugs.

Results

Cytogenetic analysis showed polyploidy reduction after development of MDR in U87-TxR. Losses of 6q in all resistant cancer cell lines and inactivation of p53 in U87-TxR and PTEN in DLD1-TxR were also revealed. Overexpression of P-gp was observed in all MDR cancer cell lines. We evaluated the anticancer activities and MDR reversal potential of Akt inhibitor GSK690693, Ras inhibitor Tipifarnib, and two P-gp inhibitors (jatrophane diterpenoids). Their effects vary due to the cell-type differences, existence of MDR phenotype, presence of mdr1 SNP, and tumor suppressors’ alterations. Tipifarnib and jatrophane diterpenoids significantly sensitized MDR cancer cells to paclitaxel.

Conclusion

In conclusion, investigated MDR cancer cells obtained new molecular and cytogenetic characteristics that may serve as potential clinical prognostic markers. In addition, these MDR cancer cell lines present a valuable model for preclinical evaluation of new anticancer agents.     

Molecular profiling of patient-derived breast cancer xenografts

Introduction

Identification of new therapeutic agents for breast cancer (BC) requires preclinical models that reproduce the molecular characteristics of their respective clinical tumors. In this work, we analyzed the genomic and gene expression profiles of human BC xenografts and the corresponding patient tumors.

Methods

Eighteen BC xenografts were obtained by grafting tumor fragments from patients into Swiss nude mice. Molecular characterization of patient tumors and xenografts was performed by DNA copy number analysis and gene expression analysis using Affymetrix Microarrays.

Results

Comparison analysis showed that 14/18 pairs of tumors shared more than 56% of copy number alterations (CNA). Unsupervised hierarchical clustering analysis showed that 16/18 pairs segregated together, confirming the similarity between tumor pairs. Analysis of recurrent CNA changes between patient tumors and xenografts showed losses in 176 chromosomal regions and gains in 202 chromosomal regions. Gene expression profile analysis showed that less than 5% of genes had recurrent variations between patient tumors and their respective xenografts; these genes largely corresponded to human stromal compartment genes. Finally, analysis of different passages of the same tumor showed that sequential mouse-to-mouse tumor grafts did not affect genomic rearrangements or gene expression profiles, suggesting genetic stability of these models over time.

Conclusions

This panel of human BC xenografts maintains the overall genomic and gene expression profile of the corresponding patient tumors and remains stable throughout sequential in vivo generations. The observed genomic profile and gene expression differences appear to be due to the loss of human stromal genes. These xenografts, therefore, represent a validated model for preclinical investigation of new therapeutic agents.     

Clinicopathological features of stomach cancer with invasive micropapillary component

Background

Invasive micropapillary carcinoma has been recognized as a rare disease entity with aggressive tumor behavior. However, few reports have described invasive micropapillary carcinoma in the gastrointestinal tract, particularly its involvement in gastric cancer.

Methods

We retrospectively analyzed 930 patients diagnosed with gastric cancer who underwent gastrectomy, and we then histopathologically evaluated the existence of a regional invasive micropapillary component. Clinicopathological features were investigated in patients with an invasive micropapillary component and compared with such features in 100 patients with gastric adenocarcinoma, selected as stage-matched controls, who underwent gastrectomy during the same period.

Results

Of the 930 patients, 14 were histopathologically diagnosed with gastric cancer with a regional invasive micropapillary component. There were no significant differences in age, gender, tumor location, macroscopic type, or type of surgery between patients with an invasive micropapillary component and the pT-matched controls. Histopathologically, significant differences were observed in lymphatic infiltration, venous invasion, the percentage of cases with lymph node metastasis, and the median number of metastatic lymph nodes. The three-year disease-free and overall survival rates of patients with an invasive micropapillary component were 40.5 and 59.3%, respectively, compared with those for the stage-matched controls, which were 72.6 and 80.6%, respectively (p?=?0.02 and 0.07).

Conclusions

Patients with gastric cancer with a regional invasive micropapillary component showed marked cancer infiltration in the lymphatic pathway and poor prognosis after gastrectomy.     

Pharmacokinetics of single-agent axitinib across multiple solid tumor types

Purpose

Axitinib, a potent and selective inhibitor of vascular endothelial growth factor receptors, showed antitumor activity as a single agent against several solid tumor types in Phase II and III trials. This study was conducted to evaluate axitinib pharmacokinetics across a variety of solid tumors.

