Enhancement of trimetrexate cytotoxicity in vitro and in vivo by carboxypeptidase G(2) Journal Article
| Authors: | Romanini, A.; Sobrero, A. F.; Chou, T. C.; Sherwood, R. F.; Bertino, J. R. |
| Article Title: | Enhancement of trimetrexate cytotoxicity in vitro and in vivo by carboxypeptidase G(2) |
| Abstract: | Carboxypeptidase G2 (CPG2), an enzyme produced by Pseudomonas strain RS-16, hydrolyzes the glutamate residue from methotrexate and other folates. The possibility of enhancing trimetrexate cytotoxicity by CPG2 induced folate depletion was investigated in vitro in a human leukemia ceU line, CCRF-CEM, and in three sublines of these cells each with a different methotrexate resistance phenotype. The cytotoxic effect in vitro was detected using a colorimetric assay with a tetrazolium salt, 3-4,5-dimethylthiazol-2-yl)-2,5-iiphenyltetrazolium bromide. Dose-effect relationships of drugs alone and in combination were analyzed by the median effect principle and by the combination indices for quantitation of synergy or antagonism with the aid of a computer program. Trimetrexate alone was cytotoxic against the parent and all the resistant cell lines with the drug concentrations required to decrease the cell count to 50% of control in the nanomolar range (1.4, 1.6, 1.5, and 0.7 nM in CCRF-CEM, CCRF-CEM/E, CCRF-CEM/P, and CCRF-CEM/T, respectively) following 5 days of exposure. The concentration of CPG2 required to decrease the cell count to 50% control for these cell lines was 3.5, 2.6, 26.6, and 7.9 x HT5 units/ml for CCRF-CEM, CCRF-CEM/E, CCRF-CEM/P, and CCRF-CEM/T, respectively. A synergistic cytotoxic effect of trimetrexate after simultaneous continuous exposure with CPG2 was observed with CCRF-CEM ceUs and with the three resistant cell lines. This drug combination given to BALB/c x DBA/2 Fi mice bearing LI 210 cells also produced synergy over a narrow range of drug doses. The activity of this combination in both methotrexate sensitive and methotrexate resistant cell lines indicates that clinical trials of this combination should be undertaken. © 1989, American Association for Cancer Research. All rights reserved. |
| Keywords: | human cell; drug potentiation; mouse; animal; mice; cell survival; cell line; animal experiment; drug resistance; drug synergism; mice, inbred strains; cell culture; folic acid; drug cytotoxicity; radioisotope; quinazolines; clone cells; carboxypeptidase; trimetrexate; carboxypeptidase g2; gamma-glutamyl hydrolase; cysteine endopeptidases; tumor stem cell assay; leukemia l1210; human; priority journal; support, non-u.s. gov't; support, u.s. gov't, p.h.s. |
| Journal Title: | Cancer Research |
| Volume: | 49 |
| Issue: | 21 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 1989-11-01 |
| Start Page: | 6019 |
| End Page: | 6023 |
| Language: | English |
| PUBMED: | 2529027 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 14 April 2020 -- Source: Scopus |
Citation Impact
Related MSK Work