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Laurane G. Mendelsohn - One of the best experts on this subject based on the ideXlab platform.
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Preclinical and Clinical Evaluation of the Glycinamide Ribonucleotide Formyltransferase Inhibitors Lometrexol and LY309887
Antifolate Drugs in Cancer Therapy, 1999Co-Authors: Laurane G. Mendelsohn, John F. Worzalla, Jackie M. WallingAbstract:The importance of the purine de novo pathway in providing DNA precursors for cancer cell growth led to the hypothesis that novel antifolate inhibitors of glycinamide ribonucleotide formyltransferase (GARFT), the first folate-dependent enzyme in this pathway, might have utility in the treatment of cancer. In 1987, clinical investigations were initiated with Lometrexol (6R-dideazatetrahydrofolic acid, 6R-DDATHF), a novel “tight-binding” inhibitor of GARFT with potent antitumor activity in a number of murine and human xenograft solid tumors. Unexpected observations of delayed cumulative toxicity in phase I clinical trials prompted extensive preclinical investigations of the dynamics of folate status on the efficacy and toxicity of GARFT inhibitors and other antifolates (1). In addition, structure-activity studies have led to the identification of a second generation GARFT inhibitor, LY309887 (2´, 5´-thienyl-dideazatetrahydrofolic acid), which is more potent than Lometrexol and has greater antitumor efficacy in vivo (2). Biochemical and pharmacological differences between LY309887 and Lometrexol with respect to potency to inhibit GARFT, differential transport and storage in liver, and polyglutamation suggest that LY309887 may have greater antitumor efficacy and more manageable toxicity in the clinic than Lometrexol. A murine model of the delayed cumulative toxicity seen with Lometrexol has been refined and characterized to provide greater understanding of the pharmacokinetics and pharmacodynamics of these events. In concert with recently published nutritional data on the folate status of humans and more sophisticated methods of assessing and modulating antifolate toxicities through vitamin supplementation, antifolate therapy may be poised to enter a new phase of clinical success. In this report, we describe LY309887, a GARFT inhibitor with unique biochemical and pharmacological properties that has antitumor activity against a broad panel of human xenograft tumors, and greater potency than Lometrexol both as an inhibitor of GARFT and as an inhibitor of tumor growth in vivo. An overview of the phase I clinical results with Lometrexol and the design of the phase I clinical trial with LY309887 will be presented.
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Biochemistry and pharmacology of glycinamide ribonucleotide formyltransferase inhibitors: LY309887 and Lometrexol
Investigational new drugs, 1996Co-Authors: Laurane G. Mendelsohn, Chuan Shih, Richard M. Schultz, John F. WorzallaAbstract:Lometrexol, a tight-binding antifolate inhibitor of the purine de novo enzyme glycinamide ribonucleotide formyltransferase (GARFT), was the first GARFT inhibitor to be investigated clinically. Unexpected observations of delayed cumulative toxicity prompted a search for a second generation antimetabolite with a more favorable biochemical, pharmacological and toxicological profile. LY309887, 6R-2′,5′-thienyl-5,10-dideazatetrahydrofolic acid, had 9-fold greater potency to inhibit GARFT (Ki = 6.5 nM) compared to Lometrexol. Like Lometrexol, LY309887 was activated by folypolyglutamate synthetase, however, it had a lower first order rate constant. In vitro and in vivo data were consistent with these observations: polyglutamation of LY309887 was less extensive compared to Lometrexol and livers of mice accumulated fewer polyglutamates of LY309887 than polyglutamates of Lometrexol. The affinities of these two compounds for isoforms of human folate receptors (FR) were compared. Lometrexol had a 6-fold higher affinity for FRα than LY309887 and both compounds had higher affinity for the α isoform compared to the β isoform. The selectivity of LY309887 for FRα (β(Ki)/α(Ki) = 10.5) was twice that of Lometrexol's (β/α = 5.0). Lometrexol and LY309887 were potent cytotoxic compounds against the human leukemia cell line CCRF-CEM with IC50's of 2.9 nM and 9.9 nM, respectively. In vivo, LY309887 was more potent than Lometrexol at inhibiting tumor growth in the C3H mammary murine tumor model and several tumor xenografts. Excellent efficacy was achieved by both compounds in several colon xenografts. In two pancreatic human xenografts, LY309887 achieved greater efficacy than Lometrexol. In summary, the biochemical and pharmacological properties of Lometrexol and LY309887 support the hypothesis that these antifolates will have clinical activity against human solid tumors. LY309887 is a second generation GARFT inhibitor with biochemical and pharmacological properties which distinguish it from Lometrexol and suggest that it will have broad antitumor activity, a different pharmacokinetic profile and produce less toxicity than Lometrexol in cancer patients.
