Progress in the studies on the molecular mechanisms associated with multidrug resistance in cancers

Chemotherapy is one of the important methods to treat cancer, and the emergence of multidrug resistance (MDR) is one major cause for the failure of cancer chemotherapy. Almost all anti-tumor drugs develop drug resistance over a period of time of application in cancer patients, reducing their effects on killing cancer cells. Chemoresistance can lead to a rapid recurrence of cancers and ultimately patient death. MDR may be induced by multiple mechanisms, which are associated with a complex process of multiple genes, factors, pathways, and multiple steps, and today the MDR-associated mechanisms are largely unknown. In this paper, from the aspects of protein-protein interactions, alternative splicing (AS) in pre-mRNA, non-coding RNA (ncRNA) mediation, genome mutations, variance in cell functions, and influence from the tumor microenvironment, we summarize the molecular mechanisms associated with MDR in cancers. In the end, prospects for the exploration of antitumor drugs that can reverse MDR are briefly discussed from the angle of drug systems with improved targeting properties, biocompatibility, availability, and other advantages.

Antimicrobial resistance and genomic characteristics of Salmonella enterica serovar Derby isolates from clinical patients and food sources in Hangzhou / 中华微生物学和免疫学杂志

Objective:To analyze the antimicrobial resistance and genomic characteristics of Salmonella enterica serovar Derby strains isolated from human and food sources in Hangzhou. Methods:A total of 60 Salmonella enterica serovar Derby strains isolated in Hangzhou during the period from 2015 to 2020 were subjected to antimicrobial susceptibility testing, pulsed field gel electrophoresis (PFGE) typing and whole-genome sequencing. Multilocus sequence typing (MLST), core genome multilocus sequence typing (cgMLST) and the identification of antimicrobial resistance genes were performed using the sequencing data. Phylogenetic tree based on the single nucleotide polymorphism (SNP) sites in the 60 genomes from Hangzhou and 379 genomes from public databases was constructed. Results:No significant difference was observed in the drug resistance rates between the clinical strains and food strains in Hangzhou. The multidrug resistance (MDR) rate was 76.7% (46/60). All of the 60 Salmonella Derby strains were positive for the antimicrobial resistance genes aac(6′)- Iaa and fosA7. The 60 strains were subtyped into 46 molecular types by PFGE and 53 molecular types by cgMLST(HC2). Except for one strain belonging to ST3220, the other Salmonella Derby strains were ST40. The phylogenetic analysis showed that some strains isolated in Hangzhou were close to the strains in Southeast Asia, suggesting the possibility of cross-border transmission of ST40 strains, with the main food sources being pork and fish; other strains were close to those circulating in Beijing, Guangzhou, Hubei, Chongqing and other provinces, suggesting the possibility of cross-province transmission of the strains, with the main food sources being pork, beef and chicken. Conclusions:The epidemic of Salmonella Derby in Hangzhou was mainly caused by the spread of ST40 strains and MDR was common. Clinical infections might be closely related to the consumption of pork, beef, chicken and fish. There was the possibility of cross-border transmission of Salmonella Derby between Hangzhou and Southeast Asia and cross-province transmission in China.

Therapeutic effect of propolis on Staphylococcus aureus induced oxidative stress in kidney of BALB/c mice. A biochemical and histopathological study

Due to emerging drug resistance in pathogenic organisms, most of the second generation antibiotics are not effective in controlling the disease. As a consequence, the dosage and duration of drug intake has increased leading to drug induced toxicity and various side effects. A large number of natural products are being reported to ameliorate the toxicity and oxidative stress caused by antibiotics. Here, we explored the antioxidative potential of honey bee product propolis alone as well as in combination with antibiotics in Staphylococcus aureus infected BALB/c mice. For experimental design, mice were divided in to seven groups and decapitated after experimental period. Kidney was excised, homogenized and then used for different biochemical and histopathological estimations. Results observed after treatment with propolis and antibiotics were compared with those of S. aureus infected group. Results showed increase in lipid peroxidation, decrease in reduced glutathione levels and antioxidant enzymes such as; catalase, superoxide dismutase, glutathione-S-transferase, glutathione peroxidase and glutathione reductase. On the contrary, treatment with propolis, led to reduction in levels of LPO and increase in activities of antioxidant enzymes. Also, histopathology of kidney and all kidney function enzymes were restored to near normal.

