Z Gastroenterol 2008; 46 - A63
DOI: 10.1055/s-2008-1079667

Alterations of MDR1 and MRP1 functional activity of colorectal malignancies in a prospective clinical trial

T Micsik 1, T Mersich 2, Z Baranyai 2, I Besznyák 2, A Zaránd 2, K Dede 2, P Nagy 2, B Atkári 2, F Jakab 2, A Lőrincz 1, G Kéri 3, I Peták 4, R Schwab 5
  • 1Rational Drug Design Laboratories Cooperative Research Center, Budapest
  • 2Department of Surgery, Uzsoki Teaching Hospital, Budapest
  • 3Vichem Chemie Research Ltd.
  • 4KPS Medical Biotechnology and Healthcare Services Ltd., Budapest
  • 5Kelen Private Hospital, Budapest

Background: The ABC-transporters MDR1 and MRP1 are expressed in the normal mucosa of gastrointestinal tract. These proteins are extruding various drugs from cells and therefore can alter the sensitivity of colorectal cancer (CRC) cells – a phenomenon extensively studied previously by immune-histochemistry and real-time PCR techniques. However, posttranslational modifications influence the functional activity (MDR Activity Factor: MAF) of MDR proteins, so determination of functional activity can bring new insights into understanding the connection between resistance of colorectal cancer and ABC transporters. This is the first prospective clinical study to evaluate this effect.

Methods: Functional activity of MDR1 and MRP1 transporters in surgical samples of normal mucosa (NM) and primary and metastatic CRCs was performed. Tissue and blood samples were taken after prospective, consecutive patient enrollment with informed consent (98 primary CRC, 38 hepatic metastases and 23 healthy mucosa). Samples were brought into one-cell suspension in vitro with collagenase. MDR1/MRP1 MAF of viable epithelial cells and peripheral blood leukocytes (PBL) were determined with the MDQuant calcein-assay (www.solvo.com).

Results: Mean MDR1 functional activity of primary CRC was lower than in NM. MDR1-MAF significantly increased in metastases without reaching activity of the NM. MRP1 activity was similarly low in NM and primary CRCs, whereas slightly elevated in metastatic tumors. The elevation of MAF in metastatic cases was also found in peripheral blood leukocytes.

Conclusion: MDR-functional activity slightly decreases in primary CRC. The relative increase in MDR activity in metastases may be induced by the adjuvant chemotherapy, supported by the increase of MAF-values of the PBLs. This phenomenon may have significant clinical value with novel treatment modalities, which are known MDR-substrates and result in better survival (e.g. irinotecan and oxaliplatin). Here, survival differences may also be more prominent, which warrants further prospective trials.