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PubMed2004

[Establishment of in vivo adriamycin-induced multidrug resistance models of subcutaneous and hepatic transplanted human liver cancer in nude mice].

BACKGROUND & OBJECTIVE: Multidrug resistance (MDR) phenotype is the obstacle of chemotherapy in tumors and inspired research interesting. This study was to establish multidrug resistance (MDR) models induced with adriamycin in vivo of subcutaneous or in situ hepatic transplanted human liver cancer in nude mice (BALB/C nu/nu), and explore the biological characteristics and mechanism of multidrug resistance, which can provide an ideal animal model for the basic,and clinical study of MDR. METHODS: After successful performing either subcutaneous or hepatic transplantation in nude mice with liver cancer cell line HepG2, adriamycin (ADM) was injected into abdominal cavity to induce multidrug resistance. The chemosensitivity of HepG2 and ADM-cultured HepG2 cells was determined by MTT assay. P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), and cell pump-efflux to Rhodamine 123 (R123) were determined by flow cytometry. The mRNA expression of P-gp, MRP, and LRP was assessed with reverse transcriptase polymerase chain reaction(RT-PCR). RESULTS: Most biological characteristics of either subcutaneous or hepatic transplanted HepG2 liver cancer in nude mice like the parent HepG2 liver cancer. Both of them showed significant multidrug resistance. Among them, the resistance index of ADM was 26.4 times in hepatic transplanted group, and 24.6 times in subcutaneous transplanted group higher than that of parent cell line HepG2. In subcutaneous,and hepatic transplanted ADM-cultured groups, P-gp [(77.3+/-2.1)%, and (78.1+/-1.9)%], MRP [(72.1+/-4.3)%, and (72.7+/-5.0)%], and LRP [(31.1+/-1.0)%, and (32.2+/-1.4)%] positive cells increased significantly, their mRNA positive expression increased also, and the cell pump-efflux to R123 strengthened. However, no significant difference of above data was observed between subcutaneous,and hepatic transplanted tumor group (P >0.05). CONCLUSION: Both MDR subcutaneous and hepatic HepG2 transplanted models induced by in vivo injection of adriamycin in nude mice have the same biological characteristics as parent HepG2 liver cancer. These 2 animal models could be used as in vivo MDR models to explore the mechanism of MDR and reversing therapeutic methods.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Expression of multidrug resistance-related markers in primary neuroblastoma.

BACKGROUND: Multidrug resistance is associated with a poor prognosis in various human cancers. However, the clinical significance of the expression of multidrug resistance-related markers in neuroblastoma is still on debate. In this study, the effect of the expression of p-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and lung resistance protein (LRP) in neuroblastoma was evaluated. METHODS: The streptavidin-biotin immunoperoxidase (SP) technique was used to evaluate the expression of P-gp, MRP, and LRP in 70 cases of untreated primary neuroblastoma. RESULTS: The frequencies of the expression of P-gp, MRP, and LRP were 61.4%, 38.6%, and 24.3%, respectively. A significant positive correlation was observed between P-gp and MRP expression (P=0.001), as well as between LRP and MRP expression (P=0.01). The rates of expression of P-gp and MRP were higher in tumors from patients aged greater than one year old than in tumors from patients aged less than 1 year old at time of diagnosis (P=0.01 and 0.018, respectively). MRP expression in tumors that had metastasized was significantly more frequent than in tumors that had not metastasized (P=0.015). The expression of all tested proteins showed a significant relationship with whether or not the tumor had differentiated (P=0.006, 0.000 or 0.001, respectively). MRP expression was significantly associated with a reduction in both median survival time and 2-year cumulative survival (P=0.02). By contrast, P-gp and MRP expression did not correlate with survival. According to Cox regression analysis, only the co-expression of P-gp and MRP had significant prognostic value (relative hazard, 3.513, P=0.033). CONCLUSIONS: The intrinsic, multidrug resistance of neuroblastoma involves the combined effects of P-gp, MRP, and LRP. MRP expression may be an important factor determining prognosis in neuroblastoma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Effect of lung resistance-related protein on the resistance to cisplatin in human ovarian cancer cell lines.

