PubMed · 2485939
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M Lyagoubi, D Fassin. 1989. [Malaria prophylaxis].. https://pubmed.ncbi.nlm.nih.gov/2485939/
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A human lymphoblastoid line (RPMI-1788), a methotrexate-sensitive human fibrosarcoma cell line (HT-1080), and a naturally resistant mixed mesodermal human sarcoma cell line with impaired methotrexate polyglutamylation (HS-42), recently established in our laboratory, were used to compare the ability of leucovorin to prevent trimetrexate cytotoxicity. Growth inhibition and an in situ thymidylate synthesis activity assay showed that inhibitory effects of trimetrexate (1 to 10 microM), 24-h exposure, were prevented by 10 microM leucovorin in the RPMI-1788 and HT-1080 cell lines but not in the HS-42 cell line. Total intracellular reduced folates increased about 2-fold in the three cell lines after exposure to leucovorin (10 microM) for 4 h, and after a 6-hour efflux remained elevated (1.5- and 1.3-fold of control levels) in RPMI-1788 and HT-1080 cells but decreased to 80% of control levels in HS-42 cells. Although uptake of leucovorin and levels of N5,N10-methylenetetrahydrofolate achieved after leucovorin administration were similar in RP-MI-1788 and HS-42 cells, polyglutamylate forms of this coenzyme were less in the HS-42 cells as compared to RPMI-1788 cells. Based on these studies, the combination of trimetrexate with leucovorin should be further investigated as a way to increase the therapeutic index in some patients with soft tissue sarcomas.
The biochemical and molecular basis for the elevation of glutathione (GSH) levels commonly detected in many drug-resistant cells has not been elucidated. In a series of L-phenylalanine mustard-resistant human prostate carcinoma cell lines (DU-145), resistance was associated with elevated GSH levels, increased activity of gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH biosynthesis, and a marked increase in the steady-state levels of GCS-specific transcripts (4.0 and 3.2 kilobases). Loss of the resistant phenotype was accompanied by a reduction in GSH and a return of GCS activity and transcript levels to values comparable to those detected in the drug-sensitive parent cells. These data strongly implicate up-regulation of GCS activity as an important mechanism in the evolution of drug resistance associated with increased levels of intracellular GSH. The results further suggest that the ability to synthesize GSH may be more indicative of resistance than steady-state GSH levels per se.
A series of 21 N-substituted phenoxazines has been synthesized in an effort to find more specific and less toxic modulators of multidrug resistance (MDR) in cancer chemotherapy. Thus, N-(omega-chloroalkyl)- and N-(chloroacyl)phenoxazines were found to undergo iodide-catalyzed nucleophilic substitution on reaction with various secondary amines, including N,N-diethylamine, N,N-diethanolamine, morpholine, piperidine, pyrrolidine and (beta-hydroxyethyl)piperazine. Products were characterized by UV, IR, 1H-, and 13C-NMR, mass spectral data, and elemental analyses. All of the compounds were examined for cytotoxicity and for their ability to increase the accumulation of the vinca alkaloids, vincristine (VCR) and vinblastine (VLB) in multidrug-resistant GC3/Cl (human colon adenocarcinoma) and KBChR-8-5 (HeLa variant) cell lines. Compounds were compared to the standard modulator verapamil (VRP). Substitutions on the phenoxazine ring at position 10 were associated with an increase in antiproliferative and anti-MDR activities. Modification of the length of the alkyl bridge and the type of amino side chain also influenced the potency of these effects. From among the compounds examined, 10 derivatives were found to increase the accumulation of VCR and VLB in GC3/Cl and KBChR-8-5 cells relative to the effect of VRP, suggesting that with the exception of pyrrolidinyl, the tertiary amine attachments to the phenoxazine nucleus linked through a three- or four-carbon alkyl chain resulted in enhanced anti-MDR activity. On the basis of their 50% growth inhibitory (IC50) values, five of the ten compounds, namely, 10-(3'-chloropropyl)phenoxazine, 10-[3'-[N-bis(hydroxyethyl)- amino]propyl]phenoxazine, 10-(3'-N-morpholinopropyl)phenoxazine, 10-(4'-N-morpholinobutyl)phenoxazine and 10-(N-piperidinoacetyl)phenoxazine were selected as relatively nontoxic chemosensitizers. These modulators, at nontoxic concentrations, potentiated the cytotoxicity of VCR and VLB in GC3/Cl and KBChR-8-5 cells. Further, two compounds 10-(3'-N-morpholinopropyl)phenoxazine, and the butyl derivative, enhanced accumulation of VLB in GC3/Cl, KBChR8-5 and highly resistant KB-V1 cells to a level significantly greater than the maximal level achieved with VRP. Additional experiments to understand the mechanism of action of these agents in modulating MDR are in progress.