Enhancement of chemosensitivity in 5-fluorouracil-resistant colon cancer cells with carcinoembryonic antigen-specific RNA aptamer.

Colorectal cancer (CRC) is one of the most common cancers, and rates of incidence and diagnosis of CRC have gradually increased. Carcinoembryonic antigen (CEA) is overexpressed in patients with CRC and is associated with cell adhesion, anoikis resistance, and promotion of metastasis to the liver. 5-Fluorouracil (5-FU) is a chemotherapeutic drug used to treat cancer, including CRC. However, a major issue of 5-FU therapy is the occurrence of chemoresistance, and the fact that 5-FU induces CEA overexpression, which may induce the 5-FU resistance. We previously isolated a CEA-specific RNA aptamer that was able to inhibit hepatic metastasis of colon cancer cells in a mouse model. In the present study, we tested whether protecting CEA using the CEA aptamer could enhance 5-FU sensitivity in chemoresistant LS174T colon cancer cells. We observed that the CEA aptamer sensitized the 5-FU-resistant colon cancer cell line to 5-FU more than five-fold (IC50 ~ 5.995 µM), compared with cells treated with 5-FU alone (IC50 ~ 31.46 µM). Moreover, treatment with CEA aptamer combined with 5-FU synergistically regressed growth of chemoresistant tumors in mouse xenografted models. Combinatorial treatment of 5-FU and CEA aptamer augmented caspase-8 activity in the 5-FU-resistant colon cancer cell line via aptamer-mediated disruption of CEA interaction with death receptor 5 and in mouse xenograft tumors. In conclusion, CEA-specific aptamer improved 5-FU sensitivity in chemoresistant colon cancer cells in vitro and in vivo, and thus represents a novel 5-FU adjuvant to overcome the chemoresistance in CRC patients.

Impact of CEA-targeting Nanoparticles for Drug Delivery in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common causes of cancer-related death in the world, mainly owing to distant metastasis events. Developing targeted strategies to treat and follow individuals in more developed stages is needed. The carcinoembryonic antigen (CEA) is a cell surface-overexpressed glycoprotein in most CRC patients, and the evaluation of its serum levels is recommended in the clinic. These reasons motivated the production of CEA-targeted nanotechnologies for monitorization of CRC progression, but only a few centers have reported their use for drug delivery. The cellular internalization of CEA-linked nanosystems occurs by the natural recycling of the CEA itself, enabling longer retention and sustained release of the cargo. The functionalization of nanoparticles with lower affinity ligands for CEA is possibly the best choice to avoid their binding to the soluble CEA. Here, we also highlight the use of nanoparticles made of poly(lactic-co-glycolic acid) (PLGA) polymer, a well known material, owing to its biocompatibility and low toxicity. This work offers support to the contribution of antibody fragment-functionalized nanoparticles as promising high affinity molecules to decorate nanosystems. The linkers and conjugation chemistries chosen for ligand-nanoparticle coupling will be addressed herein as an elements essential to the modulation of nanosystem features. This review, to our knowledge, is the first that focuses on CEA-targeted nanotechnologies to serve colorectal cancer therapy and monitorization.

Vandetanib Tumor Shrinkage in Metastatic Medullary Thyroid Cancer Allowing Surgical Resection of the Primary Site: A Case Report.

Vandetanib has been shown to improve progression-free survival in adults with advanced medullary thyroid cancer. This article describes a pediatric patient with metastatic medullary thyroid cancer secondary to sporadic multiple endocrine neoplasia 2B, treated with vandetanib. At presentation, he had an inoperable primary tumor, with carotid encasement, and pulmonary metastases. Vandetanib induced a significant response: calcitonin and carcinoembryonic antigen levels both fell considerably, primary tumor maximal diameter decreased by 68%, and pulmonary metastases became no longer detectable. This allowed surgical resection of the primary tumor. The patient remains well after over 6 years of vandetanib therapy, with no treatment toxicity.

Unexpected and durable response with regorafenib in a metastatic colorectal cancer patient without KDR mutation: A case report.

