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Clinical Cancer Research Vol. 11, 7593-7598, November 1, 2005
© 2005 American Association for Cancer Research

Human Cancer Biology

Multidrug Resistance Proteins in Gastrointestinal Stromal Tumors: Site-Dependent Expression and Initial Response to Imatinib

Nathalie Théou1,3, Sophie Gil5, Anne Devocelle5, Catherine Julié8,10, Anne Lavergne-Slove6, Alain Beauchet9, Patrice Callard7, Robert Farinotti5, Axel Le Cesne4, Antoinette Lemoine2,3, Laurence Faivre-Bonhomme1,5 and Jean-François Emile3,8,10

Authors' Affiliations: 1 Pharmacy and 2 Biochemistry Departments, Paul Brousse Hospital; 3 Institut National de la Sante et de la Recherche Medicale U602; 4 Oncology Department, Institut Gustave Roussy, Villejuif, France; 5 Unité Propre de l'Enseignement Supérieur 2706, Faculty of Pharmacy, Université Paris XI; 6 Pathology Department, Lariboisière Hospital; 7 Pathology Department, Tenon Hospital, Paris, France; 8 Pathology and 9 Public Health and Medical Information Departments, Ambroise Paré Hospital, Boulogne, France; and 10 Faculty of Medicine, Paris-Ile de France Ouest, Garches, France

Requests for reprints: Jean-François Emile, Service d'anatomie pathologique, Hôpital Ambroise Paré, 9 Av. Ch. de Gaulle, 92104, Boulogne Cedex, France. Phone: 33-1-49-09-57-25; Fax: 33-1-49-09-58-72; E-mail: jean-francois.emile{at}apr.aphp.fr.


   Abstract
Top
 Abstract
Patients and Methods
 Results
 Discussion
 References
 
Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors of the digestive tract and respond poorly to chemotherapy. A tyrosine kinase inhibitor treatment, imatinib mesylate, was recently shown to have antitumor effects in metastatic patients. However, this drug is a substrate for multidrug resistance (MDR) proteins. Therefore, we investigated the expression of ABCB1 (P-glycoprotein), ABCC1 (MRP1), and ABCG2 (BCRP) by Western blotting in 21 GISTs and 3 leiomyosarcomas. All the GISTs were positive for either ABCB1 (86% of cases) or ABCC1 expression (62%), but negative for ABCG2. ABCB1 was expressed in all gastric GISTs, but in only 67% of nongastric GISTs. By contrast, ABCC1 expression was more common in nongastric tumors (78% versus 42%). The levels of these MDR proteins in gastric GISTs were higher for ABCB1 (P = 0.007) and lower for ABCC1 (P = 0.004) compared with nongastric GISTs. We found no correlation between MDR protein expression and the risk assessment. None of the six patients treated with imatinib was resistant, although all were positive for at least one MDR protein. These results confirm that gastric and nongastric GISTs have different biological characteristics and suggest that MDR proteins do not impair the initial response of the tumor to imatinib.

Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors of the digestive tract (1). They may occur along the entire length of the gastrointestinal tract, from the esophagus to the anus, and sometimes in the omentum or the mesentery. GISTs are now considered as a distinct type of tumor in which diagnosis is based on histology and expression of the KIT tyrosine kinase membrane receptor (CD117, stem cell factor receptor; refs. 2–4). Several studies have investigated the factors determining the prognosis of GISTs (5, 6) and have identified tumor size and the mitotic index as the main factors. Some studies have reported that the presence of KIT mutations in GISTs were of prognostic value (7–9), whereas others failed to confirm this (9–11). GISTs are less responsive to cancer chemotherapy than other soft tissue sarcomas (12, 13). It was recently shown that treatment with a tyrosine kinase inhibitor, imatinib mesylate, had antitumor effects in metastatic patients (14, 15).

The expression of P-glycoprotein (ABCB1) and multiresistance protein 1 (MRP1 or ABCC1) is implicated in the multidrug resistance (MDR) of several soft tissue sarcoma (16–18). MDR proteins confer drug resistance by reducing intracellular drug accumulation due to an active efflux. ABCB1 and ABCC1 expel a similar spectrum of drugs, including anthracyclines, Vinca alkaloids, and epipodophyllotoxins (19). Recently, some studies have shown that ABCB1, ABCC1, and ABCG2 interact directly with several tyrosine kinase inhibitors in vitro and particularly with imatinib (20, 21).

