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Expression of folylpolyglutamyl synthetase predicts poor response to methotrexate therapy in patients with rheumatoid arthritis.

OBJECTIVE: The enzyme folylpolyglutamyl synthetase (FPGS) is involved in the resistance to methotrexate in tumor cell lines. The aim of the present study was to determine the impact of FPGS mRNA expression on resistance to methotrexate therapy in patients with rheumatoid arthritis (RA). METHODS: We determined the expression of FPGS mRNA using the Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) in 141 patients with RA. All patients received methotrexate therapy. The primary outcome measures were disease activity as determined by a disease activity score (DAS) and response to therapy. RESULTS: Seventy-eight of 141 patients (55%) showed expression of FPGS mRNA. FPGS mRNA expression was not associated with age, sex, disease duration, white blood cell count, erythrocyte sedimentation rate, C-reactive protein (CRP), number of swollen joints, number of painful joints, and combined therapy with other disease-modifying antirheumatic drugs (DMARDs) or additional corticosteroids. The response rate to methotrexate therapy was 44% for the total study population. Patients without FPGS mRNA expression showed a significantly higher response rate than patients with FPGS mRNA expression (57% versus 33%; p = 0.005). Multivariate logistic regression analysis revealed that female sex (p = 0.009) and FPGS mRNA expression (p = 0.004) were independent predictive factors for failure to achieve a response to methotrexate therapy. CONCLUSION: FPGS mRNA expression is an independent predictive factor associated with poor response to methotrexate therapy in RA patients.

Adult↗

PubMed2003

[Methotrexate in conjunction with meloxicam for treating ankylosing spondylitis: a clinical observation of the efficacy and safety].

OBJECTIVE: To evaluate the efficacy and safety of combined use of methotrexate and meloxicam for treating of ankylosing spondylitis (AS), and to determine the optimal dosage of methotrexate. METHODS: Thirty-two patients with AS were divided into group A (n=14) to receive oral methotrexate at the dose of 12.3+/-3.6 mg once a week and group B (n=18) at the dose of 21.3+/-3.2 mg once a week. Each of the patients in both groups also took oral meloxicam (7.5 mg) for 3 months. RESULTS: After treatment, the clinical indexes and inflammatory parameters of the patients significantly improved in both groups, with a total efficacy of 78.6% in group A and 88.9% in group B. CONCLUSION: The combination of methotrexate with meloxicam may achieve satisfactory results in AS treatment, which is not positively related to methotrexate dosage. In short-term usage, meloxicam does not increase the toxicity of methotrexate.

Adult↗

PubMed1992

Effects of folate receptor expression following stable transfection into wild type and methotrexate transport-deficient ZR-75-1 human breast cancer cells.

Two biochemically distinct systems, the high affinity folate receptor and the lower affinity reduced-folate carrier, have each been implicated in mediating the transport of folates and antifolates into cells. Previous studies from our laboratory have shown that methotrexate accumulation into wild type (WT) ZR-75-1 human breast cancer cells involves a system with characteristics of the reduced-folate carrier, that this system is deficient in methotrexate resistant (MTXR) ZR-75-1 cells in which methotrexate transport is undetectable and that neither breast cancer cell line expresses folate receptors. In this report we examined the possible interaction of the reduced-folate carrier with folate receptors by stably transfecting both WT ZR-75-1 and MTXR ZR-75-1 cells with an expression vector containing a folate receptor cDNA. Clones of stably transfected MTXR ZR-75-1 and WT ZR-75-1 cells expressing comparable levels of folate receptors were studied and compared to the nontransfected cell lines. Although nontransfected WT and MTXR ZR-75-1 cell lines require concentrations > or = 100 nM folic acid for growth, the expression of folate receptors in transfected WT and MTXR ZR-75-1 cells permitted the growth of both cell lines in low concentrations (1 nM) of folic acid. While the defect in the reduced-folate carrier system in MTXR ZR-75-1 cells inhibits their growth in medium containing low concentrations of folinic acid (< or = 1 microM), MTXR ZR-75-1 cells expressing folate receptors display uninhibited growth in 1 nM folinic acid. The accumulation of folic acid, folinic acid, and methotrexate is enhanced in folate receptor-transfected WT ZR-75-1 cells and MTXR ZR-75-1 cells. Furthermore, the accumulation of folates and antifolate was similar in both transfected WT and MTXR ZR-75-1 cell lines that expressed folate receptors. This suggests that alterations in the reduced-folate carrier do not affect folate receptor function. We also examined the effect of folate receptor expression on the sensitivity of WT and MTXR ZR-75-1 cells to methotrexate and to the lipophillic antifolate trimetrexate. Increased folate receptor expression decreased the sensitivity of WT ZR-75-1 cells toward the antifolate trimetrexate, presumably through increased uptake of reduced folates. Although the expression of the folate receptor enhanced the growth of both cell lines in low folate concentrations, it did not affect the sensitivity of either WT or MTXR ZR-75-1 cells to methotrexate.