The mechanisms of drug-resistance in human ovarian cancer cells have not been entirely clarified. The purpose of this study was to investigate whether LRP is involved in the resistance of ovarian cancer cell lines to cisplatin and its molecular mechanism. Human ovarian cisplatin-resistant cancer cell lines (A2780/DDP and COC1/DDP) and their parental cisplatin-sensitive cell lines (A2780 and COC1), alone or transfected with antisense LRP-specific oligonucleotides (ODN) or sense ODN, were treated with cisplatin to induce differentiation. Expression of LRP was examined by RT-PCR and Western blot analysis. The sensitivities of cells to cisplatin were assessed using sulforhodamine B (SRB) assay and flow cytometry, and the accumulation and efflux of cisplatin in the cells and isolated nuclei were examined by high performance liquid chromatographic (HPLC) assay. The expressions of LRP in A2780/DDP and COC1/DDP cells were higher than those in A2780 and COC1 cells and conferred resistance to cisplatin. Transfection of LRP AsODN into A2780/DDP and COC1/DDP cells down-regulated LRP expression and reversed the resistance phenotype. Levels of cisplatin accumulating in cells were increased by LRP-specific AsODN and anti-LRP monoclonal antibody. Isolated nuclei from A2780 and COC1 cells or A2780/DDP and COC1/DDP cells incubated with anti-LRP antibody contained more cisplatin than the nuclei of A2780/DDP and COC1/DDP cells not treated with anti-LRP antibody. Efflux of cisplatin was greater from the nuclei of A2780/DDP and COC1/DDP cells than those of A2780 and COC1 cells, and was inhibited by anti-LRP monoclonal antibody. Thus, LRP was involved in the resistance of ovarian cancer cells to cisplatin and has an important role in the transport of cisplatin both in exocytotic vesicles and between the nucleus and cytoplasm.

Antineoplastic Agents↗
PubMed2004

[Effect of arsenic trioxide on drug transporting molecules in acute promyelocytic leukemia cell line].

OBJECTIVE: To study the effect of arsenic trioxide (As2O3) on expression of drug transporting molecules in APL MR2 cell line. METHODS: MR2 resistant to all-trans retinoic acid (ATRA) and non-ATRA resistant APL cell line NB4 was used in this in vitro study. Expression of P-glycoprotein (Pgp), multidrug resistance protein (MRP) and lung resistance-related protein (LRP) was detected by immunocytochemical assay. RESULTS: The expression of Pgp was significantly higher in MR2 (30%-40%) than in NB4 (10%-20%) (P < 0.001), and that of MRP was also higher in MR2 (56.9 +/- 3.4-21.2 +/- 1.1) than in NB4 (20.6 +/- 5.3-16.7 +/- 1.2) (P < 0.001). As2O3 at concentrations ranging from 0.5 approximately 2.0 micromol/L could significantly decrease the expression of Pgp and MRP, but not that of LRP. The decrease in the expression of Pgp and MRP in MR2 cell line was negatively correlated with the dose and duration of action of As2O3. CONCLUSION: Pgp and MRP, but not LRP, may be the sensitive targets of As2O3 to overcome drug-resistance. ATRA might be the substrates of Pgp and MRP.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

The ex vivo characterization of XR5944 (MLN944) against a panel of human clinical tumor samples.

XR5944 (MLN944) is a novel DNA targeting agent with potent antitumor activity, both in vitro and in vivo, against several murine and human tumor models. We have used an ATP-tumor chemosensitivity assay to assess the ex vivo sensitivity of a variety of solid tumors (n = 90) and a CCRF-CEM leukemia cell line selected with XR5944. Differences in gene expression between the parental CCRF-CEM and the resistant subline were investigated by quantitative reverse transcription-PCR. Immunohistochemistry for topoisomerases I and IIalpha and multidrug resistance (MDR1) protein was done on those tumors for which tissue was available (n = 32). The CCRF-CEM XR5944 line showed increased mRNA levels of MDR1, major vault protein, and MDR-associated protein 1 compared with the parental line, whereas the expression of topoisomerases I, IIalpha, and IIbeta was essentially unchanged, suggesting that XR5944 is susceptible to MDR mechanisms. The median IC90 and IC50 values for XR5944 in tumor-derived cells were 68 and 26 nmol/L, respectively, 6-fold greater than in resistant cell lines. XR5944 was 40- to 300-fold more potent than the other cytotoxics tested, such as doxorubicin, topotecan, and paclitaxel. Breast and gynecologic malignancies were most sensitive to XR5944, whereas gastrointestinal tumors showed greater resistance. A positive correlation (r = 0.68; P < 0.0001) was found between the IC50 values of XR5944 and P-glycoprotein/MDR1 staining but not with either topoisomerase I or IIalpha immunohistochemistry index. These data support the rapid introduction of XR5944 to clinical trials and suggest that it may be effective against a broad spectrum of tumor types, especially ovarian and breast cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

[Expression of lung resistance-related protein gene in transitional cell carcinoma of the bladder].