Here, we investigated the expression of ABCB1, ABCC1, and ABCG2 in 21 GIST using Western blotting and correlated these results with clinicopathologic characteristics.


   Patients and Methods
Top
 Abstract
 Patients and Methods
Results
 Discussion
 References
 
Patients. The study included 21 patients with GISTs and three patients with leiomyosarcomas. The GISTs originated from the stomach (n = 12), intestine (n = 5), colon (n = 2), peritoneum (n = 1), and mesentery (n = 1). The pathology of all cases was reviewed on sections from paraffin-embedded samples. Risk assessment was evaluated as recommended by the international workshop (4). Immunohistochemistry was done using anti-CD117 (KIT polyclonal rabbit, Dakopatts, Copenhagen, Denmark), anti-CD34 (clone QBEND mouse, Immunotech, Marseilles, France), anti-ABCC1 (MC-201, Syrinx-Diagnostika, Frankfurt, Germany) and anti-S100 protein (polyclonal rabbit, Dakopatts) antibodies. Clinical records were reviewed and no patients received chemotherapy or imatinib before surgical resection of the tumor. All molecular analyses were done on primary tumors. All the human samples were obtained between 1995 and 2003 by surgical resection done for therapeutic purposes according to local ethical guidelines.

Western blot. Frozen tumors were mechanically homogenized (Mixer Mill MM 300) in lysis buffer (20 mmol/L Tris, 150 mmol/L NaCl, 1 mmol/L sodium orthovanadate, 10 mmol/L NaF, 1 mmol/L phenylmethylsulfonyl fluoride, 0.5 µg/mL leupeptin, 1 µg/mL pepstatin, 10 KIU/mL aprotinin, and 1% Triton X-100). The lysates were shaken gently for 30 minutes at 4°C and then centrifuged to remove insoluble material. The protein concentration of the supernatants was determined using Bradford solution and was normalized. Total lysates were resuspended in Laemmli buffer and 10 µg of proteins were subjected to SDS-PAGE (8%) under reducing conditions in 25 mmol/L Tris-HCl (pH 8.3), including 0.1% SDS and 0.2 mol/L glycine at room temperature at 20 mA. For quantification and to compare results, two identical positive samples were included on each gel. The proteins were electroblotted onto nitrocellulose membranes (Amersham Biosciences, Chalfort St. Giles) for 15 hours at 4°C at 40 V in 25 mmol/L Tris-HCl (pH 8.3) containing 0.2 mol/L glycine, 20% methanol, and 0.1% SDS. Nonspecific binding sites were blocked by incubation with 10% skimmed milk in Tris buffer [20 mmol/L Tris-HCl (pH 7.5), 0.2 mol/L, 0.1% Tween 20] for 1 hour at room temperature. Western blots were carried out using anti-ABCB1 monoclonal antibodies (C219 1/100, DAKO, Copenhagen, Denmark), and anti-ABCC1 (1/500, Chemicon, Chandlers Ford, United Kingdom) and anti-ABCG2 (BXP-21 1/100, Chemicon, United Kingdom) antibodies. Immunoreactive bands were visualized using the appropriate secondary horseradish peroxidase–conjugated antibodies and enhanced chemiluminescence (Amersham Biosciences). ABCB1 and ABCC1 proteins were quantified by densitometry using Scion Image program and analyzed using Excel software (Microsoft, Courtaboeuf, France). The ABCB1 and ABCC1 signals in the GIST samples were expressed relative to the signal measured in placenta extracts and ABCC1 colon extracts, respectively.

Mutations analysis. DNA was extracted from either paraffin-embedded tumors or frozen tumors after histologic control. PDGFRA (exons 12 and 18) and KIT (exons 9, 11, 13, and 17) mutations were detected by length analysis of PCR products and direct sequencing as previously described (22, 23).