Biological Transport↗

PubMed1992

Depletion of 5,10-methylenetetrahydrofolate and 10-formyltetrahydrofolate by methotrexate in cultured hepatoma cells.

The effect of the inhibition of dihydrofolate reductase by methotrexate on the cellular folates involved in de novo purine and thymidylate biosynthesis has been measured in H35 hepatoma cells grown in 4 microM folic acid or 20 nM folinic acid. The major cellular folate species in cells from medium with folate or folinate is 10-formyltetrahydrofolate (approximately 5 microM), with lesser amounts of 5,10-methylenetetrahydrofolate and tetrahydrofolate. Cultures were exposed to a pulse dose of methotrexate, resulting in the accumulation of nearly exclusively methotrexate polyglutamates (predominantly Glu3, Glu4, and Glu5), or a continuous exposure to the poorly glutamylated analog threo-4-fluoromethotrexate, resulting in 93% intracellular monoglutamate. At 4 hr and 18 hr after exposure to either compound there was extensive depletion of the reduced folate coenzymes, which generally corresponded to the extent of inhibition of glycine and deoxyuridine incorporation. This was accompanied by an increase of the cellular dihydrofolate and 10-formyldihydrofolate. In the H35 cells the effect of methotrexate polyglutamates on the reduced folate coenzyme pools was restricted to dividing cultures, because the reduced folate coenzymes were not depleted in confluent cultures. The results demonstrate that the methotrexate and methotrexate polyglutamates that initially accumulate within dividing H35 cells readily inhibit dihydrofolate reductase but are not adequate to inhibit thymidylate synthase and prevent the depletion of reduced folate coenzymes. Thus, inhibition of de novo glycine and deoxyuridine incorporation into DNA as a result of dihydrofolate reductase inhibitors appears to be closely related to a reduction in the intracellular concentration of 10-formyltetrahydrofolate and 5,10-methylenetetrahydrofolate, the respective folate coenzymes for de novo purine and thymidylate synthesis.

Animals↗

PubMed2003

Treatment compliance and dosage administration among rheumatoid arthritis patients receiving infliximab, etanercept, or methotrexate.

OBJECTIVE: To examine treatment compliance and dosage administration associated with infliximab, etanercept, and methotrexate therapy for rheumatoid arthritis (RA). STUDY DESIGN: Retrospective analysis using administrative and claims data from a large US health plan. PATIENTS AND METHODS: Patients were Medicare or commercial enrollees in a health plan with a pharmacy benefit and had a diagnosis of RA. The first (index) claim for infliximab, etanercept, or methotrexate occurred between July 1, 1998, and December 31, 2000. Continuous enrollment in the plan was required from 182 days before to 365 days after the index claim. Treatment groups were compared according to compliance (defined as the actual number of therapy administrations or filled prescriptions divided by the expected number) and changes in dosage administration over time. The costs of infliximab therapy also were explored. RESULTS: A total of 2662 patients (infliximab = 141; etanercept = 853; and methotrexate = 1668) were included in the analyses. Infliximab patients were older and more likely to have a Medicare benefit. In addition, infliximab patients had more comorbidities and had greater medical costs preceding the index claim. Compliance with at least 80% of the expected dosages was significantly lower for etanercept (odds ratio [OR] 0.462; 95% confidence interval [CI] 0.290-0.736) and methotrexate (OR 0.385; 95% CI 0.245-0.604) patients than infliximab patients. Methotrexate patients had the largest dosage increases (61.6%), followed by infliximab (37.4%) and etanercept (7.4%) patients. Assuming 6.5 dosages per year, the annual cost of infliximab was dollars 10446 to dollars 12363, or dollars 1887 to dollars 1902 per administration, depending on site of service. CONCLUSIONS: Compliance is higher with infliximab compared with etanercept or methotrexate; whereas, fewer etanercept patients change dosages. The cost of infliximab was lower than expected based on previous predictions, even with a 37% increase in dosage.

Adult↗

PubMed2005

Response to initial treatment of low and intermediate risk gestational trophoblastic disease with methotrexate and folinic acid.