OBJECTIVE: To investigate the role of lung resistance-related protein (LRP) in intrinsic multidrug resistance (MDR) of bladder cancer and detect the relationship of LRP expression with the clinical pathologic parameters. METHODS: 66 patients were studied with newly diagnosed primary bladder cancer (T(a) = 12, T(1) = 26, T(2) = 11, T(3) = 10, T(4) = 7; G(1) = 35, G(2) = 19, G(3) = 12). No patient was treated preoperatively with either radiation or chemotherapy. Reverse transcription-polymerase chain reaction (RT-PCR) was performed for measure of mRNA expression for LRP, multidrug-resistance gene 1 (MDR1), and multidrug resist nce-associated protein 1 (MRP1). Expressions of LRP, P53 and P63 proteins were examined by immunohistochemistry staining. RESULTS: LRP mRNA had the highest expression rate (64%, 42/66) among three MDR markers in primary bladder cancers without chemotherapy and its level was significantly higher in normal bladder tissue than in TCC of bladder (t = 2.82, P < 0.01), in low grade than in high grade cancers (t = 4.14, P < 0.01), and in superficial than in invasive cancers (t = 3.58, P < 0.05). LRP mRNA expression showed no correlation with either MDR1 or MRP1, but close correlation with LRP protein level (r = 0.89, P < 0.01). LRP was associated with low-grade (r = 0.81, P < 0.01) and low-stage (r = 0.78, P < 0.05) cancers, but not with tumor suppressor P53 or P63 (P > 0.05). CONCLUSIONS: The grade and stage-related expression pattern of LRP indicates that it may be a predictive index for intrinsic MDR in bladder cancer. Anti-cancer drugs out of the MDR spectrum of LRP may be more effective for patients with early bladder cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Effects of selected flavonoids and carotenoids on drug accumulation and apoptosis induction in multidrug-resistant colon cancer cells expressing MDR1/LRP.

The effects of various flavonoids and carotenoids on Rhodamine 123 accumulation in multidrug-resistant Colo 320 human colon cancer cells expressing MDR1/LRP were studied. The Colo 205 cell line was used as a drug-sensitive control. Rotenon, Catechin, Neohesperidin, Naringin, Robinin, Phloridzin, Robinetin, Dihydrobinetin, Dihydrofisetin, Kampferol, Dihidroquercetin, Sakuranin and Sakuranetin were tested on Colo 320 cells: only Rotenon was found to be effective as regards multidrug resistance (MDR) reversal, while a majority of the flavonoids, such as Catechin, Neohesperidin, Naringin, Robinin, Phloridzin, Dihydrobinetin and Sakuranetin, had only marginal effects on Rhodamine 123 accumulation. The tested carotenoids (beta-Cryptoxanthin, Luteoxanthin, Anteroxanthin, Violeoxanthin, Apple peel fetoxanthin, Lutein, Violaxanthin and Neoxanthin) were able to increase Rhodamine 123 accumulation in Colo 320 cells. Verapamil was applied as a resistance-modifying positive control. The levels of apoptosis induction in drug-resistant and sensitive cell lines were also compared. The results indicated that the tested flavonoids were weak apoptosis inducers on MDR and parent cells, without significant differences. A majority of the carotenoids induced only early apoptosis, but apoptosis and cell death were not induced in MDR colon cancer cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

[Hypoxia-inducible factor-1 alpha dependent expression and significance of the related multidrug resistance genes induced by hypoxia in human hepatocarcinoma cell].