   Results
Top
 Abstract
 Patients and Methods
 Results
Discussion
 References
 
The mean age of the patients was 60.3 years (range 39-78) and the male-to-female ratio was 12:9 (Table 1). All GISTs were KIT positive. More than 10% of the tumor cells in 11 of 12 (92%) gastric GISTs and in 4 of 9 (44%) nongastric GISTs were CD34 positive. Except for one GIST, mutations were present in all gastric GISTs, and involved exon 11 of KIT in nine cases and exon 18 of PDGFRA in two cases. Only three of the nongastric GISTs exhibited mutations in exon 9 (n = 1) or exon 11 (n = 2) of KIT. After the initial surgery, six patients were treated with imatinib for tumor progression or metastasis.


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  		Table 1. Characteristics of the 21 patients with a GIST

 
Multidrug resistance protein expression. First, we analyzed a series of 11 patients with GISTs and found a higher expression of ABCB1 in gastric tumors (Fig. 1). We then analyzed all 21 patients and compared the results to a control placenta sample (Fig. 2).



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  		Fig. 1. Expression of ABCB1 in GISTs. Western blot analysis of whole tumor lysate with anti-ABCB1 antibody C219. In this first series of tumors, the levels of expression of ABCB1 were higher in gastric (G; 71224, 71227, 71183, 71229, 71100, and 71562) than nongastric (NG; 71103, 71105, 71385, and 71181) GISTs. Placenta sample was used as a positive control (T).

 


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  		Fig. 2. Expression of ABCB1 in gastric and nongastric GISTs. Top gel contains gastric GISTs, all of which had high levels of expression of ABCB1. The levels of expression of ABCB1 were usually lower in nongastric GISTs (bottom gel). Placenta sample was used as positive control.

 
We found ABCB1 expression in 18 of the 21 GISTs (86%). This larger series confirmed that ABCB1 was more frequently expressed in gastric tumors than nongastric tumors. Indeed, all 12 gastric GISTs were positive for ABCB1, where only six of the nine (67%) nongastric tumors were positive. In most gastric GISTs, the level of ABCB1 expression was higher than in the control placenta sample, whereas only one nongastric tumor had a higher expression than the control. Although this nongastric tumor was a 40 cm mesenteric tumor, retrospective analysis of the surgical report cannot exclude a primitive gastric origin. Quantification of ABCB1 expression in gastric and nongastric GISTs revealed an average level of expression of 2.56 and 0.73, respectively, compared with the control placenta sample (P = 0.007, two-sided nonparametric Wilcoxon test).

We detected ABCC1 expression in 13 of 21 GISTs (62%), which was less than for ABCB1 expression. In contrast to ABCB1 expression, ABCC1 was less frequently expressed in gastric tumors than in nongastric tumors, 5 of 12 (42%) versus 7 of 9 (78%), respectively (Fig. 3). Moreover, the level of multiresistance protein expression was lower in gastric GISTs compared with nongastric GISTs (P = 0.004, two-sided nonparametric Wilcoxon test). Immunohistochemistry confirmed the variable expression of ABCB1 by GIST cells (Fig. 4).



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  		Fig. 3. Expression of ABCC1 in gastric and nongastric GISTs. ABCC1 expression was weak or absent in gastric GISTs (top), in contrast to its higher level of expression in nongastric GISTs (bottom). Colon sample was used as positive control.

 


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  		Fig. 4. Immunohistochemical detection of ABCC1 in GIST. Expression of ABCC1 was detected by immunohistochemistry (brown staining) within tumor cells of some GISTs. As observed with Western blot, ABCC1 was abundant (left), moderately abundant (middle), or absent (right) in the GISTs cells. Original magnification, x400.

 
Both ABCB1 and MRP1 was expressed in 9 of 21 (43%) GISTs, and no GIST was negative for both ABCB1 and ABCC1.

We then compared the level of expression of ABCB1 in gastric and nongastric GIST to their levels of expression in leiomyosarcomas (Fig. 5). We found that the level of expression of ABCB1 in gastric GIST was far higher than in leiomyosarcomas.



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  		Fig. 5. Expression of ABCB1 in GISTs and leiomyosarcomas. ABCB1 expression was stronger in gastric GISTs compared with nongastric GISTs and to leiomyosarcomas (L). Placenta sample was used as positive control.

 
Lastly, neither gastric nor nongastric GIST expressed ABCG2 (Fig. 6).



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  		Fig. 6. Expression of ABCG2 in gastric and nongastric GISTs. No expression of ABCG2 in all GISTs (gastric or nongastric). Placenta sample was used as positive control.