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A Novel Class of Monoglutamated Antifolates Exhibits Tight-binding Inhibition of Human Glycinamide Ribonucleotide Formyltransferase and Potent Activity against Solid Tumors
Cancer research, 1994Co-Authors: L L Habeck, Lynn S Gossett, Chuan Shih, Tracy A. Leitner, Katherine A. Shackelford, Richard M. Schultz, Sherri L. Andis, Gerald B. Grindey, Laurane G. MendelsohnAbstract:Tight-binding inhibition of recombinant human monofunctional glycinamide ribonucleotide formyltransferase by Lometrexol (6R-5,10-dideazatetrahydrofolate) requires polyglutamation. LY254155 and LY222306 differ from 5,10-dideazatetrahydrofolate in the replacement of the 1',4'- phenylene moiety by a 2',5'-thiophene and a 2',5'-furan, respectively. Compared to Lometrexol, the thiophene and furan analogues had 25- and 75-fold greater inhibitory potencies against human monofunctional glycinamides ribonucleotide formyltransferase (Ki = 2.1 and 0.77 nM, respectively). The binding affinities of the thiophene and furan analogues for membrane folate-binding protein from human KB cells were 6- and 350-fold weaker than Lometrexol, respectively. Both the thiophene analogue and 5,10-dideazatetrahydrofolate inhibited the in vivo growth of murine 6C3HED lymphosarcoma, murine C3H mammary carcinoma, and human xenograft HXGC3, HC1, and VRC5 colon carcinomas by 95-100%. The thiophene analogue was efficacious against human xenograft PANC-1, a pancreatic carcinoma which was completely resistant to 5,10- dideazatetrahydrofolate. These novel antifolates represent the first monoglutamated tight-binding inhibitors of glycinamide ribonucleotide formyltransferase. By eliminating the need for polyglutamation, this class of antifolates may have clinical activity in the treatment of solid tumors expressing low levels of folylpolyglutamate synthetase or tumors resistant to antifolate therapy due to increased gamma-glutamyl hydrolase activity.
James K Coward - One of the best experts on this subject based on the ideXlab platform.
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synthesis of 6r and 6s 5 10 dideazatetrahydrofolate oligo γ glutamates kinetics of multiple glutamate ligations catalyzed by folylpoly γ glutamate synthetase
Organic and Biomolecular Chemistry, 2005Co-Authors: John W Tomsho, John J Mcguire, James K CowardAbstract:Folylpoly-γ-glutamate synthetase (FPGS, EC 6.3.2.17) catalyzes the ATP-dependent ligation of glutamic acid to reduced folates including (6S)-5,6,7,8-tetrahydrofolate (H4PteGlu), as well as to anticancer drugs such as 5,10-dideaza-5,6,7,8-tetrahydrofolate ((6R)-DDAH4PteGlu1, (6R)-DDATHF, Lometrexol™). Synthesis of unlabeled mono- and polyglutamates, DDAH4PteGlun (6R, n = 1–6; 6S, n = 1–2), as well as (6R)-DDAH4Pte[14C]Glu1, was effected from (6R)- or (6S)-5,10-dideazatetrahydropteroyl azide and glutamic acid, H-Glu-γ-Glun-γ-Glu-OH (n = 0–4), or [14C]glutamic acid, respectively. These compounds were evaluated as FPGS substrates to determine steady-state kinetic constants. Michaelis–Menten kinetics were observed for (6R)-DDAH4PteGlu1, the isomer corresponding to H4PteGlu, whereas marked substrate inhibition was observed for (6S)-DDAH4PteGlun (n = 1–2) and (6R)-DDAH4PteGlun (n = 2–5), but not (6R)-DDAH4PteGlu6. Multiple ligation of glutamate renders a quantitative analysis of these data difficult. However, approximate values of KM = 0.65–1.6 µM and KI = 144–417 µM for DDAH4PteGlun were obtained using a simple kinetic model.
M D'incalci - One of the best experts on this subject based on the ideXlab platform.