Multidrug Resistance in Breast Cancer and Coping Strategies of Chinese Medicine： A Review / 中国实验方剂学杂志

Breast cancer， as a kind of malignant tumor with high incidence rate in female population， poses a great threat to people's health. At present， chemotherapy is the main treatment for breast cancer besides surgery and radiotherapy. However， chemotherapy is often accompanied by multidrug resistance （MDR）， which results in a series of severe consequences such as low efficacy， relapse of cancer after drug withdrawal， increased consumption of medical resources， and increased burden of medical system. Previous studies showed that the mechanism of MDR in breast cancer was quite complex， involving drug efflux， deoxyribonucleic acid （DNA） damage repair， tumor microenvironment， autophagy， epigenetic regulation， tumor stem cells， lipid metabolism， and so on. In addition， there were extensive connections among the mechanisms of MDR. Therefore， it is necessary to reveal the mechanism of MDR and develop corresponding drugs to reverse MDR， thus improving the effect of chemotherapy on treating breast cancer. Chinese medicine has the advantages of high efficiency， low toxicity， multi targets， and overall regulation. Various studies found that Chinese medicine monomer， single drug， and compound were able to reverse MDR in breast cancer by regulating the expression of drug efflux protein， promoting apoptosis， and regulating autophagy， showing the potential of anti-MDR in breast cancer. This paper summarized the research progress of the mechanism of MDR in breast cancer and the strategies of Chinese medicine in coping with MDR in breas cancer in recent years， and provided references for further research.

Effectiveness of malabaricone-A in P-glycoprotein over-expressing cancer cell lines

Background: A major impediment in treatment for cancers is resistance to chemotherapy and is primarily attributed to over-expression of efflux pumps. This study aimed to establish the cytotoxicity of malabaricone-A (MAL-A) in P-glycoprotein/multidrug resistance (P-gp/MDR) over-expressing hematopoietic cancer cell lines.Methods: Leukemia and multiple myeloma cell lines were indirectly evaluated for their P-gp/MDR status by examining Calcein-AM fluorescence and cell viability was assessed by the MTS-PMS assay.Results: The fluorescence of calcein was significantly decreased in three cell lines LP-1, RPMI-8226 and CEM-ADR 5000 and reversal with verapamil endorsed their P-gp/MDR activity. The mean IC50 of MAL-A in these MDR+ cell lines (5.40±1.41 to 12.33±0.78 µg/ml) was comparable with the MDR- leukemic (9.72±1.08 to 19.26±0.75 µg/ml) and multiple myeloma cell lines (9.65±0.39 to 18.05±0.17 ?g/ml).Conclusions: Irrespective of their P-gp activity, the cytotoxicity of MAL-A was comparable, making it worthy of future pharmacological consideration in multidrug resistance.

Research progress on anticancer drugs with quercetin as lead compound / 中草药

Quercetin has the effects of anti-oxidation, prevention of cardiovascular and cerebrovascular diseases, chemical prevention, and anticancer. Because of the low bioavailability, poor water solubility, rapid metabolism, and enzyme degradation, its clinical application is limited. Due to the good solubility, high bioavailability, stable metabolism, and little the poisonous side effects, quercetin derivatives are the hot spots of the study on the modification of quercetin structure. In the last 10 years, researchers have synthesized a large number of quercetin ethers, esters, metal complexes, C-4 carbonyl oxygen substituted derivatives, and A, B ring modified compounds, and the detection of anticancer activity was conducted in vitro. In this paper, the anticancer activity of quercetin derivatives in recent 10 years is reviewed.

ABCG2 inhibition as a therapeutic approach for overcoming multidrug resistance in cancer.

Breast cancer resistance protein (BCRP, ABCP or MXR)/ATP-binding cassette subfamily G member 2 (ABCG2) was characterized as a multidrug resistance efflux transporter in 1998. ABCG2 physiologically acts as a part of a selfdefence mechanism for the organism; it enhances eliminating of toxic xenobiotic substances and harmful agents in the intestine, as well as through the blood–brain barrier and placenta. ABCG2 recognizes and transports numerous anticancer drugs including conventional chemotherapeutic and new targeted small therapeutic molecules in clinical usage. Development of ABCG2 inhibitors for clinical usage may allow increased penetration of therapeutic agents into sanctuary sites and increases their intestinal absorption. Here we review the mechanisms that modulate MDR mediated by the ABC transporter ABCG2 in normal and cancer cells by different levels including, epigenetic modifications, transcriptional, post-transcriptional, translation and post-translational regulation. Some clinical applications of ABCG2 inhibitors are also explained.