 
Correlation of multidrug resistance protein expression with other patient characteristics. Three patients tested negative for ABCB1 and positive for ABCC1. All these patients had an nongastric GIST without KIT or PDGFRA mutations (Table 2).


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  		Table 2. Quantification of MDR proteins

 
Ten patients tested positive for both ABCB1 and ABCC1. Of these patients, half had gastric GISTs with either KIT or PDGFRA mutations. The five other cases were nongastric GISTs, of which three had KIT mutations (Table 2).

Eight patients tested positive for ABCB1 and negative for ABCC1. All patients except one were men, and all but one had gastric GISTs, with either KIT or PDGFRA mutations (Table 2).

Neither ABCB1, ABCC1, nor their coexpression were correlated with the risk assessment.

After the initial resection, six patients were treated with 400 to 800 mg/d of imatinib for metastatic malignant GISTs. A partial response to treatment was seen in four patients, with the other two having a stable disease during the first 6 months of treatment. After an initial partial response, two patients suffered a disease progression.


   Discussion
Top
 Abstract
 Patients and Methods
 Results
 Discussion
References
 
The expression of MDR proteins in soft tissue sarcoma has been correlated with a worse survival rate (24) or with a higher histologic grade (25). Leiomyosarcomas have been shown to have a weaker response to chemotherapy compared with other histologic types of sarcoma (26). However, until recently, GISTs were frequently misdiagnosed as leiomyosarcomas (1). Recent studies have shown that GISTs are more resistant to chemotherapies than leiomyosarcomas (12, 13). Therefore, we investigated the expression of MDR proteins in GISTs.

We investigated MDR protein expression by Western blot on proteins extracted from frozen tumors, including 21 KIT-positive GISTs. We showed that the level of ABCB1 expression was higher in GISTs than in leiomyosarcomas. Plaat et al. (27) showed similar results using a different technique; however, only 15 of the 22 GISTs in this study were KIT positive. We found that GISTs were positive for ABCB1 and ABCC1 expression in 86% and 62% of cases, respectively, whereas both proteins were expressed in 68% of GISTs in the study of Plaat et al. (27). In our study, we found that no GIST was negative for both ABCB1 and ABCC1, whereas all GISTs were negative for ABCG2. The more frequent and higher levels of expression of MDR proteins in GISTs compared with leiomyosarcomas may contribute to the different responses to chemotherapy (12) and may be related to the resistance of GISTs to some cytotoxic chemotherapy (28).

We found that ABCB1 was expressed in all gastric GISTs, but in only 67% of nongastric tumors, whereas ABCC1 was more often expressed in nongastric tumors than gastric GISTs (78% versus 42%). Although not underlined in the study of Plaat et al. (27), the expression of ABCB1 was also more common in gastric GISTs (83% versus 54%). Other differences between gastric and nongastric GISTs have also been observed. For example, CD34 was shown to be more frequently expressed in gastric GISTs (2, 11). Some mutations, including internal tandem duplication of KIT exon 11 and PDGFRA mutations, are more specific of gastric GISTs (29–31), whereas KIT exon 9 mutations are closely associated with intestinal GISTs (11, 32, 33). Gastric and nongastric GISTs have also been distinguished by their gene expression profile (34). Although the anti-MDR treatment, VX-710, failed to reverse the resistance of GISTs to anthracycline (13), clinical prospective or retrospective studies should assess the different responses of GISTs to anti-MDR treatments according to the initial site of the GIST. Some studies have shown a correlation of MDR protein expression with histologic grade of soft tissue sarcoma (18, 22, 35–37). MDR protein expression was also correlated with tumor response (38) and survival (24). By contrast, Plaat et al. (27) found no correlation between MDR protein expression and histologic grade in GISTs, and we also found no correlation with the risk assessment.

The role of these three MDR proteins toward imatinib has been widely debated. Imatinib is an actively transported substrate of the human ABCB1 glycoprotein (20). Overexpression of ABCB1 has been shown to induce resistance of K562 cells to imatinib (39–43), although other studies failed to confirm these results (44). Imatinib is not a substrate of ABCC1 (20, 39), but the low expression of this MDR protein has been shown to be an independent predictor of response to imatinib in myeloid blast crisis of chronic myelogenous leukemia (45). Imatinib has been considered an actively transported substrate of the human ABCG2 (21, 42, 43), although other studies have suggested that imatinib is a potent inhibitor of ABCG2 (46).