Methods

The current study analyzed the pharmacokinetics of axitinib in 110 patients with non-small cell lung cancer (NSCLC), thyroid cancer, or melanoma from three Phase II trials plus 127 healthy volunteers, using nonlinear mixed-effects modeling. Boxplots of maximum observed plasma concentration (C _max) and area under the plasma concentration–time curve (AUC) of data from these tumor populations was compared to C _max and AUC from the final population pharmacokinetic model developed for metastatic renal cell carcinoma (mRCC) to compare axitinib pharmacokinetics across different tumor types.

Results

Axitinib disposition based on data from 237 subjects was best described using a two-compartment model with first-order absorption and lag time. Population estimates for systemic clearance, central volume of distribution, absorption rate constant, absolute bioavailability, and lag time were 20.1 L/h, 56.2 L, 1.26/h^?1, 0.663, and 0.448 h, respectively. Statistically significant covariates included gender on clearance, and body weight on central volume of distribution. However, predicted changes due to gender and body weight were found not clinically meaningful. The final analysis indicated that the pharmacokinetic model for mRCC was able to successfully describe axitinib pharmacokinetics in patients with NSCLC, thyroid cancer, and melanoma.

Conclusion

The pharmacokinetics of axitinib appears to be similar across a variety of tumor types.     

Pathologie des ösophagogastralen Adenokarzinoms

Context

Adenocarcinomas of the esophagogastric junction and the stomach share similar preneoplastic lesions and genetic alterations but are different according to their risk profiles and epidemiological characteristics.

Objective

The aim of the review was the comparison of pathohistological, molecular and therapeutic similarities and differences of these tumor entities.

Material and methods

The following review relied on a literature database search comprising the pathohistological, molecular and clinical characteristics of adenocarcinomas of the esophagogastric junction and the stomach.

Results

For both entities comparable alterations have been published even correlating with the pathohistological subtypes.

Conclusions

Despite many similarities concerning pathogenesis, the TNM classification for both tumor entities recommended by the WHO depends on the localization and is of particular importance for the clinical practice. Molecular targets for therapy optimization include Her2/neu and in the future, perhaps also c-Met.     

Evaluation of HER2-based biology in 1,006 cases of gastric cancer in a Japanese population

Background

The ToGA trial demonstrated the beneficial effect of trastuzumab in gastric cancer patients with human epidermal growth factor receptor 2 (HER2)-overexpressing tumors. Therefore, evaluation of the relationship between HER2 expression and gastric cancer biology using a validated system has become an even more important task. Herein, we verified the correlation between HER2 overexpression in the tumor and the clinical course of gastric cancer patients.

Methods

A total of 1,006 consecutive patients with gastric cancer who underwent surgery at the National Cancer Center Hospital East between January 2003 and July 2007 were examined using the tissue microarrays approach. HER2 expression was determined based on an immunohistochemistry score of 3+, or an immunohistochemistry score of 2+ plus HER2 gene amplification as detected by double-color fluorescent in situ hybridization. A retrospective review of the medical records was conducted to determine the correlation between the presence of HER2 overexpression and clinicopathological factors. Then, in 948 patients who had undergone curative resection, HER2 status was compared with the survival.

Results

HER2 overexpression was detected in 118 (11.7 %) patients. HER2 overexpression was correlated with age, gender, grade of differentiation, expanding growth pattern, and nodal status. In the survival analysis, HER2 overexpression was not found to be correlated with either disease-specific survival or recurrence-free survival.

Conclusions

HER2 overexpression in the tumor was not identified as a significant prognostic factor in patients with operable gastric cancer. The HER2-targeted therapy may be beneficial in a proportion of cases.     

Autophagy,a novel target for chemotherapeutic intervention of thyroid cancer

Purpose

Thyroid cancers with unsatisfactory curative effect nowadays are the most common malignant tumors of the endocrine system. Apoptosis evasion, a hallmark of cancer, has driven the search of stimulating novel cell death way in cancer therapy. This review aims to explore the relationship between autophagy and thyroid cancer, especially the chemotherapy agents which are based on autophagy in treating thyroid cancers.