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Role of membrane folate-binding protein in the cytotoxicity of 5,10-dideazatetrahydrofolic acid in human ovarian carcinoma cell lines in vitro
British Journal of Cancer, 1996Co-Authors: S Sen, E Erba, M D'incalci, F Bottero, S Canevari, A TomassettiAbstract:Lometrexol (5,10-dideazatetrahydrofolic acid; DDATHF), is a specific inhibitor of glycinamideribonucleosyl (GAR) transformylase with anti-tumour activity in murine and human carcinomas. The cytotoxicity activity of DDATHF was evaluated in vitro in NIH/3T3 cells transfected with human alpha-folate-binding protein (FBP) complementary DNA to examine the role of the receptor. In FBP-transfected NIH/3T3 (FBP-tNIH/3T3) cells, which internalised about three times more 5-methyltetrahydrofolic acid than the mock-transfected cells, the cytotoxtic potential of DDATHF showed a clear increase. Subsequently, we analysed four ovarian carcinoma cell lines (OVCAR3, IGROV1, SKOV3, and SW626) expressing different amounts of FBP. Cells were conditioned to grow in medium depleted of folic acid then tested by MOv18 and folic acid binding. Only SKOV3 and SW626 cells grown in folic acid-depleted medium showed increased FBP expression, about 3- and 8-fold respectively. The cytotoxic potential of DDATHF was evaluated by a standard clonogenic assay. In a medium containing 2.27 microM folic acid the DDATHF IC50 values were 50 nm on OVCAR3, 500 nM on SW626 and 1000 nM on IGROV1. In folic acid-free medium IC50 values were 2 nM on OVCAR3 and Sw626 and 40 nM on IGROV1. Only on SKOV3 cells was DDATHF cytotoxicity the same regardless of the amount of folic acid in the medium (IC50 8 nM). Thus, DDATHF did not inhibit the growth of IGROV1 cells depleted of folic acid after stripping FBP with phosphatidylinositol-phospholipase C, even at a dose toxic for cells constitutively expressing FBP. Although FBP expression is certainly one of the parameters affecting drug toxicity, taken alone it is not a sufficiently reliable predictor of cancer cell sensitivity to DDATHF.
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Mechanism of cytotoxicity of 5,10-dideazatetrahydrofolic acid in human ovarian carcinoma cells in vitro and modulation of the drug activity by folic or folinic acid
British Journal of Cancer, 1994Co-Authors: E Erba, S Sen, C Sessa, Fl Vikhanskaya, M D'incalciAbstract:Inhibition of clonogenic potential by the glycinamideribonucleosyl transformylase inhibitor 5,10-dideazatetrahydrofolic acid (DDATHF, Lometrexol) was evaluated in vitro in a human ovarian carcinoma cell line, SW626. Drug-induced inhibition of clonogenic potential is a function of the dose and time of exposure and is independent of the formation of DNA single-strand breaks or de novo synthesis of protein. Simultaneous treatment with 100 microM hypoxanthine completely prevented the inhibition of clonogenic potential caused by 0.5 microM DDATHF. DDATHF blocked cells in the early-middle S-phases of the cell cycle, and there was a corresponding marked reduction in the rate of DNA synthesis after drug withdrawal. The cytotoxic potential of DDATHF was modulated by the folic acid concentration present in the medium. In a medium containing 0.22 microM folic acid, DDATHF cytotoxicity was at least 100 times that in a regular medium containing 2.22 microM folic acid, levels which, however, are about 100 times those found in human plasma. DDATHF cytotoxicity differed moderately when folic acid concentrations varied between 0.22 and 0 microM, suggesting that folic acid does not necessarily antagonise DDATHF anti-tumour activity. Folinic acid at a concentration as low as 0.1 microM can completely rescue cells when given simultaneously with 0.5 microM DDATHF. When folinic acid was given 24 h after DDATHF, a reversal of cytotoxicity was observed at 0.5 and 1 microM, but to a much lesser extent than simultaneous treatment. When folinic acid was added after 48 or 72 h of DDATHF washout, even at a high concentration and for a long time, no reduction in DDATHF cytotoxicity was found. In conclusion, the study highlights the modulation of DDATHF cytotoxicity by folic acid or by folinic acid and provides further rationale for in vivo clinical investigation with these combinations.
S Sen - One of the best experts on this subject based on the ideXlab platform.