We provide the first data of MDR protein expression in GISTs from patients treated with imatinib. The six patients of our series tested positive for ABCB1, and three also tested positive for ABCC1. None of the six patients presented a primary resistance to imatinib treatment. Although further studies are needed, these results suggest that MDR proteins have little effect on initial response of the tumor to imatinib. The biological role of the differential and high levels of expression of MDR proteins still remains to be investigated with respect to the anatomic origin of GISTs.


   Acknowledgments
 
We thank C. Boucheix, E. Rubinstein, R. Saffroy, and F. Chiappini for fruitful discussions and A. Le Moal for excellent technical assistance.


   Footnotes
 
Grant support: Programme Hospitalier de Recherche Clinique AOR03055, and Bonus Qualité Recherche 2004 Faculté de Médecine Paris Ile de France Ouest.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/31/05; revised 6/20/05; accepted 7/11/05.


   References
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 Abstract
 Patients and Methods
 Results
 Discussion
 References
 

  1. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 2002;33:459–65.[CrossRef][Medline]
  2. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998;279:577–80.[Abstract/Free Full Text]
  3. Miettinen M, Sobin L, Sarlomo-Rikala M. Immunohistochemical spectrum of GISTs at different sites and their differential diagnosis with a reference to CD117 (KIT). Mod Pathol 2000;13:1134–42.[CrossRef][Medline]
  4. Berman J, O'Leary TJ. Gastrointestinal stromal tumor workshop. Hum Pathol 2001;32:578–82.[CrossRef][Medline]
  5. Miettinen M, El-Rifai W, Sobin LH, Lasota J. Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review. Hum Pathol 2002;33:478–83.[CrossRef][Medline]
  6. Ernst SI, Hubbs AE, Przygodzki RM, Emory TS, Sobin LH, O'Leary TJ. KIT mutation portends poor prognosis in gastrointestinal stromal/smooth muscle tumors. Lab Invest 1998;78:1633–6.[Medline]
  7. Lasota J, Jasinski M, Sarlomo-Rikala M, Miettinen M. Mutations in exon 11 of c-Kit occur preferentially in malignant versus benign gastrointestinal stromal tumors and do not occur in leiomyomas or leiomyosarcomas. Am J Pathol 1999;154:53–60.[Abstract/Free Full Text]
  8. Taniguchi M, Nishida T, Hirota S, et al. Effect of c-kit mutation on prognosis of gastrointestinal stromal tumors. Cancer Res 1999;59:4297–300.[Abstract/Free Full Text]
  9. Sakurai S, Fukasawa T, Chong JM, Tanaka A, Fukayama M. C-kit gene abnormalities in gastrointestinal stromal tumors (tumors of interstitial cells of Cajal). Jpn J Cancer Res 1999;90:1321–8.[CrossRef][Medline]
  10. Rubin BP, Singer S, Tsao C, et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 2001;61:8118–21.[Abstract/Free Full Text]
  11. Emile JF, Théou N, Tabone S, et al. Clinicopathologic, phenotypic, and genotypic characteristics of gastrointestinal mesenchymal tumors. Clin Gastroenterol Hepatol 2004;2:597–605.[CrossRef][Medline]
  12. Edmonson JH, Marks RS, Buckner JC, Mahoney MR. Contrast of response to dacarbazine, mitomycin, doxorubicin, and cisplatin (DMAP) plus GM-CSF between patients with advanced malignant gastrointestinal stromal tumors and patients with other advanced leiomyosarcomas. Cancer Invest 2002;20:605–12.[CrossRef][Medline]
  13. Bramwell VH, Morris D, Ernst DS, et al. Safety and efficacy of the multidrug-resistance inhibitor biricodar (VX-710) with concurrent doxorubicin in patients with anthracycline-resistant advanced soft tissue sarcoma. Clin Cancer Res 2002;8:383–93.[Abstract/Free Full Text]
  14. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001;344:1052–6.[Free Full Text]
  15. Van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacy of Imatinib Mesylate (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 2001;358:1421–3.[CrossRef][Medline]