Methods

A computerized literature search of MEDLINE was performed using the following search terms: autophagy and thyroid cancer.

Results

Recent studies have found that several chemotherapeutic agents and knockdown of specific microRNA may contribute to autophagic tumor cell death in most thyroid cancer types.

Conclusions

Stimulating autophagy may be an effective alternative treatment to most types of thyroid cancer.     

Comparisons of 5-aminolevulinic acid photodynamic therapy and after-loading radiotherapy in vivo in cervical cancer

Objective

To compare the differences between 5-aminolevulinic acid photodynamic therapy (5-ALA-PDT) with traditional after-loading radiotherapy in aspects of efficacies and side effects.

Materials and methods

MTT assay was adopted to detect the inhibitive effects of 5-ALA-PDT on Hela cells proliferation. Flow cytometry was used to analyze cell apoptosis. After establishment of human cervical cancer xenograft model, the comparisons between 5-ALA-PDT with radiotherapy were performed with respect to treatment efficacies (survival rate, body weight, and tumor volume) and side effects (appearance and behavior, ovarian endocrine functions, and skin lesion around the tumor).

Results

5-Aminolevulinic acid photodynamic therapy exerted killing effects on cervical cancer cells. Morphological changes and flow cytometric analyses indicated apoptosis to be one of the mechanisms for tumor growth suppression. Both proliferation inhibition and cell apoptosis showed dependency on photosensitizer concentration and irradiation intensity. Repeated photodynamic therapy presented stronger inhibitive effects on tumor growth compared to after-loading radiotherapy, while producing milder impairment of ovarian endocrine functions and skin lesions around the tumors.

Conclusions

5-Aminolevulinic acid photodynamic therapy has great potential to be an alternative treatment modality for cervical cancer.     

Common NOD2/CARD15 variants are not associated with susceptibility or the clinicopathologic characteristics of sporadic colorectal cancer in Hungarian patients

Background

To evaluate the feasibility and therapeutic effect of chemotherapy combined with regional radio frequency hyperthermia for pretreated locally advanced non-small cell lung cancer.

Methods

29 patients with stage III non-small cell lung cancer were enrolled in present study, received chemotherapy up to 4 cycles and radio frequency hyperthermia up to 32 times. The primary end points were grade 3,4 hematological or non-hematological toxicities and progression free survival, the secondary end points were response rate, tumor control rate and overall survival. Method of Kaplan-Meier was used for the survival analysis.

Results

21 patients completed their arranged treatments. The most common grade 3,4 toxicity was neutropenia (24.1%). Median progression free survival was 4 months (range 0–13 months), one year progression free survival rate was 10.3%. Overall response rate was 25.9%, tumor control rate was 66.6%. Median overall survival was 11 months (range 2–18⁺ months), one year overall survival rate was 44.8%.

Conclusion

Treatment of chemotherapy in conjunction with regional hyperthermia was safe and well tolerant, it suggested an impressive tumor control rate and an acceptable one year progression free survival. Further study might be needed.     

A genome-wide map of aberrantly expressed chromosomal islands in colorectal cancer

Background

Cancer development is accompanied by genetic phenomena like deletion and amplification of chromosome parts or alterations of chromatin structure. It is expected that these mechanisms have a strong effect on regional gene expression.

Results

We investigated genome-wide gene expression in colorectal carcinoma (CRC) and normal epithelial tissues from 25 patients using oligonucleotide arrays. This allowed us to identify 81 distinct chromosomal islands with aberrant gene expression. Of these, 38 islands show a gain in expression and 43 a loss of expression. In total, 7.892 genes (25.3% of all human genes) are located in aberrantly expressed islands. Many chromosomal regions that are linked to hereditary colorectal cancer show deregulated expression. Also, many known tumor genes localize to chromosomal islands of misregulated expression in CRC.

Conclusion

An extensive comparison with published CGH data suggests that chromosomal regions known for frequent deletions in colon cancer tend to show reduced expression. In contrast, regions that are often amplified in colorectal tumors exhibit heterogeneous expression patterns: even show a decrease of mRNA expression. Because for several islands of deregulated expression chromosomal aberrations have never been observed, we speculate that additional mechanisms (like abnormal states of regional chromatin) also have a substantial impact on the formation of co-expression islands in colorectal carcinoma.     