Application of co-delivery systems in cancer treatment / 国际药学研究杂志

Chemotherapy plays an important role in cancer treatment. However ,the low water-solubility and serious side effects are still the biggest obstacles in clinic. In addition,the wide use of chemotherapeutic drugs would result in the multidrug resis?tance(MDR)and the single chemotherapy could not meet the demand of clinic anymore. Combination therapy by two or more drugs used in the same time,has become the best choice for cancer patients. It not only enhances the cytotoxicity of the chemotherapeutic drugs due to the synergistic effect of the drugs,but also inhibits the MDR to improve uptake and cytotoxicity of the chemotherapeutic drugs when adding MDR inhibitors. The drug delivery system can improve the water-solubility due to the good biocompatibility of bio?degradable material which is the most property for drug delivery carriers. In addition,the targeting ability of the system and the con?trolled release of chemotherapeutic drugs can also reduce the side effects of drugs such as the cardiotoxicity of doxorubicin. The co-deliv?ery system loading two or more chemotherapeutic drugs in the same carrier can get better cytotoxicity than the combination therapy using free drugs due to the efficient delivery of chemotherapeutic drugs to cancer cells ,and are even better than the combination of single drug-loaded drug delivery systems because the chemotherapeutic drugs can get into the cancers cells in the same time. In addi?tion,with the rapid development of gene therapy,the co-delivery of drugs and genes has also been a hot topic these days. In this paper, we focus on the preparation,characteristics and application of drug+drug and drug+gene co-delivery system,which can produce the synergistic effects or inhibit the MDR of cancer cells.

Application of co-delivery systems in cancer treatment / 国际药学研究杂志

Chemotherapy plays an important role in cancer treatment. However, the low water-solubility and serious side effects are still the biggest obstacles in clinic. In addition, the wide use of chemotherapeutic drugs would result in the multidrug resistance (MDR)and the single chemotherapy could not meet the demand of clinic anymore. Combination therapy by two or more drugs used in the same time, has become the best choice for cancer patients. It not only enhances the cytotoxicity of the chemotherapeutic drugs due to the synergistic effect of the drugs, but also inhibits the MDR to improve uptake and cytotoxicity of the chemotherapeutic drugs when adding MDR inhibitors. The drug delivery system can improve the water-solubility due to the good biocompatibility of biodegradable material which is the most property for drug delivery carriers. In addition, the targeting ability of the system and the controlled release of chemotherapeutic drugs can also reduce the side effects of drugs such as the cardiotoxicity of doxorubicin. The co-delivery system loading two or more chemotherapeutic drugs in the same carrier can get better cytotoxicity than the combination therapy using free drugs due to the efficient delivery of chemotherapeutic drugs to cancer cells, and are even better than the combination of single drug-loaded drug delivery systems because the chemotherapeutic drugs can get into the cancers cells in the same time. In addition, with the rapid development of gene therapy, the co-delivery of drugs and genes has also been a hot topic these days. In this paper, we focus on the preparation, characteristics and application of drug+drug and drug+gene co-delivery system, which can produce the synergistic effects or inhibit the MDR of cancer cells.

Molecular Detection of Antimicrobial Resistance Gene Cassettes Associated with Class 2 Integron in Salmonella Serovars Isolated in Iran.

Aim: Salmonella is an important food-borne pathogen in humans and a broad range of animals. Antimicrobial resistance in Salmonella spp. is a serious health problem in human and veterinary medicine worldwide. The aim of this study was to detect integrons, the natural recombination systems that can be transferred in companion with mobile genetic elements and play a major role in spreading antibiotic resistance genes in clinical isolates. Place and Duration of Study: Salmonella clinical isolates were provided by a number of institutes and hospitals over the country through the years 2008-2009. Methodology: Antimicrobial susceptibility testing and serotyping were carried out for eighty four epidemiologically unrelated clinical isolates of Salmonella serovars collected from different provinces of Iran through the years 2008-2009. PCR assays were carried out to detect intI2 gene (integrase I attributed to class 2 integron) and internal variable regions (IVRs) of class 2 integron. These sequences were deposited in EMBL/GenBank database (www.ncbi.nlm.nih.gov). Results: Eleven isolates (13.1%) which were resistant to at least 4 groups of antimicrobial agents were considered as MDR (multidrug resistant) Salmonella serovars. PCR assays detected intI2 gene (integrase I attributed to class 2 integron) and internal variable regions (IVRs) of class 2 integron in Fourteen (16.7%) and eleven (78.6%) of Salmonella clinical isolates respectively. Analysis of the sequence data revealed 3 gene cassette arrays deposited in Genbank databases including the dhfrA1 (0.75 kb), dfrA14- lsp (1 kb), dhfrA1- sat2-aadA1 (3 kb) with three IVR distribution patterns. An artifact PCR product of 2 kb was reported in this study to be amplified together with IVRs of class 2 integrons which was associated with the fhuE- ptsG genes. Conclusions: Presence of MDR Salmonella serovars demonstrates that antimicrobial selection pressure is widespread in our clinical settings. Detection of class 2 integron carrying gene cassettes which confer resistance to different classes of antibiotics such as aminoglycosides, and trimethoprim confirms that integron-mediated antimicrobial gene cassettes are prevalent in Salmonella serovars isolated in Iran.