OBJECTIVE: To explore the mechanism of multidrug resistance of hepatocellular carcinoma induced by hypoxia and the potential role of hypoxia-inducible factor-1 alpha (HIF-1 alpha) and multidrug resistance related genes. METHODS: Human hepatocarcinoma cell lines HepG2 cells were exposed to hypoxia and were transfected by plasmid HIF-1 alpha/PCDNA3, respectively. The expressions of multidrug resistance gene (mdr1), multidrug resistance protein (MRP1), and lung resistance protein (LRP) gene at the mRNA and the protein levels in the above two groups were respectively analyzed by real-time fluorescent quantitative PCR and Western-blot technique. RESULTS: In the hypoxia group, the expressions of mdr1, MRP1 and LRP were stepped up correlating to the degree of hypoxia, especially the prominent increase in the expression of MRP1. Furthermore, they were synchronous with the changes of the expression of HIF-1 alpha. Also the increased expression of mdr1, MRP1, and LRP gene was observed in transfected HepG2 cells by plasmid HIF-1 alpha/PCDNA3. CONCLUSIONS: Resistance of hepatocellular carcinoma to chemotherapeutics could be induced by hypoxia. HIF-1 alpha may be critical to the upregulation of the expression of the related multidrug resistance genes induced by hypoxia. HIF-1 alpha and these related multidrug resistance genes could be potential molecular targets for reversing multidrug resistance of hepatocellular carcinoma.

Blotting, Western↗
PubMed2005

[Relationship between expression of multidrug-resistant genes in nasopharyngeal carcinoma tissue and sensitivity to chemotherapy].

OBJECTIVE: To study the relationship between multidrug-resistant (MDR) expression in nasopharyngeal carcinoma (NPC) and its sensitivity to chemotherapy. METHODS: The specimens of 23 NPC cases were studied by immunohistochemistry with monoclonal antibody of P-glycoprotein (P-gp), multidrug resistance relation protein (MRP), lung-resistance related protein (LRP), topoisomerase II (Topo II), thymidylate synthase (TS), glutathione-S-transferase (GST-pi). Among them, 20 specimens were taken from primary NPC lesion which were treated with two course of cisplatin (DDP) and 5-fluorouracil (5-FU), 3 specimens were taken from cervical lymph-node of recurrent NPC patients who were treated by radical dissection. RESULTS: Various MDR parameters were expressed differently in 22 cases except for 1 clear cell carcinoma case. The difference was statistically significant (P < 0.05). However, there were no significant difference of MDR expression either among various carcinoma pathomorphology cell groups or among different clinical stage groups. Expression of LRP and TS were found in 10 and 14 cases respectively and the chemotherapy responders rates were 20% (2/10) and 28.5% (4/14) respectively. While the chemotherapy responders rates were 70% (7/10) and 5/6 in cases without expression. There was significant difference (P < 0.001, and P < 0.05). CONCLUSION: The NPC patients with LRP and TS expression may be less sensitive to chemotherapy with DDP + 5-FU.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

[Detection of glutathione S-transferase and lung resistance-related proteins in acute leukemia and its clinical significance].

OBJECTIVE: To explore the relationship among intracellular glutathione S-transferase activity (GST), the expression of lung resistance-related proteins (LRP) in acute leukemia, and its clinical effects. METHODS: The GST activity of bone marrow mononuclear cells and LRP expression in 57 acute leukemia patients were detected by the spectrophotometry assay and immuno-cytochemistry (SABC), respectively. RESULTS: The GST activity of bone marrow mononuclear cells in the acute leukemia group was significantly higher than that of the control group (P < 0.01). The GST activity of mononuclear cells in acute leukemia was positively correlated with the percentage of blast in the bone marrow (r = 0.30, P < 0.05). The GST activity of mononuclear cells in the untreated acute leukemia group was obviously higher than that of the complete remission group (P <0.01). The GST activity in the refractory or relapsed acute leukemia group was significantly higher than that of the complete remission group and untreated leukemia group (P <0.05). In post-chemotherapy 13 of 17 the LRP-positive patients were the non-remission, 12 of the 20 LRP-negative patients were the complete remission. The curative rate of the LRP-positive group was the significantly lower than the LRP-negative group (P < 0.05). The GST activities of non-remission patients in the LRP-positive and LRP-negative group obviously increased. CONCLUSION: The increase of GST activity in the bone marrow mononuclear cells is related to the clinical curative effects and the proliferation of blast in acute leukemia. Detection of LRP and GST activities in acute leukemia may have a reference value in judging the leukemia with drug resistance and estimating the prognosis.

Adolescent↗
PubMed2005

[Expression of lung resistance protein and multidrug resistance-associated protein in naive childhood acute leukemia and their clinical significance].

