Mechanisms of myeloid-derived suppressor cell-mediated immunosuppression in colorectal cancer and related therapies

Severe immunosuppression is a hallmark of colorectal cancer(CRC).Myeloid-derived suppressor cells(MDSCs),one of the most abundant components of the tumor stroma,play an important role in the invasion,metastasis,and immune escape of CRC.MDSCs create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells,including T and natural killer cells,as well as by inducing the proliferation of immunosuppressive cells,such as regulatory T cells and tumor-associated macrophages,which,in turn,promote the growth of cancer cells.Thus,MDSCs are key contributors to the emergence of an immunosup-pressive microenvironment in CRC and play an important role in the breakdown of antitumor immunity.In this narrative review,we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment,the current therapeutic approaches and technologies targeting MDSCs,and the therapeutic potential of modulating MDSCs in CRC treatment.This study provides ideas and methods to enhance survival rates in patients with CRC.

Drug resistance and new therapies in colorectal cancer

Colorectal cancer(CRC) is often diagnosed at an advanced stage when tumor cell dissemination has taken place. Chemo-and targeted therapies provide only a limited increase of overall survival for these patients. The major reason for clinical outcome finds its origin in therapy resistance. Escape mechanisms to both chemo-and targeted therapy remain the main culprits. Here, we evaluate major resistant mechanisms and elaborate on potential new therapies. Amongst promising therapies is α-amanitin antibodydrug conjugate targeting hemizygous p53 loss. It becomes clear that a dynamic interaction with the tumor microenvironment exists and that this dictates therapeutic outcome. In addition, CRC displays a limited response to checkpoint inhibitors, as only a minority of patients with microsatellite instable high tumors is susceptible. In this review, we highlight new developments with clinical potentials to augment responses to checkpoint inhibitors.

Tumor budding predicts response to anti-EGFR therapies in metastatic colorectal cancer patients

AIM:To investigate whether the evaluation of tumor budding can complement K-RAS analysis to improve the individualized prediction of response to anti-epidermal growth factor receptor based therapies in metastatic colorectal cancer (mCRC) patients. METHODS:Forty-three patients with mCRC treated with cetuximab or panitumumab were entered into this study. According to the Response Evaluation Criteria in Solid Tumors criteria, 30 patients had stable or progressive disease (non-responsive), while 13 patients had a partial response. Tumor buds were evaluated from whole tissue sections stained for pan-cytokeratin, evaluated in the densest region using a 40 × objective and "high-grade" tumor budding was defi ned as 15 buds/high-power f ield.RESULTS: Tumor buds and K-RAS mutation both correctly classif ied 68% of patients. All patients with K-RAS mutation (n=7) or high-grade tumor budding (n=11) were non-responsive, of which 4 patients had both features. All 13 partial responders were K-RAS wild-type with low-grade tumor budding. Combined, the predictive value of K-RAS and tumor budding was 80%. Additionally, high-grade tumor budding was significantly related to worse progression-free survival [HR (95% CI): 2.8 (1.3-6.0, P=0.008)].CONCLUSION: If confirmed in larger cohorts, the addition of tumor budding to K-RAS analysis may represent an effective approach for individualized patient management in the metastatic setting.

Research progress in tumor angiogenesis and drug resistance in breast cancer

Angiogenesis is considered a hallmark pathophysiological process in tumor development. Aberrant vasculature resulting from tumor angiogenesis plays a critical role in the development of resistance to breast cancer treatments, via exacerbation of tumor hypoxia, decreased effective drug concentrations within tumors, and immune-related mechanisms. Antiangiogenic therapy can counteract these breast cancer resistance factors by promoting tumor vascular normalization. The combination of antiangiogenic therapy with chemotherapy, targeted therapy, or immunotherapy has emerged as a promising approach for overcoming drug resistance in breast cancer. This review examines the mechanisms associated with angiogenesis and the interactions among tumor angiogenesis, the hypoxic tumor microenvironment, drug distribution, and immune mechanisms in breast cancer. Furthermore, this review provides a comprehensive summary of specific antiangiogenic drugs, and relevant studies assessing the reversal of drug resistance in breast cancer. The potential mechanisms underlying these interventions are discussed, and prospects for the clinical application of antiangiogenic therapy to overcome breast cancer treatment resistance are highlighted.