Anticancer and multidrug-resistance reversing potential of traditional medicinal plants and their bioactive compounds in leukemia cell lines / 中国天然药物

Multidrug resistance remains a serious clinical problem in the successful therapy of malignant diseases. It occurs in cultured tumor cell lines, as well as in human cancers. Therefore, it is critical to develop novel anticancer drugs with multidrug-resistance modulating potential to increase the survival rate of leukemia patients. Plant-derived natural products have been used for the treatment of various diseases for thousands of years. This review summarizes the anticancer and multidrug-resistance reversing properties of the extracts and bioactive compounds from traditional medicinal plants in different leukemia cell lines. Further mechanistic studies will pave the road to establish the anticancer potential of plant-derived natural compounds.

Expression and Function of ABC Transporters as Multidrug Resistance Mechansims in Gastric Cancer Cells

PURPOSE: Multidrug resistance (MDR) is a phenomenon whereby tumor cell acquire resistance to a broad range of structurally and functionally diverse chemotherapeutic drugs. The most widely implicated mechanism of MDR is that of altered membrane transporter in tumor cells. P-glycoprotein (Pgp), multidrug resistance protein (MRP), and breast cancer-resistance protein (BCRP) are well known membrane transporters, which pump out antitumor agents via an ATP-dependent process, the so called ATP-binding cassette (ABC) superfamily or transporter. This study was undertaken to test the prevalence of each ABC transporter, and which of then exhibit functional activity in various gastric cancer cells. METHODS: The expressions of Pgp, MRP, and BCRP mRNA were determined by RT-PCR assay on 10 gastric cancer cells. The sensitivity to anticancer agents, substrates for each ABC transporter in the gastric cancer cells was determined using the MTT assay. The intracellular accumulation of fluorescent compounds for the functional detection of each ABC transporter was determined using flow cytometry. RESULTS: The Pgp mRNA was expressed at various levels in 9 out of the 10 gastric cancer cells tested, but significantly low. MRP mRNA was constitutively expressed in all the cells. BCRP mRNA was differentially expressed in 5 of the gastric cancer cells. There was no relation between the expressions of Pgp and MRP and the cytotoxicity to each substrate. It was observed that the accumulations of paclitaxel and VP-16 were significantly increased on the additions of PSC833 and probenecid, respectively, in all tested cells. The reversal effect of drug accumulation by each inhibitor was much higher in the MRP than Pgp. With BCRP, the observed cytotoxic effect and amount of mitoxanthrone accumulation were less than in the cells expressing the highest levels of BCRP compared to those that did not. However the mitoxanthrone accumulation was not increased on the addition of FTC in the either cell type. CONCLUSION: This study suggests that of the ABC transporters, MRP has primarily functional activity, whereas that of Pgp is only slight, in the gastric cancer cells. Other possible MDR mechanisms involved will have to be explored in further studies.

Expression and Function of ABC Transporters as Multidrug Resistance Mechansims in Colon Cancer Cells

