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Right arrow Lung - cancer

J Thorac Cardiovasc Surg 2002;123:862-868
© 2002 The American Association for Thoracic Surgery

General Thoracic Surgery (GTS)

Despite some expression of folate receptor {alpha} in human mesothelioma cells, internalization of methotrexate is predominantly carrier mediated

Nushmia Z. Khokhar, MDa, Alicia F. Y. Lam, BSa, Valerie W. Rusch, MDb, F. M. Sirotnak, PhDa

From the Program of Molecular Pharmacology and Experimental Therapeuticsa and Department of Surgery,b Memorial Sloan-Kettering Cancer Center, New York, NY.

Supported in part by National Cancer Institute grants CA08748 and CA55617.

Received for publication July 5, 2001. Revisions requested Aug 24, 2001; revisions received Sept 7, 2001. Accepted for publication Sept 14, 2001. Address for reprints: F. M. Sirotnak, PhD, Laboratory for Molecular Therapeutics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021 (E-mail: sirotnaf{at}mskcc.org).

Objective: As a response to a published report documenting some expression of folate receptor {alpha} in human mesothelioma, studies were carried out examining the role of this receptor versus that of the reduced folate carrier in the internalization of folate analogs in this neoplasm.
Methods: Influx measurements of tritiated methotrexate were carried out in 4 mesothelioma cell lines, and 2 additional cell lines were used as comparators. Relative gene-expression analysis for the carrier and receptor gene was done by using real-time reverse transcriptase-polymerase chain reaction in the above-mentioned cell lines and mesothelioma tumor tissues obtained from patients.
Results: Internalization of tritiated methotrexate in mesothelioma cell lines grown at physiologic folate levels was carrier mediated rather than receptor mediated. Influx of this model permeant by these cells exhibited characteristics of carrier-mediated membrane transport and was only minimally reduced by the addition of 5 µmol/L folic acid, a concentration of this natural folate that would have completely inhibited influx by the folate receptor. Gene-expression analysis revealed prominent expression of the folate receptor in some but not all mesothelioma cell lines, and in only one case was expression of this receptor gene greater than expression of the reduced folate carrier gene. Similar analysis of human mesothelioma tumor tissue showed that, with few exceptions, receptor gene expression was substantially less than that for the carrier gene.
Conclusion: In view of the ongoing reduced folate carrier-mediated internalization that occurs in mesothelioma cells, these results would seem to argue against a role for the folate receptor in the internalization and cellular pharmacokinetics of methotrexate and other classic folate analogs in this neoplasm. Identifying the mediated route for internalization of these agents in tumor cells is a prerequisite for improving their structural design.




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