Clinical Effects of the Dichloro and Monochlorophenyl Analogues of Diamino Pyrimidine: Antagonists of Folic Acid12

Murphy, Michele; Rr, Ellison; Da, Karnofsky; Jh, Burchenal

doi:10.1172/jci103016

Cited by 54 publications

(12 citation statements)

References 11 publications

(13 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Early clinical trials of metoprine in acute leukaemia were abandoned because of severe and prolonged drug toxicity (Murphy et al, 1954 (Stickney et al, 1973;Hall, Benjamin & Tenczynski, 1978). We have confirmed the persistence of considerable dihydrofolate reductase inhibitory activity following a single dose of metoprine.…”

Section: Discussionsupporting

confidence: 65%

“…Metoprine (DDMP) (2,4-diammino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine ( Figure 1) is a lipidsoluble inhibitor of dihydrofolate reductase that produces antitumor effects in mice (Burchenal, Goetchius & Stock, 1952;Sirotnak, Dorick & Moccio, 1976), rats (Denlinger, Cavallito & Nichol, 1976), and man (Murphy, Ellison & Kamofsky, 1954 0306-5251/81/110675406 $01.00 (Murphy et al, 1954;Alberto, Brugarolas, & DeJager, 1979;Currie, Kempin & Young, 1981;Miller, Nichol & Rundles, 1976;Pnrce, Goldie & Hill, 1975;Price & Hill, 1976;Price, Goldie & Hill, 1977). In the murine sarcoma 180 model, improvement in the therapeutic index of the DDMP has been noted with the incorporation of citrovorum-factor rescue into dosage schedules (Price & Hill, 1976); clinical studies at Memorial Hospital were conducted to evaluate this regimen in man.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Kinetics of metoprine, a lipid‐soluble antifolate.

Jones¹,

Gordon²,

Umans³

et al. 1981

Brit J Clinical Pharma

View full text Add to dashboard Cite

1 Using a dihydrofolate reductase inhibition assay, we have conducted eight pharmacokinetic studies in six patients receiving metoprine. 2 The serum level v time-curve for metoprine equivalents was irregular; first-order elimination was not observed during the study period of 0-120 h. A model-independent analysis was therefore performed, employing the area under the curve during the first 120 h (AUC). 3 At an oral dose of 65 mg/M2 without leucovorin, a peak level of 0.6 ,g/ml and an AUC of 52 /kg ml-' h produced significant leukopenia and thrombocytopenia. 4 At doses ranging from 100 mg/M2 to 175 mg/M2 orally, with leucovorin administration 40 mg/M2 intravenously at 24 and 96 h, haematologic toxicity was seen in only 1 patient who received 175 mg/M2. This patient also had the highest peak serum level (2.8 ,ug/ml) and AUC (228 pLg ml-' h).5 One partial response and one minor regression were observed in the studied patients; these two patients had the 175 mg/M2 dose, highest peak levels (2.4 and 2.8 jig/ml) and highest AUCs (197 and 228 ,ug ml-' h). The other patients had lower peak levels and AUCs and had neither therapeutic response nor hematologic toxicity. 6 The AUC and peak serum levels were linearly related to each other (P < 0.001). 7 Total urinary excretion of dihydrofolate reductase inhibitors (as metoprine equivalents) in the first 120 h ranged from 5 to 17% of the administered dose.

show abstract

Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Kinetics of metoprine, a lipid‐soluble antifolate.

Jones¹,

Gordon²,

Umans³

et al. 1981

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…The lipophilic antifolate PYR exerts strong proapoptotic activity in addition to its antiprotozoal effects. Several PYR analogues, such as DDEP and DDMP, have also been investigated as antitumor agents (36).…”

Section: Discussionmentioning

confidence: 99%

Antifolate Activity of Pyrimethamine Enhances Temozolomide-Induced Cytotoxicity in Melanoma Cells