BACKGROUND & OBJECTIVE: Previous studies revealed that lung resistance protein (LRP) and multidrug resistance-associated protein (MRP) relate to drug resistance of childhood leukemia, which is not caused by only one mechanism. This study was to evaluate the expression of LRP and MRP genes in childhood leukemia and their correlation. METHODS: The expression of LRP and MRP in 38 children with acute leukemia and 6 healthy children were measured with reverse transcription-polymerase chain reaction (RT-PCR); their clinical significance was analyzed according to complete remission (CR) rate of the patients after chemotherapy. RESULTS: CR rate of the 38 patients was 68.4%. LRP was expressed in 11 of the 38 patients, and didn't express in healthy controls; CR rate was significantly lower in LRP-positive patients than in LRP-negative patients (27.3% vs. 85.2%, P < 0.05). MRP was overexpressed in 21 of the 38 patients; CR rate was significantly lower in MRP-positive patients than in MRP-negative patients (47.6% vs. 94.1%, P < 0.05). The positive rate of LRP was significantly lower in acute lymphoblastic leukemia (ALL) than in acute nonlymphocytic leukemia (ANLL) [18.5% (5/27) vs. 45.5% (6/11), P < 0.05]; however, the positive rate of MRP was 59.3% (16/27) in ALL, and 45.5% (5/11) in ANLL (P > 0.05). The positive rate of MRP was 28.6% in LRP-positive patients, and 29.4% in LRP-negative patients; there was no correlation between LRP and MRP. CONCLUSION: Childhood acute leukemia patients with overexpression of LRP and MRP suffer severe disease and achieve low remission rateû lower remission rate of childhood ANLL patients may relate to LRP expression.

Adolescent↗
PubMed2005

[The effect of tetrandrine on the expression of the P170, LRP and TOPO II in S180's tumor cell induced by chemotherapy in the mice with acquired multi-drug resistance].

OBJECTIVE: To observe the effect of tetrandrine on the P170 production expressed by multi-drug resistance gene, lung resistant protein (LRP), and topoisomeras II and elucidate the underlying molecular mechanism. METHOD: Cellular model of multi-drug resistance was established in S180 tumor cell by means of the scheme of PFC chemotherapy at the dosage lower than that with curative effect. P170, LRP and TOPO II were measured by flow cytometry after the mouse model was treated with tetrandrine for 4 weeks. RESULT: tetrandrine obviously reduced the enhancement of express of P170, LRP and the activity of TOPO II in the tumor cells with multi-drug resistance induced by chemotherapy. CONCLUSION: Tetrandrine significantly inhibits the multi-drug resistance of tumor cells induced by chemotherapy via diminishing both the expression of multi-drug resistance gene and the activity of topoisomeras II.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

[Synergistic effect of bromocriptine combining tumor necrosis factor-alpha on reversing multidrug resistance in a nude mouse model of liver neoplasm].

OBJECTIVE: To investigate synergistic effect of bromocriptine (BCT) combining tumor necrosis factor-alpha (TNF-alpha) on reversing multidrug resistance in a nude mouse model of liver neoplasm. METHODS: Human hepatocarcinoma cell line HepG(2) (HepG(2) group), drug resistant hepatocarcinoma cell line HepG(2)/adriamycin (HepG(2)/ADM group) and hepatocarcinoma cell line transfected with TNF-alpha gene HepG(2)/ADM/TNF (TNF group and BCT group) were injected into the liver of nude mice via orthotopic implantation to establish multidrug resistance model of liver neoplasm in vivo. All the mice were injected with 5-fluouracil + adriamycin + mitomycin in abdominal cavity for 7 d. The mice in BCT group was simultaneously given bromocriptine through gastric canal. Size and weight of the tumor were measured. Furthermore tumor histological character and growth of the nude mice was observed and its chemosensitivity was tested. MDR associated genes and proteins (MRP, LRP) of implanted tumors were detected by immunohistochemical staining and reverse transcriptive polymerase chain reaction (RT-PCR), and apoptosis rate of hepatocarcinoma cells was detected by TUNEL assay. RESULTS: The nude mouse model of each cell line was all inoculated successfully. The tumor growth rate and weight were significantly different among groups (P < 0.05). After chemotherapy tumor growth inhibition rate was higher in BCT group (67%) compared to ADM and TNF groups (P < 0.01), and similar to HepG(2) group (54%). MDR1 and LRP mRNA could be detected in all groups, but TNF-alpha was detected only in TNF-alpha and BCT groups. Furthermore, MDR1 and LRP protein expression of tumors in TNF-alpha and BCT groups was low similar to HepG(2) group. The apoptosis rate of hepatocarcinoma cells was much higher in BCT group than in other groups (P < 0.05) with TUNEL assay. CONCLUSIONS: TNF-alpha gene can down-regulate the MDR associated genes and proteins expression for example MDR1, LRP, and lower its tumorgenesis. Moreover, bromocriptine can enhance the susceptibility of HepG(2)/ADM cells to cytotoxic drugs.