Tumor microenvironment involvement in colorectal cancer progression via Wnt/β-catenin pathway:Providing understanding of the complex mechanisms of chemoresistance

Colorectal cancer(CRC)continues to be one of the main causes of death from cancer because patients progress unfavorably due to resistance to current therapies.Dysregulation of the Wnt/β-catenin pathway plays a fundamental role in the genesis and progression of several types of cancer,including CRC.In many subtypes of CRC,hyperactivation of theβ-catenin pathway is associated with mutations of the adenomatous polyposis coli gene.However,it can also be associated with other causes.In recent years,studies of the tumor microenvironment(TME)have demonstrated its importance in the development and progression of CRC.In this tumor nest,several cell types,structures,and biomolecules interact with neoplastic cells to pave the way for the spread of the disease.Cross-communications between tumor cells and the TME are then established primarily through paracrine factors,which trigger the activation of numerous signaling pathways.Crucial advances in the field of oncology have been made in the last decade.This Minireview aims to actualize what is known about the central role of the Wnt/β-catenin pathway in CRC chemoresistance and aggressiveness,focusing on crosscommunication between CRC cells and the TME.Through this analysis,our main objective was to increase the understanding of this complex disease considering a more global context.Since many treatments for advanced CRC fail due to mechanisms involving chemoresistance,the data here exposed and analyzed are of great interest for the development of novel and effective therapies.

The diverse functions and therapeutic implications of cancerassociatedfibroblasts in colorectal cancer

In the development of colorectal cancer(CRC),cancer-associatedfibroblasts(CAFs)play a pivotal role in establishing tumor-permissive extracellular matrix structures,angiogenesis,and modulating the immune status of the tumor microenvironment(TME),thereby influencing tumor metastasis and resistance to radiotherapy and chemotherapy.The pleiotropic effects of CAFs in the TME may be attributed to the heterogeneous origin and high plasticity of their population.Given the specificity of CAFs,they provide a variety of potential target molecules for future CRC treatment,which may play an indispensable role in CRC therapeutic strategies.This review summarizes the origin of CAFs and their roles in the CRC tumor microenvironment,including the interaction between exosomes and CAFs in CRC.Additionally,we discuss potential therapeutic strategies targeting CAFs.

Functionalized magnetic nanoparticles for drug delivery in tumor therapy

The side effects of chemotherapy are mainly the poor control of drug release. Magnetic nanoparticles(MNPs) have super-paramagnetic behaviors which are preferred for biomedical applications such as in targeted drug delivery, besides, in magnetic recording, catalysis, and others. MNPs, due to high magnetization response, can be manipulated by the external magnetic fields to penetrate directly into the tumor, thus they can act as ideal drug carriers. MNPs also play a crucial role in drug delivery system because of their high surface-to-volume ratio and porosity. The drug delivery in tumor therapy is related to the sizes, shapes, and surface coatings of MNPs as carriers. Therefore, in this review, we first summarize the effects of the sizes, shapes, and surface coatings of MNPs on drug delivery, then discuss three types of drug release systems, i.e., p H-controlled, temperature-controlled, and magnetic-controlled drug release systems, and finally compare the principle of passive drug release with that of active drug release in tumor therapy.