OBJECTIVES: To evaluate the response and toxicity of methotrexate and folinic acid given as primary treatment of low and intermediate risk gestational trophoblastic disease (GTD). MATERIAL AND METHOD: Medical records review was performed in patients who received methotrexate and folinic acid as a primary treatment of low and intermediate risk persistent GTD between January 1992 and December 2001. Response was defined as decline of beta human chorionic gonadotropin (hCG) to < or = 5 mlU/ml (remission) after methotrexate and folinic acid treatment. Response rate was estimated and factors associated with response were evaluated. RESULTS: Ninety four eligible patients were treated with intramuscular methotrexate and folinic acid. Complete remission was achieved in 64 cases (68%, 95% CI 58-78%). Mucositis (6.4%) and hepatotoxicity (6.4%) were the most common toxicity of methotrexate in the present study and none of these toxic effects was life threatening. Factors associated with response were initial serum hCG < or = 10,000 mlU/ml and stage I disease. CONCLUSION: Methotrexate with folinic acid is effective treatment for low and intermediate risk GTD with minimal severe toxicity.

Adult↗

PubMed2005

[The influence of IL-6 polymorphism on efficacy of treatment of rheumatoid arthritis patients with methotrexate and prednisone].

Rheumatoid arthritis (RA) is a chronic inflammatory disease in which cytokines play an important role. The therapy of RA is associated with application of the drugs modulating the immune response via inhibiting the cytokine production. The common drugs used in RA therapy are methotrexate and prednisone. Recent investigations showed the importance of genetically determined differences in cytokine production in RA activity and therapy. The aim of the present study was to examine the influence of - 174 interleukin-6 (IL-6) promoter polymorphism on the efficacy of treatment of RA patients with methotrexate and prednisone. Polymerase chain reaction amplification was used for analysis of the polymorphism at IL-6 gene. Seventy patients with RA diagnosed according to the criteria of the American College of Rheumatology were investigated. The patients were divided into two subgroups. The first subgroup included patients who have obtained remission for at least 6 months after therapy with methotrexate and glucocorticosteroids. The second subgroup included patients with active disease despite at least 6 months of therapy with methotrexate and glucocorticosteroids. It has been shown that the incidence of remission after therapy with methotrexate and glucocorticosteroids was significantly lower in patients with GG genotype as compared with GC and CC genotypes p< 0.05. We suggest that -174 IL-6 promoter polymorphism may be a genetic risk factor determining the effectiveness of RA treatement with methotrexate and glucocorticosteroids.

Adult↗

PubMed1991

Heterogeneity of methotrexate binding in human colon tumor cells.

[3H]-methotrexate binding at pH 5.0 and pH 7.2 by the cytosol of tumor tissues and the surrounding normal areas of the gastrointestinal tract of patients suffering from colon or gastric cancer has been used to identify in these cells the presence of a binder of methotrexate having low-affinity for this drug in addition to the enzyme dihydrofolate reductase. Scatchard analysis of the [3H]-methotrexate binding data by a colon tumor sample also reveals that there are two binders of this drug present in the cytosol of these cells. The association constant (Kass) for one binder of methotrexate is = 5.6 x 10(7) M-1 while the Kass for the second binder is = 1.0 x 10(6) M-1. The two binders do not differ very much in their apparent molecular weight. Upon isoelectric focusing, the tumor cell cytosol resolves into 4 major isoproteins each having the ability not only to bind [3H]-methotrexate but also reduce [3H]-pteroylglutamic acid to [3H]-tetrahydropteroylglutamic acid. This suggests that the two binders of methotrexate may be the two forms of dihydrofolate reductase having different affinities for this anticancer drug.

Carcinoma↗

PubMed1975

Effect of N-bromosuccinimide modification on dihydrofolate reductase from a methotrexate-resistant strain of Escherichia coli. Activity, spectrophotometric, fluorescence and circular dichroism studies.