Inhibition of HSP27 alone or in combination with pAKT inhibition as therapeutic approaches to target SPARC-induced glioma cell survival

Background

The current treatment regimen for glioma patients is surgery, followed by radiation therapy plus temozolomide (TMZ), followed by 6 months of adjuvant TMZ. Despite this aggressive treatment regimen, the overall survival of all surgically treated GBM patients remains dismal, and additional or different therapies are required. Depending on the cancer type, SPARC has been proposed both as a therapeutic target and as a therapeutic agent. In glioma, SPARC promotes invasion via upregulation of the p38 MAPK/MAPKAPK2/HSP27 signaling pathway, and promotes tumor cell survival by upregulating pAKT. As HSP27 and AKT interact to regulate the activity of each other, we determined whether inhibition of HSP27 was better than targeting SPARC as a therapeutic approach to inhibit both SPARC-induced glioma cell invasion and survival.

Results

Our studies found the following. 1) SPARC increases the expression of tumor cell pro-survival and pro-death protein signaling in balance, and, as a net result, tumor cell survival remains unchanged. 2) Suppressing SPARC increases tumor cell survival, indicating it is not a good therapeutic target. 3) Suppressing HSP27 decreases tumor cell survival in all gliomas, but is more effective in SPARC-expressing tumor cells due to the removal of HSP27 inhibition of SPARC-induced pro-apoptotic signaling. 4) Suppressing total AKT1/2 paradoxically enhanced tumor cell survival, indicating that AKT1 or 2 are poor therapeutic targets. 5) However, inhibiting pAKT suppresses tumor cell survival. 6) Inhibiting both HSP27 and pAKT synergistically decreases tumor cell survival. 7) There appears to be a complex feedback system between SPARC, HSP27, and AKT. 8) This interaction is likely influenced by PTEN status. With respect to chemosensitization, we found the following. 1) SPARC enhances pro-apoptotic signaling in cells exposed to TMZ. 2) Despite this enhanced signaling, SPARC protects cells against TMZ. 3) This protection can be reduced by inhibiting pAKT. 4) Combined inhibition of HSP27 and pAKT is more effective than TMZ treatment alone.

Conclusions

We conclude that inhibition of HSP27 alone, or in combination with pAKT inhibitor IV, may be an effective therapeutic approach to inhibit SPARC-induced glioma cell invasion and survival in SPARC-positive/PTEN-wildtype and SPARC-positive/PTEN-null tumors, respectively.     

Pathologie als Gatekeeper

Background

Lung cancer is the cancer type with the highest number of cancer deaths and non-small cell lung cancer (NSCLC) is the most frequent subtype. In the last years the knowledge on this tumor type has developed rapidly and fortunately this has led to an improvement in diagnostic stratification and new therapeutic opportunities.

Objectives

This review represents a selective overview on recent results of the tumor pathology of NSCLC and highlights the importance of the interaction between pathology and clinical disciplines. The main focus is laid on novel aspects of morphological and molecular tumor classification.

Material and methods

This overview is based on recent publications and the involvement of the authors in committees and panels that are related to the classification and therapy of lung cancer patients.

Results and conclusion

The report provides on the one hand a short outlook on the new WHO classification of lung tumors that is currently in preparation. On the other hand it reviews molecular changes of lung cancer with a special emphasis on those alterations that may have potential therapeutic relevance.     

Nativity disparities in late-stage diagnosis and cause-specific survival among Hispanic women with invasive cervical cancer: an analysis of Surveillance, Epidemiology, and End Results data

Purpose

While cervical cancer screening and risk behaviors have been found to vary among US- and foreign-born Hispanic women, many cancer epidemiology studies have conceptualized Hispanics as a homogenous group. Here, we examine differences in cervical cancer stage at diagnosis and survival among Hispanic women by nativity.

Methods

We use data from the Surveillance, Epidemiology, and End Results program, 1998–2008. Nativity was based on place of birth and was categorized as US versus foreign born. Distant and regional tumors were classified as late stage, while local tumors were classified as early stage.