Erythropoietin-induced hepatocyte receptor A2 regulates effect of pyroptosis on gastrointestinal colorectal cancer occurrence and metastasis resistance

Erythropoietin-induced hepatocyte receptor A2(EphA2)is a receptor tyrosine kinase that plays a key role in the development and progression of a variety of tumors.This article reviews the expression of EphA2 in gastrointestinal(GI)colorectal cancer(CRC)and its regulation of pyroptosis.Pyroptosis is a form of programmed cell death that plays an important role in tumor suppression.Studies have shown that EphA2 regulates pyrodeath through various signaling pathways,affecting the occurrence,development and metastasis of GI CRC.The overexpression of EphA2 is closely related to the aggressiveness and metastasis of GI CRC,and the inhibition of EphA2 can induce pyrodeath and improve the sensitivity of cancer cells to treatment.In addition,EphA2 regulates intercellular communication and the microenvironment through interactions with other cytokines and receptors,further influencing cancer progression.The role of EphA2 in GI CRC and its underlying mechanisms provide us with new perspectives and potential therapeutic targets,which have important implications for future cancer treatment.

Challenges and exploration for immunotherapies targeting cold colorectal cancer

In recent years,immune checkpoint inhibitors(ICIs)have made significant breakthroughs in the treatment of various tumors,greatly improving clinical efficacy.As the fifth most common antitumor treatment strategy for patients with solid tumors after surgery,chemotherapy,radiotherapy and targeted therapy,the therapeutic response to ICIs largely depends on the number and spatial distribution of effector T cells that can effectively identify and kill tumor cells,features that are also important when distinguishing malignant tumors from“cold tumors”or“hot tumors”.At present,only a small proportion of colorectal cancer(CRC)patients with deficient mismatch repair(dMMR)or who are microsatellite instability-high(MSI-H)can benefit from ICI treatments because these patients have the characteristics of a“hot tumor”,with a high tumor mutational burden(TMB)and massive immune cell infiltration,making the tumor more easily recognized by the immune system.In contrast,a majority of CRC patients with proficient MMR(pMMR)or who are microsatellite stable(MSS)have a low TMB,lack immune cell infiltration,and have almost no response to immune monotherapy;thus,these tumors are“cold”.The greatest challenge today is how to improve the immunotherapy response of“cold tumor”patients.With the development of clinical research,immunotherapies combined with other treatment strategies(such as targeted therapy,chemotherapy,and radiotherapy)have now become potentially effective clinical strategies and research hotspots.Therefore,the question of how to promote the transformation of“cold tumors”to“hot tumors”and break through the bottleneck of immunotherapy for cold tumors in CRC patients urgently requires consideration.Only by developing an in-depth understanding of the immunotherapy mechanisms of cold CRCs can we screen out the immunotherapy-dominant groups and explore the most suitable treatment options for individuals to improve therapeutic efficacy.

Systemic therapy in gastrointestinal stromal tumors

Gastrointestinal stromal tumors(GISTs)are the most common type of soft tissue sarcoma in the gastrointestinal tract.Most GISTs have been attributed to activated gain-of-function mutations in either KIT or platelet-derived growth factor receptorα,making these molecular features essential targets for therapeutic interventions.Although surgery is the standard treatment for localized GISTs,patients often experience relapse and disease progression even after surgery.In recent years,targeted therapy has significantly improved the prognosis of patients with advanced GISTs.Imatinib mesylate,a KIT inhibitor,is the first-line treatment for advanced GISTs and has revolutionized the treatment of this disease.However,drug resistance remains a major issue with imatinib treatment,as a significant majority of patients become resistant to imatinib either after initiation or after 2–3 years of treatment.Consequently,novel tyrosine kinase inhibitors such as sunitinib,regorafenib,ripretinib,and avapritinib have been introduced to address drug resistance.Immunotherapy has emerged as a potential approach for the treatment of advanced GISTs.This review comprehensively summarizes the pathogenesis of GISTs and the development of targeted therapies and immunotherapies,provides an overview of the emergence of drug resistance in advanced GISTs,and discusses the challenges and prospects associated with the treatment of GISTs.