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Role of membrane folate-binding protein in the cytotoxicity of 5,10dideazatetrahydrofolic acid in human ovarian carcinoma cell lines in vitro
2013Co-Authors: S Sen, F Bottero, S Canevari, E Erbal, A TomassettiAbstract:Summary Lometrexol (5,10-dideazatetrahydrofolic acid; DDATHF), is a specific inhibitor of glycinamideribonucleosyl (GAR) transformylase with anti-tumour activity in murine and human carcinomas. The cytotoxicity activity of DDATHF was evaluated in vitro in NIH/3T3 cells transfected with human a-folatebinding protein (FBP) complementary DNA to examine the role of the receptor. In FBP-transfected NIH/3T3 (FBP-tNIH/3T3) cells, which internalised about three times more 5-methyltetrahydrofolic acid than the mock-the cytotoxic potential of DDATHF showed a clear increase. Subsequently, we analysed four transfected cells, ovarian carcinoma cell lines (OVCAR3, IGROVI, SKOV3 and SW626) expressing different amounts of FBP. Cells were conditioned to grow in medium depleted of folic acid then tested by MOvl8 and folic acid binding. Only SKOV3 and SW626 cells grown in folic acid-depleted medium showed increased FBP expression, about 3-and 8-fold respectively. The cytotoxic potential of DDATHF was evaluated by a standard clonogenic assay. In a medium containing 2.27,IM folic acid the DDATHF IC50 values were 50 nm on OVCAR3, 500 nm on SW626 and 1000 nm on IGROVI. In folic acid-free medium IC50 values were 2 nm on OVCAR3 and SW626 and 40 nm on IGROVI. Only on SKOV3 cells was DDATHF cytotoxicity the same regardless of the amount of folic acid in the medium (IC50 8 nM). Thus, DDATHF did not inhibit the growth of IGROVI cells depleted of folic acid after stripping FBP with phosphatidylinositol-phospholipase C, even at a dose toxic for cells constitutively expressing FBP. Although FBP expression is certainly one of the parameters affecting drug toxicity, taken alone it is not a sufficiently reliable predictor of cancer cell sensitivity to DDATHF
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Role of membrane folate-binding protein in the cytotoxicity of 5,10-dideazatetrahydrofolic acid in human ovarian carcinoma cell lines in vitro
British Journal of Cancer, 1996Co-Authors: S Sen, E Erba, M D'incalci, F Bottero, S Canevari, A TomassettiAbstract:Lometrexol (5,10-dideazatetrahydrofolic acid; DDATHF), is a specific inhibitor of glycinamideribonucleosyl (GAR) transformylase with anti-tumour activity in murine and human carcinomas. The cytotoxicity activity of DDATHF was evaluated in vitro in NIH/3T3 cells transfected with human alpha-folate-binding protein (FBP) complementary DNA to examine the role of the receptor. In FBP-transfected NIH/3T3 (FBP-tNIH/3T3) cells, which internalised about three times more 5-methyltetrahydrofolic acid than the mock-transfected cells, the cytotoxtic potential of DDATHF showed a clear increase. Subsequently, we analysed four ovarian carcinoma cell lines (OVCAR3, IGROV1, SKOV3, and SW626) expressing different amounts of FBP. Cells were conditioned to grow in medium depleted of folic acid then tested by MOv18 and folic acid binding. Only SKOV3 and SW626 cells grown in folic acid-depleted medium showed increased FBP expression, about 3- and 8-fold respectively. The cytotoxic potential of DDATHF was evaluated by a standard clonogenic assay. In a medium containing 2.27 microM folic acid the DDATHF IC50 values were 50 nm on OVCAR3, 500 nM on SW626 and 1000 nM on IGROV1. In folic acid-free medium IC50 values were 2 nM on OVCAR3 and Sw626 and 40 nM on IGROV1. Only on SKOV3 cells was DDATHF cytotoxicity the same regardless of the amount of folic acid in the medium (IC50 8 nM). Thus, DDATHF did not inhibit the growth of IGROV1 cells depleted of folic acid after stripping FBP with phosphatidylinositol-phospholipase C, even at a dose toxic for cells constitutively expressing FBP. Although FBP expression is certainly one of the parameters affecting drug toxicity, taken alone it is not a sufficiently reliable predictor of cancer cell sensitivity to DDATHF.