Results

Forty-seven percent of cases of invasive cervical cancer among Hispanics were diagnosed at a late stage, and over half of invasive cervical cancer cases were among foreign-born women. Foreign-born Hispanic women were significantly more likely than US-born Hispanics to have late-stage diagnosis, after adjusting for age at diagnosis and tumor histology (adjusted odds ration = 1.09, p value = 0.003). There was heterogeneity in the association between nativity and survival by stage at diagnosis. Among cases with early-stage diagnosis, survival was poorer among foreign-born versus US-born Hispanics after adjusting for age at diagnosis, histology, and cancer-directed therapy [adjusted hazard ratios (HR) = 1.31, p value = 0.030]. However, among cases with late-stage diagnosis, survival was better among foreign-born Hispanics (adjusted HR = 0.81, p value < 0.001).

Conclusions

We hypothesize that nativity differences in survival may be indicative of diverse risk, screening, and treatment profiles. Given such differences, it may be inappropriate to aggregate Hispanics as a single group for cervical cancer research.     

Chirurgisches Vorgehen bei kolorektalen Lungenmetastasen

Context

Pulmonary metastasectomy is associated with low morbidity and mortality and might provide a survival advantage for selected patients.

Objective

The aim of this study was an evidence-based systematic review of the current status of the diagnostics and therapy of pulmonary metastases arising from malignant colorectal cancer.

Material and methods

A systematic literature search was performed in PubMed, Medline, current guidelines and by manual searching. Relevant publications from the last 20 years were analyzed and the results are summarized in a structured review.

Results

The indications for metastasectomy should be discussed in an interdisciplinary tumor board. Even in the absence of pre-metastasectomy chemotherapy, an observation period of at least 2 months should be recommended for assessment of the tumor biology. The 5-year survival rate ranges between 40 % and 68 % for patients undergoing pulmonary metastasectomy. Positive prognosticators for survival might be complete resection, low carcinoembryonic antigen (CEA) levels, few metastases, long disease-free interval, localization of the primary tumor in the colon, no lymph node metastases and regression or stable disease after preoperative chemotherapy and/or observation interval. Rectal cancer represents a different tumor entity compared to colon cancer even in metastasectomy patients. Rectal cancer is associated more often with multiple metastases, higher prevalence of thoracic lymph node metastases and shorter disease-free interval. Resectable liver and lung metastases or the prevalence of thoracic lymph node metastases are not a contraindication for surgery.

Conclusion

Pulmonary metastasectomy for colorectal cancer is an established treatment within multimodal treatment concepts. The indications for metastasectomy should be discussed in an interdisciplinary tumor board. Rectal cancer represents a different tumor entity compared to colon cancer even in metastasectomy patients. Resectable liver and lung metastases or the presence of thoracic lymph node metastases are not a contraindication for surgery per se.     

Supplementation of fish oil augments efficacy and attenuates toxicity of 5-fluorouracil in 1,2-dimethylhydrazine dihydrochloride/dextran sulfate sodium-induced colon carcinogenesis

Purpose

5-Fluorouracil (5-FU) is used for the treatment of colorectal cancer, but has low therapeutic response rate and severe side effects. Recently, fish oil (FO) rich in n-3 polyunsaturated fatty acids has been preferred to chemosensitize tumor cells to anticancer drugs. Therefore, the current study is designed to evaluate chemotherapeutic efficacy and toxicity profile of 5-FU in combination with FO in 1,2-dimethylhydrazine dihydrochloride/dextran sulfate sodium (DMH/DSS)-induced colon cancer model.

Methods

The therapeutic efficacy of 5-FU along with FO was analyzed through assessment of survival rate, tumor burden, volume, serum sialic acid levels, cytokeratin 19 (CK19) expression and index of cell proliferation such as cell cycle progression. Toxicological aspects were evaluated by standard functional and structural parameters related to spleen, gastrointestinal, liver and kidney.

Results

In the present study, 5-FU in combination with FO increased the survival rate in carcinogen-treated animals. Synergism of 5-FU and FO was also reflected in significant inhibition in tumor growth and serum sialic acid levels in DMH/DSS model. Moreover, the combination dosage significantly augmented the inhibition of cell cycle progression, as shown by CK19 expression. Additionally, FO ameliorated hematologic depression, gastrointestinal, hepatic and renal toxicity caused by 5-FU as substantiated by a marked improvement in structural and functional alterations of these organs.

Conclusion

The supplementation of FO is potentially a promising option for increasing the therapeutic potential and mitigating the side effects of 5-FU.