Research advancements in nanoparticles and cell-based drug delivery systems for the targeted killing of cancer cells

Nanotechnology in cancer therapy has significantly advanced treatment precision,effectiveness,and safety,improving patient outcomes and personalized care.Engineered smart nanoparticles and cell-based therapies are designed to target tumor cells,precisely sensing the tumor microenvironment(TME)and sparing normal cells.These nanoparticles enhance drug accumulation in tumors by solubilizing insoluble compounds or preventing their degradation,and they can also overcome therapy resistance and deliver multiple drugs simultaneously.Despite these benefits,challenges remain in patient-specific responses and regulatory approvals for cell-based or nanoparticle therapies.Cell-based drug delivery systems(DDSs)that primarily utilize the immune-recognition principle between ligands and receptors have shown promise in selectively targeting and destroying cancer cells.This review aims to provide a comprehensive overview of various nanoparticle and cell-based drug delivery system types used in cancer research.It covers approved and experimental nanoparticle therapies,including liposomes,micelles,protein-based and polymeric nanoparticles,as well as cell-based DDSs like macrophages,T-lymphocytes,dendritic cells,viruses,bacterial ghosts,minicells,SimCells,and outer membrane vesicles(OMVs).The review also explains the role of TME and its impact on developing smart DDSs in combination therapies and integrating nanoparticles with cell-based systems for targeting cancer cells.By detailing DDSs at different stages of development,from laboratory research to clinical trials and approved treatments,this review provides the latest insights and a collection of valuable citations of the innovative strategies that can be improved for the precise treatment of cancer.

Micelles as potential drug delivery systems for colorectal cancer treatment

Despite the significant progress in cancer therapy,colorectal cancer(CRC)remains one of the most fatal malignancies worldwide.Chemotherapy is currently the mainstay therapeutic modality adopted for CRC treatment.However,the long-term effectiveness of chemotherapeutic drugs has been hampered by their low bioavailability,non-selective tumor targeting mechanisms,non-specific biodistribution associated with low drug concentrations at the tumor site and undesirable side effects.Over the last decade,there has been increasing interest in using nanotechnology-based drug delivery systems to circumvent these limitations.Various nanoparticles have been developed for delivering chemotherapeutic drugs among which polymeric micelles are attractive candidates.Polymeric micelles are biocompatible nanocarriers that can bypass the biological barriers and preferentially accumulate in tumors via the enhanced permeability and retention effect.They can be easily engineered with stimuli-responsive and tumor targeting moieties to further ensure their selective uptake by cancer cells and controlled drug release at the desirable tumor site.They have been shown to effectively improve the pharmacokinetic properties of chemotherapeutic drugs and enhance their safety profile and anticancer efficacy in different types of cancer.Given that combination therapy is the new strategy implemented in cancer therapy,polymeric micelles are suitable for multidrug delivery and allow drugs to act concurrently at the action site to achieve synergistic therapeutic outcomes.They also allow the delivery of anticancer genetic material along with chemotherapy drugs offering a novel approach for CRC therapy.Here,we highlight the properties of polymeric micelles that make them promising drug delivery systems for CRC treatment.We also review their application in CRC chemotherapy and gene therapy as well as in combination cancer chemotherapy.

Rationally designed treatment for metastatic colorectal cancer:Current drug development strategies

The therapeutic landscape of metastatic colorectal cancer(mCRC)has changed substantially with the emergence of new molecularly targeted agents(MTA)usedas single agents or alongside standard chemotherapy.The use of these MTAs extended the overall survival ofpatients with mCRC to a level that current chemotherapeutics alone could not achieve.In addition,improvement in surgical techniques and ablation modalities offer cure to a limited subset of patients with mCRC andMTAs have been found to have a significant role heretoo,as they aid resectability.However,for the majority of patients,mCRC remains an invariably incurabledisease necessitating continued courses of combinedtreatment modalities.During the course of these treatments,either cytotoxic or biological,cancer cells maintain their ability to acquire mitogenic mutations whichrender them resistant to treatment.Key challengesremain to identify appropriate subsets of patients whowill most likely benefit from these new MTAs and effectively select these based on validated biomarkers.Moreover,better knowledge of the biology of colorectal cancer and the mechanisms via which it bypasses blockade of known signalling pathways will help us design better and more rational sequencing of these treatments,so that we can maximise the survivorship of mCRC patients.This review outlines treatment strategies for known molecular alterations with new MTAs and highlights some promising strategies.