RATIONALE: Regorafenib is an oral multikinase inhibitor and is approved as salvage therapy in the standard treatment of advanced colorectal cancer (CRC). Due to its limited efficacy, toxicity profile, and cost, it is necessary to identify those patients who may have the most benefit from regorafenib. In a previous case report, kinase insert domain receptor (KDR) mutation has been associated with exceptional clinical response (CR) in an elderly patient treated with a low dose of regorafenib; thus, it was hypothesized that it could represent a new predictive marker of drug response. PATIENT CONCERNS: A heavily pretreated 67-year-old man with a wide peripancreatic recurrence of colon carcinoma and liver metastases was subjected to treatment with regorafenib. DIAGNOSES: After 3 months of therapy, a computed tomography scan showed an impressive reduction of disease. INTERVENTIONS: Regorafenib was given at full doses (160 mg/die for 21 days, every 4 weeks). OUTCOMES: A lasting response without relevant toxicity. No KDR mutation relief was detected. After 13 months from the start of treatment, the patient died after the diagnosis of encephalic metastases. LESSONS: Regorafenib can lead to an unexpected and durable CR with consistent progression-free survival and overall survival benefit even in patients affected by polychemotherapy refractory metastatic CRC. Further studies are needed to establish the benefit of KDR mutation as predictive marker for regorafenib sensitivity for patients with CRC. We include a detailed revision of prognostic and predictive factors of clinical outcome identified in literature to optimize the use of regorafenib in this setting.

Measles vaccine strains for virotherapy of non-small-cell lung carcinoma.

INTRODUCTION: Oncolytic virus therapy is a promising therapy for numerous tumor types. Edmonston-strain measles virus (MV) has been tested in clinical trials for ovarian cancer, glioma, and myeloma. Therefore, the antitumor activity of MV against non-small-cell lung cancer (NSCLC) was assessed. METHODS: Human NSCLC cells and immortalized lung epithelial cell lines, Beas2B, were infected with either MV-producing green fluorescent protein or MV-producing carcinoembryonic antigen. Cells were assessed for viability, induction of apoptosis by caspase and poly-ADP ribose polymerase cleavage, and for viral transgene production. The dependency of MV entry on CD46 and nectin-4 were determined using blocking antibodies. The role of host translational activity on viral replication was assessed by overexpression of eIF4E and translation inhibition. Antitumor activity was assessed by measuring treated NSCLC xenografts from flanks of nude mice. RESULTS: MV infection of NSCLC cells results in potent cell killing in most of the cell lines compared with immortalized Beas2B cells and induces apoptosis. MV infection was prevented by blocking of CD46, however independent of nectin-4 blockade. Tumor weights are diminished after intratumoral injections of MV-producing carcinoembryonic antigen in one of two cell lines and result in detectable viral transgene in serum of mice. CONCLUSIONS: These data indicate that MV is oncolytic for human NSCLC and this was independent of nectin-4 expression. Dysregulated protein translational machinery may play a role in determining tumor tropism in NSCLC. MV combined with gemcitabine could be explored further as chemovirotherapy for NSCLC.

Oral contraceptive use and salivary C-erbB-2, CEA and CA15-3 in healthy women: a case-control study.

OBJECTIVES: Oral contraceptives (OCP) are highly effective, safe and widely used. Higher exposure to endogenous and exogenous estrogens is generally thought to increase the risk of breast cancer. Therefore, this study was conducted to determine if oral contraceptive use affected the expression of CA 15-3, CEA and C-erb B-2 in the saliva of healthy women. STUDY DESIGN: The participants consisted of 87 healthy women (43 controls and 44 using oral contraceptives) ranging in age from 20 to 54 years. The volunteers participated by giving one - time stimulated whole saliva samples. Then the samples were analysed for CA 15-3, CEA and C-erb B-2 concentrations. RESULTS: The student t-test was used to compare group means for variables with comparable variability. The mean of C-erb B-2, CEA, and CA 15-3 concentrations (in the case and control groups) was (1.93, 1.70), (34.46, 31.62) and (12.58, 16.19) respectively. These differences were not statistically significant. CONCLUSIONS: Our findings suggest that the levels of the cancer biomarkers C-erb B-2, CEA and CA 15-3 were not affected by increased levels of estrogens in the body.

Chemotherapy-induced transient CEA and CA19-9 surges in patients with metastatic or recurrent gastric cancer.