Animals↗
PubMed2006

Specific inhibition of gene expression of lung resistance-related protein by short interfering RNA.

OBJECTIVE: To investigate inhibitory effect of short interfering RNA (siRNA) on the expression of lung resistance-related protein (LRP) in leukemia cells. METHODS: The eukaryotic vectors of LRP, pcDNA3.0/LRP, were constructed. The transfection protocol of K562 cells grown in standard conditions consisted of different combinations of pcDNA3.0/LRP, pEGFP-C1 expressing mammalian enhanced green fluorescent protein (GFP), and their gene-specific siRNAs. RT-PCR and flow cytometry were employed to evaluate the mRNA and protein expression of LRP and fluoroscopy was performed for assay of GFP expression in the transfected cells. RESULTS: Compared with untreated K562 cells, pcDNA3.0/LRP-transfected cells showed increased LRP mRNA and protein expression and the positive cell percentage reached 30%. In the cells co-transfected with LRP gene-specific siRNA and pcDNA3.0/LRP, both LRP mRNA and protein expression decreased significantly to a level defined as negative results; the GFP expression showed no significant difference between the cells transfected with pEGFP-C1 and those co-transfected with LRP gene-specific siRNA and pEGFP-C1. LRP mRNA and protein expressions were also similar between the cells transfected with pcDNA3.0/LRP and those co-transfected with GFP gene-specific siRNA and pcDNA3.0/LRP. CONCLUSIONS: The LRP gene-specific siRNA we designed is capable of degrading LRP mRNA and inhibiting the protein expression effectively and specifically, which shed light on the potential application of siRNA for gene-specific therapy to reverse LRP-induced multidrug resistance of leukemia cells.

Drug Resistance, Multiple↗
PubMed1995

Membrane transport proteins associated with drug resistance expressed in human melanoma.

Melanoma cells often display a multidrug-resistant phenotype, but the mechanisms involved are largely unknown. We have studied here the recently identified transport-associated proteins, MRP and LRP, and the well-known drug resistance marker P-glycoprotein using a panel of 16 human melanoma cell lines and 71 benign and malignant melanocytic tissue samples. By flow cytometry and immunohistochemistry, expression of P-glycoprotein was not detectable on the protein level in the 10 cell lines analyzed, although by reverse transcriptase polymerase chain reaction, MDR-1 gene expression was demonstrated in 2 of 10 cell lines. In addition, immunohistology revealed P-glycoprotein expression in only 1 of 71 melanocytic lesions. In contrast, MRP was detected in a subset of melanoma cell lines by reverse transcriptase polymerase chain reaction and immunohistology (4 of 10). LRP expression was observed in 8 of 10 melanoma cell lines by immunochemistry and in 10 of 10 by reverse transcriptase polymerase chain reaction. Furthermore, MRP was detected immunohistologically in almost 50% of primary and metastatic melanoma specimens, although no significant differences were found between metastases taken before or after chemotherapy. Expression of LRP was detected in a subset of nevi with nevus cells exhibiting up to 25% positive LRP reactivity. In 13 of 21 primary melanomas and 23 of 37 metastases, more than 25% of tumor cells were stained by the LRP-56 monoclonal antibody. Particularly in the group of metastases with more than 50% of LRP-positive cells, 7 of 11 of the metastases had been previously exposed to chemotherapeutic drugs. Although the expression of membrane transport proteins may explain only the chemoresistance toward lipophilic, natural compounds and not resistance against alkylating agents, the lack of P-glycoprotein expression after chemotherapeutic treatment and the significant expression of MRP and LRP in melanoma cells provide first insights into the drug-resistant phenotype in melanoma. Additional studies analyzing the role of MRP and LRP in chemoresistance of melanoma are warranted.

ATP Binding Cassette Transporter, Subfamily B, Mem↗