Paradoxical role of interleukin-33/suppressor of tumorigenicity 2 in colorectal carcinogenesis: Progress and therapeutic potential

Colorectal cancer(CRC)is presently the second most prevalent global mortalityinducing cancer.CRC carcinogenesis is a multifactorial process involving internal genetic mutations and the external environment.In addition,non-neoplastic cell activities within tumor microenvironments for CRC development have been established.However,interleukin(IL)-33,secreted by such cell types,plays a pivotal role in cancer progression due to interaction with cellular constituents within the tumor-inflammation microenvironment.IL-33 belongs to the IL-1 cytokine family and acts as binding attachments for the suppressor of tumorigenicity(ST)2 receptor.Therefore,how to coordinate tumor microenvironment,design and optimize treatment strategies suitable for CRC,based on IL-33/ST2 signal is a challenge.Even though it has established influences upon immunitylinked conditions,IL-33 effects on CRC progression and prevention and related mechanisms are still controversial.Our review depicts controversial activities for IL-33/ST2 within carcinogenesis and cancer prevention.Moreover,IL-33/ST2 signaling is a potential therapeutic target for CRC.

Colorectal cancer: From prevention to personalized medicine

Colorectal cancer(CRC)is a very heterogeneous disease that is caused by the interaction of genetic and environmental factors.CRC develops through a gradual accumulation of genetic and epigenetic changes,leading to the transformation of normal colonic mucosa into invasive cancer.CRC is one of the most prevalent and incident cancers worldwide,as well as one of the most deadly.Approximately 1235108 people are diagnosed annually with CRC,and 609051 die from CRC annually.The World Health Organization estimates an increase of77%in the number of newly diagnosed cases of CRCand an increase of 80%in deaths from CRC by 2030.The incidence of CRC can benefit from different strategies depending on its stage:health promotion through health education campaigns(when the disease is not yet present),the implementation of screening programs(for detection of the disease in its early stages),and the development of nearly personalized treatments according to both patient characteristics(age,sex)and the cancer itself(gene expression).Although there are different strategies for screening and although the number of such strategies is increasing due to the potential of emerging technologies in molecular marker application,not all strategies meet the criteria required for screening tests in population programs;the three most accepted tests are the fecal occult blood test(FOBT),colonoscopy and sigmoidoscopy.FOBT is the most used method for CRC screening worldwide and is also the primary choice in most population-based screening programs in Europe.Due to its non-invasive nature and low cost,it is one of the most accepted techniques by population.CRC is a very heterogeneous disease,and with a few exceptions(APC,p53,KRAS),most of the genes involved in CRC are observed in a small percentage of cases.The design of genetic and epigenetic marker panels that are able to provide maximum coverage in the diagnosis of colorectal neoplasia seems a reasonable strategy.In recent years,the use of DNA,RNA and protein markers in different biological samples has been explored as strategies for CRC diagnosis.Although there is not yet sufficient evidence to recommend the analysis of biomarkers such as DNA,RNA or proteins in the blood or stool,it is likely that given the quick progression of technology tools in molecular biology,increasingly sensitive and less expensive,these tools will gradually be employed in clinical practice and will likely be developed in mass.