BACKGROUND: Rising serum tumor markers after chemotherapy are generally considered to indicate tumor progression. However, we have observed a transient increase in carcinoembryonic antigen (CEA) or carbohydrate antigen 19-9 (CA19-9) levels despite clinical benefits from chemotherapy in patients with metastatic or recurrent gastric cancer (MRGC). Therefore, this study was performed to determine the incidence of CEA and CA19-9 surges and their implications on the clinical outcome in MRGC patients. MATERIAL AND METHODS: Fifty-one and 40 patients who had evaluable data for CEA or CA19-9 surges, respectively, were included. Both CEA and CA 19-9 surges were defined as a > 20% increase in these tumor markers from the baseline that was followed by a > 20% drop in subsequent levels compared to the baseline. RESULTS: Of 51 evaluable patients for CEA surges, nine patients (18%) had documented CEA surges. The median time to CEA peak and the duration of the CEA surge were 2.8 (1.7 approximately 7.0) and 9.1 weeks (7.6 approximately 21.0), respectively. Of 40 evaluable patients for CA19-9 surges, seven patients (18%) had CA19-9 surges. The median time to peak and the duration of the CA19-9 surge were 2.3 (1.9 approximately 6.0) and 7.1 weeks (4.3 approximately 16.1), respectively. All patients with CEA or CA19-9 surges had radiographic evidence of benefits from chemotherapy. CONCLUSION: CEA or CA19-9 surges can be observed in MRGC patients receiving chemotherapy. All patients with these surge phenomena had clinical benefits from chemotherapy. An initial rise in CEA or CA19-9 levels after initiation of chemotherapy should not be used as an indicator of progressive disease.

Hypereosinophilia associated with increased serum levels of carcinoembryonic antigen.

We report a case of hypereosinophilia associated with increased serum levels of carcinoembryonic antigen (CEA). The patient developed fever, diarrhea, erythroderma and eosinophilia. Disorders known to be associated with eosinophilia were not detected. The typical malignant diseases related to a rise in CEA levels were not identified. The CEA value reached a maximum of 81.4 ng/ml a few weeks late for the peak of the eosinophilic count. Corticosteroid therapy was effective in improving clinical symptoms and the CEA values decreased in association with the improvement of those manifestations, suggesting a pathophysiological link between the disease activity of hypereosinophilia and the changes in CEA level.

PANVAC-VF: poxviral-based vaccine therapy targeting CEA and MUC1 in carcinoma.

PANVAC is a cancer vaccine therapy delivered through two viral vectors--recombinant vaccinia and recombinant fowlpox--which are given sequentially. Both vectors contain transgenes for the tumor-associated antigens epithelial mucin 1 and carcinoembryonic antigen, which are altered or overexpressed in most carcinomas. The vectors also contain transgenes for three human T cell costimulatory molecules required to enhance immune response: B7.1, intracellular adhesion molecule-1 and leukocyte function-associated antigen-3. PANVAC is injected subcutaneously and processed by the body's antigen-presenting cells. Preclinical studies have demonstrated the efficacy of PANVAC in inducing both carcinoembryonic antigen- and mucin 1-specific cytotoxic T lymphocyte responses in vitro and in murine models. Other strategies that enhance the immune response include the use of granulocyte-macrophage colony-stimulating factor and a prime-boost administration sequence. Clinical trials have demonstrated PANVAC's safety and its ability to induce antigen-specific T cell responses. Early clinical trials are evaluating PANVAC alone and in combination with conventional chemotherapy and/or radiation. Studies to date hold promise for the use of PANVAC as a means to stimulate the immune system against malignancies and to provide clinical benefit.

Evidence for CEA release from human colon cancer cells by an endogenous GPI-PLD enzyme.

Elevated carcinoembryonic antigen (CEA) blood levels are found in a wide variety of epithelial neoplasms. The precise mechanism of the spontaneous CEA release from normal and cancer cells has not been established yet. In this study we investigated 'in vitro' the role of an endogenous glycosylphosphatidyl inositol phospholipase D (GPI-PLD) in spontaneous CEA release from human colon carcinoma cells. We detected GPI-PLD-specific transcript expression in four human colorectal tumor cell lines, LS180, HT29, HT29/219, and SW742 by RT-PCR. Furthermore, CEA release could be activated and inhibited by incubation of LS180 cells with suramin and 1,10-phenanthroline, compounds known to activate and inhibit GPI-PLD activity, respectively. The results suggest a mechanism for the involvement of an endogenous GPI-PLD in spontaneous CEA release from human colon cancer cells.

Immune responses in advanced colorectal cancer following repeated intradermal vaccination with the anti-CEA murine monoclonal antibody, PR1A3: results of a phase I study.