PURPOSE: Multidrug resistance (MDR) is a phenomenon whereby tumor cells acquire resistance to a broad range of structurally and functionally diverse chemotherapeutic drugs. The most widely implicated mechanism of MDR is that concerned with altered membrane transporters in tumor cells. P-glycoprotein (Pgp), multidrug resistance protein (MRP), and breast-cancer-resistance protein (BCRP) are well-known membrane transporters that pump out antitumor agents by using an ATP-dependent process, the so-called ATP-binding cassette (ABC) superfamily or transporter. This study was undertaken to test the prevalence of each ABC transporter and to determine which transporter has functional acitivity in various colon cancer cells. METHODS: Expressions of Pgp, MRP, and BCRP mRNA were determined in 9 colon-cancer cell lines by using an RT-PCR assay. The sensitivity to anticancer agents substrate for each ABC transporter in the colon cancer cells determined using an MTT assay. The accumulation of fluorescent compounds for functional detection of each ABC transporter was determined by using flow cytometry. RESULTS: Pgp mRNA was variably expressed in 6 of 9 colon cancer cells lines. MRP and BCRP mRNA were expressed in all the 9 cell lines. A smaller cytotoxic effect to paclitaxel and a smaller amount of rhodamine123 accumulation were observed in Colo 320HSR expressing the highest levels of Pgp than in SNU-C5 not expressing Pgp. These effects in Colo320HSR were reversed with the addition of various Pgp inhibitors, but such a reversal did not occur in SNU-C5. The cytotoxic effect to VP-16 was not related to the expression levels of MRP in Colo320HSR and SNU-C, but the amount of calcein-AM accumulation was reversed with addition of probenecid, MRP inhibitor. The cytotoxic effect and the drug accumulation of mitoxantrone were not related to the expression levels of BCRP. CONCLUSIONS: This study suggests that of the ABC transporters, primarily Pgp and MRP have functional activity in colon cancer cell lines.

Tumor chemosensitization strategies based on apoptosis manipulations / 中国药理学通报

MDR(multidrug-resistance)is a major obstacle in the chemotherapy of cancer.Numerous mechanisms are known to contribute to MDR,alterations at the level of apoptosis control are one of those mechanisms except overexpression of drug efflux pumps.This review focuses on the research progression of alterations at the level of apoptosis inducing MDR,and some of the strategies that have been used in an attempt to chemosensitize resistant tumors by manipulating dysregulated apoptosis pathways.

The Frequency and Clinical Significance of Multidrug Resistance-1 (MDR-1) Gene Expression in Acute Myeloid Leukemia / 대한혈액학회지

BACKGROUND: The expression of the multidrug resistance-1 (MDR-1) gene which encodes p-glycoprotein, is recognized as a biological mechanism possibly contributing to treatment failure in patients with acute myeloid leukemia (AML). Recent studies indicate its association with poor risk factors such as cytogenetic pattern and surface phenotype of blasts. We analyzed the role of MDR-1 gene expression in 36 chemo-naive AML patients. METHODS: In 36 patients, clinical data were reviewed and compared to MDR-1 gene expression, immunophenotyping results on CD7 & CD34, cytogenetic pattern and other suggestive prognostic factors. RESULTS: Median follow-up period was 150 days. The MDR-1 gene expression was observed in 19 out of 36 patients (52.8%). Significant correlation between MDR-1 gene and CD7 & CD34 expression was found. Sixteen out of 17 (94.1%) MDR-1 negative patients harbored favorable cytogenetic patterns, where as 11 out of 19 (57.9%) MDR-1 positive patients had favorable cytogenetic patterns. MDR-1 gene expression was not correlated to disease free survival (DFS), nor overall survival (OS) statistically although it has shown significant correlation to complete remission (CR) rate (P =0.001). CONCLUSION: We found that lack of MDR-1 gene expression was exclusively associated to favorable cytogenetic patterns in our study. In order to clarify the relationship between the role of MDR-1 gene and clinical outcome or other prognostic features, including cytogenetic pattern, further larger studies would be necessary.

Analysis of gene expression profiles in Tca8113/CBP nude mice by microarray technique / 实用口腔医学杂志

Objective:To study the differences of gene expression between Tca8113 and Tca8113/CBP tissues in nude mice. Methods:Tca8113 cells were injected subcutaneously in both sides of armpits of nude mice at the concentration of 5?106 cells/0.1 ml. Two weeks after injection, Carboplatin was used subcutaneously around the tumor 0.01 mg/g (weight) each day in Tca8113/CBP group while Tca8113 group was injected with physiologic saline as control. Mice were sacrificed 10 weeks after drug injection. The two kinds of tissues were investigated by human 16k cDNA v2.1 SBC-R-HC-100-21 gene chip. Results:Among the 16 000 target genes, there were 719 genes whose expression levels showed differences between the two kinds of tumor tissues. Conclusion:Microarray technique can simultaneously screen different genes from above-mentioned two kinds of tissues. Further analysis of the obtained genes will be helpful to understand the molecular mechanism of multidrug resistance.

