Commentary Antiproliferative prostaglandins and the MRP/GS-X pump role in cancer immunosuppression and insight into new strategies in cancer gene therapy Paulo Ivo Homem de Bittencourt Jr. a, *, Rui Curi b a Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Rua Sarmento Leite 500, 90050-170 Porto Alegre, RS, Brazil b Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sa ˜o Paulo, Sa ˜o Paulo, SP, Brazil Abstract A dramatic complication in late-stage cancer patients is host immunosuppression. Cyclopentenone prostaglandins (CP-PGs) overpro- duced in cancer may impair the function of the immune system. These agents, if produced at high concentrations, are powerful cytostatic and cytotoxic compounds that may arrest cell proliferation and immune response in cancer. Lymphoid tissues of tumor-bearing animals accumulate large amounts of CP-PGs, whereas the tumor tissue does not. This may be because cancer cells are able to overexpress multidrug resistance-associated protein (Mg 2+ -dependent vanadate-sensitive GS-conjugate export ATPase, MRP/GS-X pump), which extrudes CP-PGs to the extracellular space as glutathione S-conjugates. In contrast, MRP/GS-X pump activity is disproportionately low in lymphocytes. This led us to propose the transfection of lymphocytes with multidrug resistance-associated protein genes (MRP) for further autologous transfusion or direct in vivo delivery to lymphocytes by using adenovirus-retrovirus chimeras in order to restore immune system function in cancer, at least partially. We are currently evaluating MRP-transfected lymphocyte (MTL) therapy, using Walker 256 tumor-bearing rats as a model. © 2001 Elsevier Science Inc. All rights reserved. Keywords: Multidrug resistance; MRP/GS-X pump; Antiproliferative prostaglandins; Glutathione metabolism; Cancer chemotherapeutics; Cancer immuno- suppression 1. Introduction Cancer-associated immunosuppression is a common complication and reason for the poor prognosis of late-stage cancer patients. The tumor itself plays a role in the development of immunosuppression through the pro- duction of substances that impair the function of the immune system. Among known immunoblocking sub- stances, PGs may be of importance in dictating the degree of immunosuppression and, thus, the rate of tumor growth. The plasma of tumor-bearing humans [1] and other mammalian models [2] exhibits high levels of PGs, espe- cially those of the E-type (mainly PGE 2 ). This is because tumor cells [2,3] as well as specialized antigen-presenting cells [4], stimulated by the manifestation of an initiating tumor, produce PGE 2 and PGD 2 [5,6], whose presence is associated with the impairment of immune function, thus leading to immunosuppression and cancer cachexia [4,7]. In vitro studies also showed that PGE 2 released by HEp-2 human larynx carcinoma cells inhibited human polymor- phonuclear leukocyte migration, which was reversed by treating HEp-2 cells with the non-steroidal anti-inflamma- tory indomethacin, a PG synthesis inhibitor [3]. PGE 2 re- duces lymphocyte proliferation and promotes unresponsive- ness to antigen challenge in normal B lymphocytes [8]. PGD 2 produced by tumor cells has also been reported to be antiproliferative for different cell types [7]. * Corresponding author. Tel.: +55-51-3316-3151; fax: +55-51-3316- 3166. E-mail address: pauloivo@vortex.ufrgs.br (P.I. Homem de Bittencourt Jr.). Abbreviations: ABC, ATP-binding cassette transporter ATPase; CP- PG, cyclopentenone prostaglandin; GSH, glutathione; GSSG, glutathione disulfide; GS-conjugate, glutathione S-conjugate; MRP/GS-X pump, Mg 2+ -dependent vanadate-sensitive GS-conjugate export ATPase; hsp, heat shock protein; MDR, multidrug resistance; MRP, multidrug resis- tance-associated protein; MTL therapy, MRP/GS-X pump-transfected lym- phocyte therapy; NF-B, nuclear factor kappa B; PG, prostaglandin; and PPAR-, peroxisome proliferator-activated receptor-gamma. Biochemical Pharmacology 62 (2001) 811– 819 0006-2952/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S0006-2952(01)00738-9