Uptake and efficacy of trimetrexate (TMQ, 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline), a non-classical antifolate in methotrexate-resistant leukemia cells in vitro

Kamen, Barton A.; Eibl, Beatrice; Cashmore, Arlene R.; Bertino, Joseph R.

doi:10.1016/0006-2952(84)90298-3

Cited by 95 publications

(22 citation statements)

References 7 publications

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“…The transport of leucovorin, methotrexate, and trimetrexate was investigated using published techniques (12,13).…”

Section: Methodsmentioning

confidence: 99%

“…[10][11][12][13][14][15][16][17][18][19][20] ['4C]trimetrexate (13.1 mCi/mmol, sp act) for specific time periods followed by centrifugation at 15,000 g for 1 min through 1 ml ofF50 silicon fluid (General Electric Co., Silicone Products Div., Waterford, NY) to separate the cells from the radiolabeled media. The cell pellets were disrupted by dissolution in 0.5 ml of I M NaOH; the extract was dissolved in 10 ml of scintillant and radioactivity counted in a liquid scintillation counter.…”

Section: Methodsmentioning

confidence: 99%

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Potent in vitro and in vivo antitoxoplasma activity of the lipid-soluble antifolate trimetrexate.

Allegra¹,

Kovacs²,

Drake³

et al. 1987

J. Clin. Invest.

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Trimetrexate, a highly lipid-soluble quinazoline antifolate now undergoing trials as an anticancer agent, was found to be a potent inhibitor of the dihydrofolate reductase (DHFR) isolated from Toxoplasma gondii. The concentration required for 50% inhibition of protozoal DHFR was 1.4 nM. As an inhibitor of this enzyme, trimetrexate was almost 600-fold (amount of antifolate required to inhibit catalytic reaction by 50%) and 750-fold (inhibition constant) more potent than pyrimethamine, the DHFR inhibitor currently used to treat toxoplasma infection. When the protozoan was incubated with 1 jiM trimetrexate, the drug rapidly reached high intracellular concentrations. Since toxoplasma organisms lack a transmembrane transport system for physiologic folates, host toxicity can be prevented by co-administration of the reduced folate, leucovorin, without reversing the antiprotozoal effect. The effectiveness of trimetrexate against toxoplasma was demonstrated both in vitro and in vivo. Proliferation of toxoplasma in murine macrophages in vitro was completely inhibited by exposure of these cells to i0' M trimetrexate for 18 h. When used alone, trimetrexate was able to extend the survival of T. gondii-infected mice.

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“…The transport of leucovorin, methotrexate, and trimetrexate was investigated using published techniques (12,13).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Potent in vitro and in vivo antitoxoplasma activity of the lipid-soluble antifolate trimetrexate.

Allegra¹,

Kovacs²,

Drake³

et al. 1987

J. Clin. Invest.

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“…Effect of MTX and TMQ on the parenteral CCRF-CEM lymphoblastic leukemia cell line and two resistant sublines. The CCRF-CEM/R 1 line has a 20-fold increase in DHFR activity, while the R3 line has normal DHFR activity, but has a markedly impaired uptake of MTX [33] Cell line transport system may be effective agents against MTX-resistant cells with impaired transport or low levels of DHFR gene amplification [33,34]. Table 4 indicates that trimetrexate is highly effective in a MTXtransport-resistant CCRF-CEM cell line (R3); and more effective than MTX in a CCRF-CEM cell line, with a 20-fold increase in DHFR (RI).…”

Section: H Eradication Of Drug-resistant Cellsmentioning

confidence: 99%

Mechanisms of Drug Resistance in Human Leukemia

Bertino¹,

Srimatkandada²,

Carman³

et al. 1985

Modern Trends in Human Leukemia VI New Results in Clinical and Biological Research Including Pediatric Oncology

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“…Trimetrexate (TMQ) is a 2,4-diaminoquinazoline antifol that is undergoing clinical evaluation as an antineoplastic agent and has been approved for the treatment of AIDS-related Pneumocystis carinii infection. Unlike methotrexate, TMQ is lipophilic and enters the cell by a transport process distinct from the reduced folate carrier (Diddens et al, 1983;Jackson et al, 1984;Kamen et al, 1984). TMQ is a direct, potent inhibitor of DHFR, and does not undergo polyglutamation.…”

mentioning

confidence: 99%

Determinants of trimetrexate lethality in human colon cancer cells

et al. 1994

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Summary We examined the cytotoxicity and biochemical effects of the lipophilic antifol trimetrexate (TMQ) in two human colon carcinoma cell lines, SNU-C4 and NCI-H630, with different inherent sensitivity to TMQ. While a 24 h exposure to 0.1 M TMQ inhibited cell growth by 50-60% in both cell lines, it did not reduce clonogenic survival. A 24 h exposure to 1 and 10 ILM TMQ produced 42% and 50% lethality in C4 cells, but did not affect H630 cells. Dihydrofolate reductase (DHFR) and thymidylate synthase were quantitatively and qualitatively similar in both lines. During drug exposure, DHFR catalytic activity was inhibited by > 85% in both cell lines; in addition, the reduction in apparent free DHFR binding capacity (,<20% of control), depletion of dTTP, ATP and GTP pools and inhibition of [6-3H]deoxyuridine incorporation into DNA were similar in C4 and H630 cells. TMQ produced a more striking alteration of the pH step alkaline elution profile of newly synthesised DNA in C4 cells compared with 630 cells, however, indicating greater interference with DNA chain elongation or more extensive DNA damage. When TMQ was removed after a 24 h exposure to 0.1 tM, recovery of DHFR catalytic activity and apparent free DHFR binding sites was evident over the next 24 -48 h in both cell lines. With 1 and 10 JAM, however, persistent inhibition of DHFR was evident in C4 cells, whereas DHFR recovered in H630 cells. These data suggest that, although DHFR inhibition during TMQ exposure produced growth inhibition, DHFR catalytic activity 48 h after drug removal was a more accurate predictor of lethality in these two cell lines. Several factors appeared to influence the duration of DHFR inhibition after drug removal, including initial TMQ concentration, declining cytosolic TMQ levels after drug removal, the ability to acutely increase total DHFR content and the extent of TMQ-mediated DNA damage. The greater sensitivity of C4 cells to TMQ-associated lethality may be attributed to the greater extent of TMQ-mediated DNA damage and more prolonged duration of DHFR inhibition after drug exposure.

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Uptake and efficacy of trimetrexate (TMQ, 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline), a non-classical antifolate in methotrexate-resistant leukemia cells in vitro

Cited by 95 publications

References 7 publications

Potent in vitro and in vivo antitoxoplasma activity of the lipid-soluble antifolate trimetrexate.

Potent in vitro and in vivo antitoxoplasma activity of the lipid-soluble antifolate trimetrexate.

Mechanisms of Drug Resistance in Human Leukemia

Determinants of trimetrexate lethality in human colon cancer cells

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