  16. Colvin OM. Drug resistance in the treatment of sarcomas. Semin Oncol 1997;24:580–91.[Medline]
  17. Jimenez RE, Zalupski MM, Frank JJ, Du W, Ryan JR, Lucas DR. Multidrug resistance phenotype in high grade soft tissue sarcoma: correlation of P-glycoprotein immunohistochemistry with pathologic response to chemotherapy. Cancer 1999;86:976–81.[CrossRef][Medline]
  18. Komdeur R, Plaat BE, Van der Graaf WT, et al. Expression of multidrug resistance proteins, ABCB1, ABCC1 and LRP, in soft tissue sarcomas analysed according to their histological type and grade. Eur J Cancer 2003;39:909–16.
  19. Cole SP, Sparks KE, Fraser K, et al. Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells. Cancer Res 1994;54:5902–10.[Abstract/Free Full Text]
  20. Hegedus T, Orfi L, Seprodi A, Varadi A, Sarkadi B, Keri G. Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and ABCC1. Biochim Biophys Acta 2002;1587:318–25. Review.[Medline]
  21. Burger H, van Tol H, Boersma AW, et al. Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump. Blood 2004;104:2940–2.[Abstract/Free Full Text]
  22. Emile JF, Lemoine A, Bienfait N, Azoulay D, Debuire B. Length analysis of PCR products (LAPP): a sensitive and reliable technique for the detection of mutations in KIT exon 11 in gastrointestinal stromal tumours. Diagn Mol Pathol 2002;11:107–12.[CrossRef][Medline]
  23. Théou N, Tabone S, Saffroy R, et al. High expression of both mutant and wild-type alleles of c-kit in gastrointestinal stromal tumors. Biochim Biophys Acta 2004;1688:250–6.[Medline]
  24. Levine EA, Holzmayer T, Bacus S, et al. Evaluation of newer prognostic markers for adult soft tissue sarcomas. J Clin Oncol 1997;15:3249–57.[Abstract]
  25. Oda Y, Schneider-Stock R, Rys J, Gruchala A, Niezabitowski A, Roessner A. Expression of multidrug resistance associated protein gene in human soft tissue sarcomas. J Cancer Res Clin Oncol 1996;122:161–5.[CrossRef][Medline]
  26. Van Glabbeke M, van Oosterom AT, Oosterhuis JW, et al. Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: an analysis of 2,185 patients treated with anthracycline containing first line regimens—a European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 1999;17:150–7.[Abstract/Free Full Text]
  27. Plaat BE, Hollema H, Molenaar WM, et al. Soft tissue leiomyosarcomas and malignant gastrointestinal stromal tumors: differences in clinical outcome and expression of multidrug resistance proteins. J Clin Oncol 2000;18:3211–20.[Abstract/Free Full Text]
  28. Ryan DP, Puchalski T, Supko JG, et al. A phase II and pharmacokinetic study of ecteinascidin 743 in patients with gastrointestinal stromal tumors. Oncologist 2002;7:531–8.[Abstract/Free Full Text]
  29. Lasota J, Dansonka-Mieszkowska A, Stachura T, et al. Gastrointestinal stromal tumors with internal tandem duplications in 3' end of KIT juxtamembrane domain occur predominantly in stomach and generally seem to have a favorable course. Mod Pathol 2003;16:1257–64.[CrossRef][Medline]
  30. Wasag B, Debiec-Rychter M, Pauwels P, et al. Differential expression of KIT/PDGFRA mutant isoforms in epithelioid and mixed variants of gastrointestinal stromal tumors depends predominantly on the tumor site. Mod Pathol 2004;17:889–94.[CrossRef][Medline]
  31. Lasota J, Dansonka-Mieszkowska A, Sobin LH, Miettinen M. A great majority of GISTs with PDGFRA mutations represent gastric tumors of low or no malignant potential. Lab Invest 2004;84:874–83.[CrossRef][Medline]
  32. Lasota J, Kopczynski J, Sarlomo-Rikala M, et al. KIT 1530ins6 mutation defines a subset of predominantly malignant gastrointestinal stromal tumors of intestinal origin. Hum Pathol 2003;34:1306–12.[CrossRef][Medline]