BACKGROUND AND AIMS: The aim was to determine the toxicity, clinical and immune responses to the murine monoclonal anti-carcinoembryonic antigen (CEA) antibody, PR1A3, in patients with advanced colorectal cancer. MATERIALS AND METHODS: Fifteen patients with advanced colorectal cancer received either 0.5-, 1.0- or 5.0-mg doses of PR1A3 mixed with 10% w/v Alum adjuvant (Superfos Biosector, Denmark) intradermally at 4-week intervals for 3 months. Patient serum was assessed for anti-idiotypic (Ab2), anti-anti-idiotypic (Ab3) and human anti-mouse antibody (HAMA) reactivity. Peripheral blood mononuclear cell (PBMC) proliferation with phytohaemagglutinin (PHA), CEA and PR1A3, stimulated IL-2, IL-4 and IFN-gamma levels and PR1A3-stimulated IL-2 receptor expression during immunotherapy were determined. Comparisons were made with 16 age-matched controls without malignant disease. RESULTS: Hyperimmune sera from 12 of the 15 patients showed Ab2 reactivity with no detectable Ab3 responses. Strong HAMA reactivity was recorded in 7 of the 15 cases with no adverse clinical effect. Delayed-type hypersensitivity (DTH) responses developed in 12 of the 15 patients. Pre-treatment PBMC proliferation with PHA was subnormal in each patient compared with controls, becoming normal (or supranormal) in all patients during immunisation (P<0.001). PBMC proliferation with CEA and PR1A3 increased during immunotherapy (P<0.001) along with stimulated production of IL-2, IFN-gamma and IL-2 receptor expression. Progressive disease was observed in 14 of the 15 patients with minimal toxicity. CONCLUSION: PR1A3 generated limited idiotypic responses but robust DTH reactivity in most patients. In vitro PBMC proliferation with mitogens and recall antigens is greatly increased during the course of immunisation, with a shift in stimulated cytokine profile.

Pilot study of celecoxib and infusional 5-fluorouracil as second-line treatment for advanced pancreatic carcinoma.

BACKGROUND: Cyclooxygenase-2 (COX-2) is up-regulated frequently and may constitute a promising therapeutic target in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Patients with advanced PDAC who had progressive disease after gemcitabine-based chemotherapy were eligible for this pilot study. Treatment was comprised of oral celecoxib (400 mg twice daily) and protracted intravenous (i.v.) infusion 5-fluorouracil (5-FU) (200 mg/m(2) per day), both given continuously for a maximum of 9 treatment months, in the absence of disease progression or unacceptable toxicity. Patients were examined weekly for toxicity and were restaged every 6-8 weeks for tumor assessment. RESULTS: Seventeen patients entered the study. Asymptomatic transaminase elevation was the most common toxicity and reached NCI-CTC (version 3.0) Grade 3-4 in 4 of 133 treatment weeks. No other hematologic or nonhematologic toxicity > Grade 2 was observed. Four patients discontinued celecoxib due to upper gastrointestinal tract toxicity. Two confirmed partial responses (durations of 23 weeks and 68 weeks, respectively) and 2 patients with stable disease (durations of 10 weeks and 13 weeks, respectively) were observed for an overall response rate of 12% (95% confidence interval, 0-27%) in the intent-to-treat population. A significant decrease (> or = 50%) in serum CA 19.9 levels was observed in 3 of 9 evaluable patients. The median time to disease progression was 8 weeks, and the median overall survival was 15 weeks. CONCLUSIONS: The combination of oral celecoxib and 5-FU by protracted i.v. infusion was found to be feasible and well tolerated, and was capable of inducing durable objective responses, even in patients with far advanced, gemcitabine-resistant/refractory PDAC. Further exploration of COX-2 inhibitor/fluropyrimidine combinations is warranted.

Drug-induced increase of carcinoembryonic antigen expression in cancer cells.

Most of gastrointestinal, breast and lung cancer cells express carcinoembryonic antigen (CEA). Therefore, this protein represents a suitable target for innovative diagnostic and immunotherapeutic strategies of various tumours. Presently CEA can be involved in three main approaches concerning cancer detection and therapy, i.e. (a) detection of tumour cells in the peripheral blood, bone marrow or lymph node using reverse transcriptase-polymerase chain reaction (RT-PCR)-based measurement of CEA mRNA; (b) targeting of anticancer agents or radionuclides by tumour-selective anti-CEA monoclonal antibodies (mAbs); (c) use of antitumour vaccines capable of eliciting major histocompatibility complex (MHC)-restricted immune responses against CEA-derived peptides. Actually, it has been shown that the expression of CEA can be up-regulated by pharmacological agents including, antineoplastic drugs (i.e. 5-fluorouracil), cytokines (i.e. interferons or interleukin-6), differentiating agents (i.e. sodium butyrate) and protein kinase inhibitors (i.e. staurosporine). Therefore, the use of drugs capable of increasing CEA expression, could amplify the sensitivity of diagnostic procedures that rely on CEA determination. Moreover, the same agents could increase the efficacy of vaccines based on immunogenic CEA-derived peptides restricted by the MHC. The purpose of this review is to describe several agents that are able to increase CEA expression and to discuss the rational bases for new strategies in cancer detection and therapy aimed at increasing the expression of tumour-associated antigens.