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Mechanism of cytotoxicity of 5,10-dideazatetrahydrofolic acid in human ovarian carcinoma cells in vitro and modulation of the drug activity by folic or folinic acid
British Journal of Cancer, 1994Co-Authors: E Erba, S Sen, C Sessa, Fl Vikhanskaya, M D'incalciAbstract:Inhibition of clonogenic potential by the glycinamideribonucleosyl transformylase inhibitor 5,10-dideazatetrahydrofolic acid (DDATHF, Lometrexol) was evaluated in vitro in a human ovarian carcinoma cell line, SW626. Drug-induced inhibition of clonogenic potential is a function of the dose and time of exposure and is independent of the formation of DNA single-strand breaks or de novo synthesis of protein. Simultaneous treatment with 100 microM hypoxanthine completely prevented the inhibition of clonogenic potential caused by 0.5 microM DDATHF. DDATHF blocked cells in the early-middle S-phases of the cell cycle, and there was a corresponding marked reduction in the rate of DNA synthesis after drug withdrawal. The cytotoxic potential of DDATHF was modulated by the folic acid concentration present in the medium. In a medium containing 0.22 microM folic acid, DDATHF cytotoxicity was at least 100 times that in a regular medium containing 2.22 microM folic acid, levels which, however, are about 100 times those found in human plasma. DDATHF cytotoxicity differed moderately when folic acid concentrations varied between 0.22 and 0 microM, suggesting that folic acid does not necessarily antagonise DDATHF anti-tumour activity. Folinic acid at a concentration as low as 0.1 microM can completely rescue cells when given simultaneously with 0.5 microM DDATHF. When folinic acid was given 24 h after DDATHF, a reversal of cytotoxicity was observed at 0.5 and 1 microM, but to a much lesser extent than simultaneous treatment. When folinic acid was added after 48 or 72 h of DDATHF washout, even at a high concentration and for a long time, no reduction in DDATHF cytotoxicity was found. In conclusion, the study highlights the modulation of DDATHF cytotoxicity by folic acid or by folinic acid and provides further rationale for in vivo clinical investigation with these combinations.
Richard M. Schultz - One of the best experts on this subject based on the ideXlab platform.
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Cell cycle effects of antifolate antimetabolites: implications for cytotoxicity and cytostasis
Cancer Chemotherapy and Pharmacology, 1997Co-Authors: John L. Tonkinson, Lynn S Gossett, Chuan Shih, Richard M. Schultz, Sherri L. Andis, Philip Marder, L G MendelsohnAbstract:Purpose : Cell cycle-related events in CCRF-CEM lymphocytic leukemia cells were examined subsequent to inhibition of thymidylate synthase (TS) or GAR formyltransferase (GARFT) and prior to cell death or stasis. Methods : Cell populations were treated with the GARFT inhibitors 6 R -5,10-dideazatetrahydrofolate (Lometrexol) or LY309887, the TS inhibitor ZD1694, or the multitargeted antifolate LY231514. DNA content, nucleoside precursor incorporation and proliferating cell nuclear antigen (PCNA) expression as functions of drug treatment were assessed by multiparameter flow cytometry. Cellular respiration was measured by MTT analysis and apoptosis was detected by extraction of DNA fragments. Results : Cell populations treated for up to 96 h with Lometrexol or LY309887 did not replicate and maintained a cell cycle distribution with distinct G_1, S and G_2/M regions. The number of S phase cells in treated populations was slightly elevated relative to control as measured by DNA content and PCNA. However, these cells were unable to incorporate 5-bromodeoxyuridine (BrdU). Throughout treatment, cells incubated with GARFT inhibitors maintained intact membranes and respired at a level comparable to untreated cells. In contrast, ZD1694 as well as LY231514, induced synchronization of the treatment population at the G_1/S interface within 12 h of drug addition. This was followed by synchronous entry of the population into S phase. After 24 h of treatment, more than 90% of the cells were capable of incorporating BrdU and stained positive for PCNA. DNA fragmentation occurred in cells treated with ZD1694 or LY231514 but not in those treated with GARFT inhibitors. In addition, the viable cells remaining after 24–48 h of treatment with ZD1694 or LY231514 were respiring at twice the level of untreated cells. Conclusion : These results demonstrate that the distinct endpoints of GARFT and TS inhibition are preceded by distinct cell cycle and metabolic alterations.
