Abstract
Conjugation of methotrexate to poly(L-lysine) markedly increases its cellular uptake and offers a new way to overcome drug resistance related to deficient transport. Conjugates using poly(L-lysines) of molecular weights varying from 3,100 to 130,000 have comparable effects on a drug resistant CHO cell line. Conjugates using poly(D-lysine), however, have no effect on either resistant or normal CHO cells. Both the L- and D-isomeric conjugates are taken up by cells in comparable fashion. Since even the biologically active conjugates are poor inhibitors of dihydrofolate reductase (5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase; EC 1.5.1.3) in vitro, it is concluded that the conjugate must give rise in the cell to a pharmacologically active breakdown product. Such a product can be detected in cells exposed to the L-isomeric, but not in cells exposed to the D-isomeric conjugates. Excess of poly(L-lysine) only moderately decreases methotrexate-poly(L-lysine) uptake but markedly decreases its inhibitory effect on cell growth.
ACKNOWLEDGMENTS We thank Dr. Wayne F. Flintoff, of the University of Western Ontario, for making available to us the methotrexate-resistant CHO cell lines; Dr. Richard A. Laursen for the amino acid analysis of the MTX-poly(L-lys) conjugates; and Ms. Lucie van Heeckeren for technical assistance.
- Copyright © 1979 by Academic Press, Inc.
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|