Establishment of a colonic adenoma cell line (GEKI-2): spectral karyotype analysis and functional characterization.

BACKGROUND AND AIMS: On the genetic level colonic carcinogenesis is best described by the adenoma-carcinoma sequence, but it may be modulated by exogenous factors, particularly by dietary factors and chemopreventive agents. The protective effects of exogenous factors are thought to be exerted rather in the early stages of the adenoma-carcinoma sequence. Thus, an in vitro model consisting of cells stemming from an colon adenoma would be desirable. However, establishing such a cell line has proven difficult. MATERIALS AND METHODS: We report the establishment of a colon adenoma cell line. The cells were generated from a colon adenoma and propagated as a stable cell line for more than 40 passages. The cells are microsatellite stable and confirmed to be of epithelial origin by cytokeratin staining. RESULTS: In contrast to commercially available colon cancer cell lines, cytogenetic analysis with spectral karyotype analysis revealed no chromosomal alterations in this adenoma cell line. Incubation with butyrate resulted in a time- and dose-dependent inhibition of proliferation and in an significant increase in cellular differentiation. The cdk inhibitor p21/waf which plays a pivotal role in growth inhibition and differentiation is expressed consecutively in GEKI-2 cells. The expression of cdk1 and cdk2, important regulatory elements in the cell cycle, is downregulated following treatment with butyrate. CONCLUSION: The presented colon adenoma cell line GEKI-2 may prove a versatile tool for further exploring the underlying mechanisms of protective and promoting factors in early colon cancerogenesis.

Immunotherapy using fusions of autologous dendritic cells and tumor cells showed effective clinical response in a patient with advanced gastric carcinoma.

Immunotherapy using tumor antigen-loaded dendritic cells is a new approach for the treatment of various types of malignant tumors. Here, we describe a patient with advanced gastric carcinoma who received immunotherapy using fused autologous dendritic cells and carcinoma cells (fusions) and showed effective clinical responses to the treatment. A 74-year-old man showed massive ascitic effusion due to peritonitis carcinomatosa after surgical operation for gastric carcinoma. A gastric carcinoma cell line was established from the patient's tumor tissue. Dendritic cells were obtained by cultivation of the adherent cell fraction of the patient's peripheral blood mononuclear cells (PBMCs) with granulocyte macrophage-colony stimulating factor, interleukin-4, and tumor necrosis factor-alpha. The cells were mixed with irradiated tumor cells and treated with 50% polyethyleneglycol (PEG) for the generation of fusions, as described previously. The PEG-treated cells were injected subcutaneously every 2 weeks. Low-grade fever was observed after the first and second treatments. After the third treatment, ascitic effusion and leg edema decreased markedly, without any other treatments. Serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 decreased to levels lower than those at the initiation of treatment. PBMCs collected after the fifth treatment elicited cytotoxic activity against autologous tumor cells. Although treatment was continued in the same way, recurrence of the disease was observed about 5 months after the start of the treatment. This is the first report of immunotherapy utilizing fusions of autologous dendritic cells and tumor cells resulting in effective clinical responses in advanced gastric carcinoma, without severe adverse effects.

Increased expression of CEA and MHC class I in colorectal cancer cell lines exposed to chemotherapy drugs.

PURPOSE: Cancer-specific immunotherapy holds great promise as an emerging treatment for advanced colorectal cancer and may be combined with standard chemotherapy to provide a synergistic inhibitory action against tumor cells. To examine the interrelationship between the immune system and chemotherapy, we studied the induction of both CEA, a tumor-associated antigen, and MHC class I, a major component of the antigen presenting system, in response to a number of chemotherapeutic agents. METHODS: The effect of a selection of standard chemotherapeutics on MHC class I and CEA expression in human colorectal cancer cell lines was determined by flow cytometry and semi-quantitative RT-PCR. In addition, studies using mice bearing tumors derived from an injected murine colon cancer cell line were performed to determine if alteration in MHC class I expression occurs in vivo following continuous infusion of chemotherapeutic agents into the peritoneal cavity, as well as to facilitate correlations between expression of this factor and therapeutic effectiveness. RESULTS: All anti-cancer drugs examined, when given at IC50 values, induced expression of MHC class I protein in the human colon cancer cell line, COLO201. However, expression of CEA mRNA was only induced upon exposure to 5-FU, in contrast to obscure induction following CDDP and SN-38 treatment. Combined treatment with 5-FU and CDDP gave additional effect on CEA expression in COLO201 cells. Regarding the in vivo studies in mice, the size of the murine colon cancer cell-derived tumors was reduced only in response to treatment with CDDP, which also mediated the highest induction of MHC class I expression. CONCLUSION: These results suggest that chemotherapeutic agents trigger the immune system and cancer-specific immunotherapy may be effective when used in combination with systemic chemotherapy.

Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer.

Curcuma spp. extracts, particularly the dietary polyphenol curcumin, prevent colon cancer in rodents. In view of the sparse information on the pharmacodynamics and pharmacokinetics of curcumin in humans, a dose-escalation pilot study of a novel standardized Curcuma extract in proprietary capsule form was performed at doses between 440 and 2200 mg/day, containing 36-180 mg of curcumin. Fifteen patients with advanced colorectal cancer refractory to standard chemotherapies received Curcuma extract daily for up to 4 months. Activity of glutathione S-transferase and levels of a DNA adduct (M(1)G) formed by malondialdehyde, a product of lipid peroxidation and prostaglandin biosynthesis, were measured in patients' blood cells. Oral Curcuma extract was well tolerated, and dose-limiting toxicity was not observed. Neither curcumin nor its metabolites were detected in blood or urine, but curcumin was recovered from feces. Curcumin sulfate was identified in the feces of one patient. Ingestion of 440 mg of Curcuma extract for 29 days was accompanied by a 59% decrease in lymphocytic glutathione S-transferase activity. At higher dose levels, this effect was not observed. Leukocytic M(1)G levels were constant within each patient and unaffected by treatment. Radiologically stable disease was demonstrated in five patients for 2-4 months of treatment. The results suggest that (a) Curcuma extract can be administered safely to patients at doses of up to 2.2 g daily, equivalent to 180 mg of curcumin; (b) curcumin has low oral bioavailability in humans and may undergo intestinal metabolism; and (c) larger clinical trials of Curcuma extract are merited.

Staurosporine increases carcinoembryonic antigen expression in a human colon cancer cell line.

Staurosporine (ST), a protein kinase C inhibitor, was found to produce antitumor effects against C22.20, a clonal subline derived from colon cancer HT-29 line, selected for low expression of carcinoembryonic antigen (CEA). However, as assessed by FACS analysis using propidium iodide, no apoptosis or cell cycle alteration was found on day 3 after treatment of C22.20 cells with ST (1-100nM). Exposure of cells to graded concentrations of the drug (i.e., from 1 to 25nM) resulted in a concentration-dependent increase in the percentage of CEA positive cells, as determined by flow cytometric analysis. However, when higher concentrations (i.e. 50nM - 100nM) of ST were used, the percentage of CEA positive cells declined compared to that detected in 25nM-treated tumor. Since these results were obtained in a clonal cell population, it is reasonable to hypothesize that induction rather than selection mechanism is involved in this phenomenon. The potential clinical interest of the present findings stems from the consideration that treatment with ST or its derivatives could improve sensitivity and efficacy of diagnostic and/or immunotherapeutic approaches based on CEA molecules.

Differentiation-inducing effect of retinoic acid, difluoromethylornithine, sodium butyrate and sodium suramin in human colon cancer cells.

We investigated the relative effectiveness of four differentiation-inducing chemicals to induce a more normal or benign phenotype in the human colon cancer cell lines Moser and HT29. The differentiation-inducing capability of all-trans retinoic acid (ATRA), difluoromethylornithine (DFMO), sodium butyrate (NaB) and sodium suramin (NaS) was evaluated in terms of the efficacy of these chemicals in inhibiting cellular proliferation, growth in soft agarose, invasion of matrigel and induction of morphological alteration. The relative ability of these chemicals to induce production of the differentiation-related molecules fibronectin and carcinoembryonic antigen was also determined. Overall, ATRA was found to be the most effective chemical in inducing differentiation as measured by these parameters. The Moser cells were more susceptible to differentiation induction by comparison with the HT29 cells. Both similarities and differences in the cellular responses to DFMO, NaB and NaS were also observed for the Moser and HT29 cells. The differences in cellular responses to these chemicals may be due to different phenotypic properties of these two cell lines and different mechanisms of action of these chemicals.