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Biochemistry and pharmacology of glycinamide ribonucleotide formyltransferase inhibitors: LY309887 and Lometrexol
Investigational new drugs, 1996Co-Authors: Laurane G. Mendelsohn, Chuan Shih, Richard M. Schultz, John F. WorzallaAbstract:Lometrexol, a tight-binding antifolate inhibitor of the purine de novo enzyme glycinamide ribonucleotide formyltransferase (GARFT), was the first GARFT inhibitor to be investigated clinically. Unexpected observations of delayed cumulative toxicity prompted a search for a second generation antimetabolite with a more favorable biochemical, pharmacological and toxicological profile. LY309887, 6R-2′,5′-thienyl-5,10-dideazatetrahydrofolic acid, had 9-fold greater potency to inhibit GARFT (Ki = 6.5 nM) compared to Lometrexol. Like Lometrexol, LY309887 was activated by folypolyglutamate synthetase, however, it had a lower first order rate constant. In vitro and in vivo data were consistent with these observations: polyglutamation of LY309887 was less extensive compared to Lometrexol and livers of mice accumulated fewer polyglutamates of LY309887 than polyglutamates of Lometrexol. The affinities of these two compounds for isoforms of human folate receptors (FR) were compared. Lometrexol had a 6-fold higher affinity for FRα than LY309887 and both compounds had higher affinity for the α isoform compared to the β isoform. The selectivity of LY309887 for FRα (β(Ki)/α(Ki) = 10.5) was twice that of Lometrexol's (β/α = 5.0). Lometrexol and LY309887 were potent cytotoxic compounds against the human leukemia cell line CCRF-CEM with IC50's of 2.9 nM and 9.9 nM, respectively. In vivo, LY309887 was more potent than Lometrexol at inhibiting tumor growth in the C3H mammary murine tumor model and several tumor xenografts. Excellent efficacy was achieved by both compounds in several colon xenografts. In two pancreatic human xenografts, LY309887 achieved greater efficacy than Lometrexol. In summary, the biochemical and pharmacological properties of Lometrexol and LY309887 support the hypothesis that these antifolates will have clinical activity against human solid tumors. LY309887 is a second generation GARFT inhibitor with biochemical and pharmacological properties which distinguish it from Lometrexol and suggest that it will have broad antitumor activity, a different pharmacokinetic profile and produce less toxicity than Lometrexol in cancer patients.
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A Novel Class of Monoglutamated Antifolates Exhibits Tight-binding Inhibition of Human Glycinamide Ribonucleotide Formyltransferase and Potent Activity against Solid Tumors
Cancer research, 1994Co-Authors: L L Habeck, Lynn S Gossett, Chuan Shih, Tracy A. Leitner, Katherine A. Shackelford, Richard M. Schultz, Sherri L. Andis, Gerald B. Grindey, Laurane G. MendelsohnAbstract:Tight-binding inhibition of recombinant human monofunctional glycinamide ribonucleotide formyltransferase by Lometrexol (6R-5,10-dideazatetrahydrofolate) requires polyglutamation. LY254155 and LY222306 differ from 5,10-dideazatetrahydrofolate in the replacement of the 1',4'- phenylene moiety by a 2',5'-thiophene and a 2',5'-furan, respectively. Compared to Lometrexol, the thiophene and furan analogues had 25- and 75-fold greater inhibitory potencies against human monofunctional glycinamides ribonucleotide formyltransferase (Ki = 2.1 and 0.77 nM, respectively). The binding affinities of the thiophene and furan analogues for membrane folate-binding protein from human KB cells were 6- and 350-fold weaker than Lometrexol, respectively. Both the thiophene analogue and 5,10-dideazatetrahydrofolate inhibited the in vivo growth of murine 6C3HED lymphosarcoma, murine C3H mammary carcinoma, and human xenograft HXGC3, HC1, and VRC5 colon carcinomas by 95-100%. The thiophene analogue was efficacious against human xenograft PANC-1, a pancreatic carcinoma which was completely resistant to 5,10- dideazatetrahydrofolate. These novel antifolates represent the first monoglutamated tight-binding inhibitors of glycinamide ribonucleotide formyltransferase. By eliminating the need for polyglutamation, this class of antifolates may have clinical activity in the treatment of solid tumors expressing low levels of folylpolyglutamate synthetase or tumors resistant to antifolate therapy due to increased gamma-glutamyl hydrolase activity.