Suppression of multidrug resistance via inhibition of heat shock factor by quercetin in MDR cells

MDR1 promoter has been shown to contain heat shock elements (HSE), and it has been reported that FM3A/M and P388/M MDR cells show a constitutively activated heat shock factor (HSF), suggesting that HSF might be an important target for reversing the multidrug resistance. Therefore, it was examined whether quercetin, which has been shown to interfere with the formation of the complex between HSE and HSF, and to downregulate the level of HSF1, can sensitize MDR cells against anticancer drugs by inhibition of HSF DNA-binding activity. In this study, quercetin appeared to inhibit the constitutive HSF DNA-binding activity and the sodium arsenite-induced HSF DNA-binding activity in the MDR cells. The basal and sodium arsenite-induced MDRCAT activities were remarkably suppressed by the treatment of quercetin. These results were well consistent with the finding that the treatment of quercetin decreased the expression level of P-gp, MDR1 gene product, in dose-dependent manner, and markedly increased the sensitivity of MDR cells to vincristine or vinblastine. These results suggest that quercetin can decrease the expression of P-gp via inhibition of HSF DNA-binding activity, and might be useful as a chemosensitizer in MDR cells.

In vitro study of Ganli Injection on reversing acquired multidrug resistance of human hepatocellular carcinoma / 中草药

Objective To study the reversal effect on acquired multidrug resistance (MDR) of human hepatocellular caricinoma (HCC) by Ganli Injection. Methods Proliferative inhibition rate of HCC BEL-7402/5-Fu cell line and reversal index of 5-Fu acquired MDR were measured by MTT assay. Cell morphological changes were observed under inverted microscope and Wright-Giemsa stain method. Fluorescence intensity of Adriamycin (ADM) was detected by Flow cytometry. Results HCC BEL-7402/5-Fu cell line exhibited cross-resistance to general chemotherapeutics in clinic. Proliferative inhibition rates of HCC BEL-7402/5-Fu cell line treated for 72 h by Ganli Injection at the (matrine) concentration of 0.230, 0.115, 0.058 mg/mL were (9.25?2.38)%, (8.46?1.90)%, and (4.23?2.05)%, respectively. The corresponding reversal indexes to 5-Fu were 5.50, 3.83, and 2.25. Pre-treatment of Galli Injection at the concentration of 0.230 mg/mL for 2 h could increase the accumulation of ADM in cells to 38.61%.Conclusion Ganli Injection has the effect on reversing 5-Fu acquired MDR of human hepatocellular carcinoma in vitro.

Three coumarins from seed of Cnidium monnieri and their multidrug resistance reversal effects / 中草药

Object To isolate the active compounds on reversing multidrug resistance (MDR) of tumor cell from the ethanol extract in the seeds of Cnidium monnieri (L ) Cuss Methods The fractionation directed by bioactivity was carried out with silica gel chromatography and RP HPLC Results Three active coumarins were obtained: imperatorin (Ⅰ), edultin (Ⅱ) and 3′ isobutyryloxy O acetyl columbionetin (Ⅲ) Their sturctures were identified by spectroscopic analysis Conclusion These three compounds have a medium reversing MDR of KBV200 in vitro

Multidrug resistance and cytotoxicity of anticancer drug by verapamil in cisplatin resistant human stomach cancer cell / 영남의대학술지

The development of multidrug-resistant tumor cell population is a major problem in the chemotherapy of human cancer. These cells are often cross resistant to unrelated drugs and the precise mechanisms of multidrug resistant phenotype of tumor cells has not been fully elucidated. Cisplatin resistant tumor cell (SNU-1/Cis₅) was induced from human stomach cancer cell line (SNU-1) in vitro. Growth profiles of survival cells were observed during 5 days by thiazolyl blue (MTT) assay. To investigate the cross resistance of various anticancer drugs in SNU-1 and SNU-1/Cis5, We compared the value of IC₅₀-drug concentration at 50% survival of control and gained relative resistances (RR). The RR for SNC-1/Cis₅ were as follows; vinblastine, > 43.0; epirubicin, 22.9; dactinomycin, 16.0; etoposide, 15.0; vincristine, 9.2; adriamycin, 5.7; aclarubicin, 5.3. But 5-fluorouracil, methotrexate, daunorubicin have not cross resistance with cisplatin. Resistant inhibition values of 10µM verapamil for SNU-1/Cis₅ were as follows; vincristine, 13.1; epirubicin, 10.0; etoposide, 6.3; vinblastine, 4.4; dactinomycin, 3.6; daunorubicin, 2.4. Membrane proteins of 51,400 and 81,300 daltons were identified by radioiodination with SDS-PAGE, which might represented the drug resistance.