Apoptotic pathways as a therapeutic target for colorectal cancer treatment

Colorectal cancer is the second leading cause of death from cancer among adults. The disease begins as a benign adenomatous polyp, which develops into an advanced adenoma with high-grade dysplasia and then progresses to an invasive cancer. Appropriate apoptotic signaling is fundamentally important to preserve a healthy balance between cell death and cell survival and in maintaining genome integrity. Evasion of apoptotic pathway has been established as a prominent hallmark of several cancers. During colorectal cancer development, the balance between the rates of cell growth and apoptosis that maintains intestinal epithelial cell homeostasis gets progressively disturbed. Evidences are increasingly available to support the hypothesis that failure of apoptosis may be an important factor in the evolution of colorectal cancer and its poor response to chemotherapy and radiation. The other reason for targeting apoptotic pathway in the treatment of cancer is based on the observation that this process is deregulated in cancer cells but not in normal cells. As a result, colorectal cancer therapies designed to stimulate apoptosis in target cells would play a critical role in controlling its development and progression. A better understanding of the apoptotic signaling pathways, and the mechanisms by which cancer cells evade apoptotic death might lead to effective therapeutic strategies to inhibit cancer cell proliferation with minimal toxicity and high responses to chemotherapy. In this review, we analyzed the current understanding and future promises of apoptotic pathways as a therapeutic target in colorectal cancer treatment.

Recent progress on nanoparticle-based drug delivery systems for cancer therapy

The development of cancer nanotherapeutics has attracted great interest in the recent decade. Cancer nanotherapeutics have overcome several limitations of conventional therapies, such as nonspecific biodistribution, poor water solubility, and limited bioavailability. Nanoparticles with tuned size and surface characteristics are the key components of nanotherapeutics, and are designed to passively or actively deliver anti-cancer drugs to tumor cells. We provide an overview of nanoparticle-based drug delivery methods and cancer therapies based on tumor-targeting delivery strategies that have been developed in recent years.

Trans-arterial chemoperfusion for the treatment of liver metastases of breast cancer and colorectal cancer: Clinical results in palliative care patients

AIM To evaluate the clinical value and efficiency of transarterial chemoperfusion(TACP) in patients with liver metastases from breast cancer(BC) and colorectal cancer(CRC).METHODS We treated 36 patients with liver metastases of BC(n = 19, 19 females) and CRC(n = 17; 8 females, 9 males) with repeated TACP. The treatment interval was 4 wk. TACP was performed with gemcitabine(1000 mg/m2) and mitomycin(10 mg/m2), administered within 1 h after positioning the catheter tip in the hepatic artery. Before treatment, the size, location, tumour volume, vascularization and number of liver tumours were evaluated using magnetic resonance imaging(MRI). Tumour response was evaluated according to the Response Evaluation Criteria in Solid Tumors guidelines.RESULTS TACP using gemcitabine and mitomycin for metastases from CRC and BC was performed without any serious side effects. The follow-up MRI showed a therapeutic response in 84.2% of the BC patients-stable disease 47.4% and partial response 36.8%. A progression was seen in 15.8%.CRC patients showed a therapeutic response in 52.9% of cases. A progression of the disease was documented in 47.1% of the patients with CRC. These data show that TACP in patients with liver metastases of BC leads to a significantly better therapeutic response compared with CRC patients(P = 0.042). The median survival time was 13.2 mo for the BC patients, which is significantly longer than for CRC patients at 9.3 mo(P = 0.001).CONCLUSION TACP for liver metastases of BC appears to be a safe and effective palliative treatment with improved outcomes in comparison to patients with CRC.

Liver-first approach of colorectal cancer with synchronous hepatic metastases: A reverse strategy