Chen

Osman

Orlow

2009

Molecular Cancer Research

View full text Add to dashboard Cite

Most metastatic melanoma patients fail to respond to available therapy, underscoring the need to develop more effective treatments. We screened 2,000 compounds from the Spectrum Library in human melanoma cell lines to identify compounds that enhanced the cytotoxic effect of temozolomide, a drug used to treat metastatic melanoma. Screening was done with the temozolomide-resistant melanoma cell line SK-MEL-19, and six compounds were identified that had little or no inherent cytotoxicity but significantly enhanced growth-inhibition by temozolomide. These compounds were tested in five additional melanoma cell lines. Cell proliferation and death assays were used to compare the efficacy of single agent temozolomide versus combination treatments. Effects of combination treatment on levels of DNA double-strand breaks, the DNA repair protein O 6 -methylguanine-DNA-methyltransferase, apoptosis[measured by cleaved caspase-3 and poly(ADP-ribose) polymerase], and cell cycle were examined. Pyrimethamine, an antiparasitic, sensitized melanoma cells to temozolomide. Temozolomide combined with Pyrimethamine synergistically inhibited cell proliferation in melanoma cells with combination index values of 0.7 or less. In addition, combination treatment induced cell cycle arrest and increased both DNA damage and apoptosis. The increase in cell death due to combination treatment was rescued by leucovorin. Other folate antagonists were also effective enhancers of temozolomide-induced cytotoxicity, and the effects of antifolates were also evident in gliomas. Our screening approach led to the identification of Pyrimethamine, an orally available drug that efficiently crosses the blood-brain barrier, as a potent enhancer of the efficacy of temozolomide as an antineoplastic agent via inhibition of folate metabolism. (Mol Cancer Res 2009;7(5):703-12)

show abstract

“…Under the conditions of testing, BW50197 was the pyrimidine analogue most effective in inhibiting tumour growth. Subsequently Murphy et al (1954) showed in a clinical study that BW50197 produced haematological improvement in 3 out of 12 children with acute leukaemia. Our interest in BW50197 was stimulated by the observation by Nichol (1968) that inhibition of a methotrexate resistant tumour (the Walker carcinoma 256) could be achieved by this drug which showed a more favourable therapeutic index against this tumour than pyrimethamine (Mishra, Rosen and Nichol, 1967;Sotobayashi, Rosen and Nichol, 1966).…”

mentioning

confidence: 99%

“…Clinically, however, a prolonged exposure to MTX is associated with severe toxicity to normal proliferating systems such as the bone marrow and gut (Bergsagel, personal communication 1970), although very high concentrations can safely be given over short periods of time (Goldie, Price and Harrap, 1972;Djerassi et al, 1,972). However, although BW50197 does produce haematological toxicity, it can be given over much longer periods than MTX (Murphy et al, 1954). Therefore, since human tumours exist which are resistant to MTX by virtue of a transport defect (Kessel, Hall and Roberts, 1968) (Goldie, Furness and Price, 1973;Wood, Ferone and Hitchings, 1961).…”

mentioning

confidence: 99%

Studies Concerned with Overcoming Resistance to Methotrexate: A Comparison of the Effects of Methotrexate and 2,4-Diamino-5-(3′,4′-Dichlorophenyl)-6-Methylpyrimidine (BW50197) on the Colony Forming Ability of L5178Y Cells

Hill¹,

Goldie²,

Price³

1973

Br J Cancer

View full text Add to dashboard Cite

Summary.-The effects of methotrexate (MTX) and 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine (BW50197) on the colony forming ability of L5178Y cells were compared. Two sub-lines of cells were used, one sensitive to methotrexate and the other resistant. In addition, the inhibitory effects of BW50197 against dihydrofolate reductase (DHFR) extracted from the MTX resistant-cells were compared with those of MTX and pyrimethamine. It was found that although BW50197 was a less effective inhibitor of DHFR than MTX, it was superior to MTX at high concentrations in killing MTX resistant cells, and this superiority increased with the time of exposure to the drugs. These findings suggest that (a) when antifolate compounds are screened for antitumour activity it is insufficient simply to assess them on the basis of their ability to inhibit DHFR and (b) BW50197 should be given clinically so as to achieve the highest possible tissue concentration for the longest possible time consistent with the safety of the patient.

show abstract

Clinical Effects of the Dichloro and Monochlorophenyl Analogues of Diamino Pyrimidine: Antagonists of Folic Acid12

Cited by 54 publications

References 11 publications

Kinetics of metoprine, a lipid‐soluble antifolate.

Kinetics of metoprine, a lipid‐soluble antifolate.

Antifolate Activity of Pyrimethamine Enhances Temozolomide-Induced Cytotoxicity in Melanoma Cells

Studies Concerned with Overcoming Resistance to Methotrexate: A Comparison of the Effects of Methotrexate and 2,4-Diamino-5-(3′,4′-Dichlorophenyl)-6-Methylpyrimidine (BW50197) on the Colony Forming Ability of L5178Y Cells

Contact Info

Product

Resources

About