  33. Antonescu CR, Sommer G, Sarran L, et al. Association of KIT exon 9 mutations with nongastric primary site and aggressive behavior: KIT mutation analysis and clinical correlates of 120 gastrointestinal stromal tumors. Clin Cancer Res 2003;9:3329–37.[Abstract/Free Full Text]
  34. Antonescu CR, Viale A, Sarran L, et al. Gene expression in gastrointestinal stromal tumors is distinguished by KIT genotype and anatomic site. Clin Cancer Res 2004;10:3282–90.[Abstract/Free Full Text]
  35. Toffoli G, Frustaci S, Tumiotto L, et al. Expression of MDR1 and GST-{pi} in human soft tissue sarcomas: relation to drug resistance and biological aggressiveness. Ann Oncol 1992;3:63–9.[Abstract/Free Full Text]
  36. Nakanishi H, Myoui A, Ochi T, Aozasa K. P-glycoprotein expression in soft-tissue sarcomas. J Cancer Res Clin Oncol 1997;123:352–6.[Medline]
  37. Baldini N, Scotlandi K, Barbanti-Brodano G, et al. Expression of P-glycoprotein in high-grade osteosarcomas in relation to clinical outcome. N Engl J Med 1995;333:1380–5.[Abstract/Free Full Text]
  38. Jimenez RE, Zalupski MM, Frank JJ, Du W, Ryan JR, Lucas DR. Multidrug resistance phenotype in high grade soft tissue sarcoma: correlation of P-glycoprotein immunohistochemistry with pathologic response to chemotherapy. Cancer 1999;86:976–81.
  39. Che XF, Nakajima Y, Sumizawa T, et al. Reversal of P-glycoprotein mediated multidrug resistance by a newly synthesized 1,4-benzothiazipine derivative, JTV-519. Cancer Lett 2002;187:111–9.[CrossRef][Medline]
  40. Mahon FX, Belloc F, Lagarde V, et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood 2003;101:2368–73.[Abstract/Free Full Text]
  41. Illmer T, Schaich M, Platzbecker U, et al. P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Leukemia 2004;18:401–8.[CrossRef][Medline]
  42. Burger H, Nooter K. Pharmacokinetic resistance to imatinib mesylate: role of the ABC drug pumps ABCG2 (BCRP) and ABCB1 (MDR1) in the oral bioavailability of imatinib. Cell Cycle 2004;3:1502–5.[Medline]
  43. Breedveld P, Pluim D, Cipriani G, et al. The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients. Cancer Res 2005;65:2577–82.[Abstract/Free Full Text]
  44. Ferrao PT, Frost MJ, Siah SP, Ashman LK. Overexpression of P-glycoprotein in K562 cells does not confer resistance to the growth inhibitory effects of imatinib (STI571) in vitro. Blood 2003;102:4499–503.[Abstract/Free Full Text]
  45. Lange T, Gunther C, Kohler T, et al. High levels of BAX, low levels of MRP-1, and high platelets are independent predictors of response to imatinib in myeloid blast crisis of CML. Blood 2003;101:2152–5.[Abstract/Free Full Text]
  46. Houghton PJ, Germain GS, Harwood FC, et al. Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res 2004;64:2333–7.[Abstract/Free Full Text]



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Improved Insight into Resistance Mechanisms to Imatinib in Gastrointestinal Stromal Tumors: A Basis for Novel Approaches and Individualization of Treatment
Oncologist, June 1, 2007; 12(6): 719 - 726.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
F.=C> Miselli, P. Casieri, T. Negri, M. Orsenigo, M. S. Lagonigro, A. Gronchi, M. Fiore, P. G. Casali, R. Bertulli, A. Carbone, et al.
c-Kit/PDGFRA Gene Status Alterations Possibly Related to Primary Imatinib Resistance in Gastrointestinal Stromal Tumors
Clin. Cancer Res., April 15, 2007; 13(8): 2369 - 2377.
[Abstract] [Full Text] [PDF]

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 J. Mol. Diagn.Home page
J. Lasota, B. Wasag, S. E. Steigen, J. Limon, and M. Miettinen
Improved Detection of KIT Exon 11 Duplications in Formalin-Fixed, Paraffin-Embedded Gastrointestinal Stromal Tumors
J. Mol. Diagn., February 1, 2007; 9(1): 89 - 94.
[Abstract] [Full Text] [PDF]

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