Recently, there has been a change in the strategy of how synchronous colorectal hepatic metastases are attributed to the development of more valuable protocols of chemotherapy and radiotherapy for neoadjuvant treatment of colorectal neoplasms and their hepatic metastases. There is a consensus that patients with synchronous colorectal hepatic metastases have lower survival than those with metachronous colorectal hepatic metastases. Currently, controversy remains concerning the best approach is sequence in a patient with colorectal cancer and synchronous hepatic metastases resection. To obtain a better patient selection, the authors have suggested the initial realization of systemic chemotherapy in the circumstance of patients with colorectal tumor stage Ⅳ, since these patients have a systemic disease. The rationale behind this liver-first strategy is initially the control of synchronous hepatic metastases of colorectal carcinoma, which can optimize a potentially curative hepatic resection and longstanding survival. The liver-first strategy procedure is indicated for patients with colorectal hepatic metastases who require downstaging therapy to make a curative liver resection possible. Thus, the liver-first strategy is considered an option in cases of rectal carcinoma in the early stage and with limited or advanced synchronous colorectal hepatic metastases or in case of patients with asymptomatic colorectal carcinoma, but with extensive liver metastases. Patients undergoing systemic chemotherapy and with progression of neoplastic disease should not undergo hepatic resection, because it does not change the prognosis and may even make it worse. To date, there have been no randomized controlled trials on surgical approach of colorectal synchronous hepatic metastases, despite the relatively high number of available manuscripts on this subject. All of these published studies are observational, usually retrospective, and often non-comparative. The patient selection criteria for the liver-first strategy should be individualized, and the approach of these patients should be performed by a multidisciplinary team so its benefits will be fully realized.

Specific CEA-producing colorectal carcinoma cell killing with recombinant adenoviral vector containing cytosine deaminase gene

AIM: To kill CEA positive colorectal carcinoma cells specifically using the E coli cytosine deaminase (CD) suicide gene, a new replication-deficient recombinant adenoviral vector was constructed in which CD gene was controlled under CEA promoter and its in vitro cytotoxic effects were evaluated. METHODS: Shuttle plasmid containing CD gene and regulatory sequence of the CEA gene was constructed and recombined with the right arm of adenovirus genome DNA in 293 cell strain. Dot blotting and PCR were used to identify positive plaques. The purification of adenovirus was performed with ultra-concentration in CsCl step gradients and the titration was measured with plaque formation assay. Cytotoxic effects were assayed with MTT method, The fifty percent inhibition concentration (IC(50)) of 5-FC was calculated using a curve-fitting parameter. The human colorectal carcinoma cell line, which was CEA-producing, and the CEA-nonproducing Hela cell line were applied in cytological tests. An established recombinant adenovirus vector AdCMVCD, in which the CD gene was controlled under CMV promoter, was used as virus control. Quantitative results were expressed as the mean +/- SD of the mean. Statistical analysis was performed using ANOVA test. RESULTS: The desired recombinant adenovirus vector was named AdCEACD. The results of dot blotting and PCR showed that the recombinant adenovirus contained CEA promoter and CD gene. Virus titer was about 5.0 X 10(14)pfu/L(-1) after purification. The CEA-producing Lovo cells were sensitive to 5-FC and had the same cytotoxic effect after infection with AdCEACD and AdCMVCD (The IC(50) values of 5-FC in parent Lovo cells, Lovo cells infected with 100 M.O.I AdCEACD and Lovo cells infected with 10 M.O.I AdCMVCD were 】15000, 216.5+/-38.1 and 128.8+/-25.4 micromol.L(-1), P【0.001, respectively), and the cytotoxicity of 5-FC increased accordingly when the m.o.i of adenoviruses were enhanced (The value of IC(50) of 5-FC was reduced to 27.9+/-4.2 micromol.L(-1) in 1000 M.O.I AdCEACD infected Lovo cells and 24.8+/-7.1 micromol.L(-1) in 100 M.O.I AdCMVCD infected Lovo cells, P【0.05, P【0.01, respectively). The CEA-nonproducing Hela cells had no effect after infection with AdCEACD, but Hela cells had the cytotoxic sensitivity to 5-FC after infection with AdCMVCD (The IC(50) of 5-FC in parent Hele cells and Hela cells infected with AdCMVCD at 10 M.O.I was 】15000 and 214.5+/-31.3 micromol.L(-1), P【0.001). AdCEACD/5-FC system also had bystander effect, and the viability was about 30 percent when the proportion of transfected cells was only 10 percent. CONCLUSION: The recombinant adenovirus vector AdCEACD has the character of cell type-specific gene delivery. The AdCEACD/5-FC system may become a new, potent and specific approach for the gene therapy of CEA-positive neoplasms, especially colon carcinoma.