When dihydrofolate reductase from a methotrexate-resistant strain of Escherichia coli B, MB 1428, is treated with approximately a 5 mol ratio of N-bromosuccinimide (NBS) to enzyme at pH 7.2 and assayed at the same pH, there is a 40% loss of activity due to the modification of 1 histidine residue and possibly 1 methionine residue before oxidation of tryptophan occurs. The initial modification is accompanied by a shift of the pH for maximal enzymatic activity from pH 7.2 to pH 5.5 Upon further treatment with N-bromosuccinimide, the activity is gradually reduced from 60 to 0% as tryptophan residues become oxidized. An NBS to enzyme mole ratio of approximately 20 results in 90% inactivation of the enzyme. When the enzyme is titrated with NBS in 6 M guanidine HCl, 5 mol of tryptophan react per mol of enzyme, a result in agreement with the total tryptophan content as determined by magnetic circular dichroism. The 40% NBS-inactivated sample posses full binding capacity for methotrexate and reduced triphosphopyridine nucleotide, and the Km values for dihydrofolate and TPNH are the same as for the native enzyme. After 90% inactivation, only half of the enzyme molecules bind methotrexate, and the dissociation constant for methotrexate is 40 nM as compared to 4 nM for native enzyme in solutions of 0.1 M ionic strength, pH 7.2 Also, TPNH is not bound as tightly to the modified enzyme-methotrexate complex as to the unmodified enzyme-methotrexate complex. Circular dichroism studies indicate the 90% NBS-inactivated enzyme has the same alpha helix content as the native enzyme but less beta structure, while the 40% inactivated enzyme is essentially the same as the native enzyme. Protection experiments were complicated by the fact that NBS reacts with the substrates and cofactors of the enzyme. Although protection of specific residues was not determined, it was clear that TPNH was partially protected from NBS reaction when bound to the enzyme, and the enzyme, and the enzyme was not inactivated by NBS until the TPNH had reacted.

Amino Acids↗

PubMed1986

Conversion of methotrexate to 7-hydroxymethotrexate and 7-hydroxymethotrexate polyglutamates in cultured rat hepatic cells.

The formation of 7-hydroxymethotrexate and its diglutamate has been established in rat hepatic parenchymal cells in culture. The formation of 7-hydroxymethotrexate increases with the extracellular methotrexate concentration (1-50 microM) and with time over a 24-h period. The majority of the 7-hydroxy derivative is found in the medium after 6- and 24-h incubations at all concentrations examined. At high methotrexate concentration (50 microM) 7% of the total extracellular methotrexate was the 7-hydroxy derivative. 7-Hydroxymethotrexate diglutamate is accumulated within the cell, although longer chain length derivatives are not observed. The inability to form longer chain length polyglutamate derivatives is consistent with a limited capacity of hepatocytes to convert radiolabeled 7-hydroxymethotrexate to the tri- and tetraglutamates although the diglutamate is readily formed. A hepatoma cell line has an extremely limited capacity to form 7-hydroxy derivatives from methotrexate but form measurable amounts of mono-, di-, and triglutamates of 7-hydroxymethotrexate. 7-Hydroxymethotrexate was a good substrate for glutamylation in the hepatoma cells with large amounts of tri- through pentaglutamate derivatives. These studies confirm that 7-hydroxymethotrexate and the diglutamate must be considered when evaluating methotrexate pharmacology and demonstrate that this will be necessary with regard to methotrexate hepatotoxicity.

Animals↗

PubMed1989

Methotrexate serum-level determinations during low-dose therapy of rheumatoid and psoriatic arthritis.

In 29 patients, 21 suffering from psoriatic arthritis and eight patients suffering from rheumatoid arthritis, methotrexate serum-levels were determined by means of radioimmunoassay. The aim of the investigation was to recognize an eventual dependence of the serum level of methotrexate on the total cumulative dose and to test the possibility of a concomitant therapy control. Beside the determinations of the serum levels of methotrexate, clinical examinations and laboratory tests were done at regular intervals. The values obtained showed no significant increase during the course of therapy compared to the values at the beginning of the treatment. Likewise no correlation to the total cumulative dose, the clinical picture or to the occurrence of side-effects could be found. Nor could any relationship between the changing of laboratory parameters and the methotrexate serum-levels be observed. No differences appeared in the methotrexate serum-levels during therapy of either rheumatoid or psoriatic arthritis patients. In conclusion it seems impossible to monitor a low-dose methotrexate therapy by continuous determinations of the serum levels of the drug.

Arthritis, Rheumatoid↗

PubMed1989

Alpha-monoamides of methotrexate as potential prodrugs.

alpha-Monoamides of methotrexate were evaluated for their potential as prodrugs. Studies on 11 alpha-monoamides and 5 gamma-monoamides of methotrexate showed that the gamma-monoamides were about as strong inhibitors of Lactobacillus casei dihydrofolate reductase as methotrexate, while I50 of the alpha-monoamides were 1-2 orders higher. The concentration for growth inhibition of murine L1210 cells for methotrexate gamma-propylamide and alpha-propylamide were respectively 1-2 and 2-3 orders higher than that of methotrexate. In contrast, only alpha-monoamides caused significant increase in life span of mice with transplanted L1210 leukaemia, the highest effect being given by the alpha-propyl and the alpha-butylamide. The possibility that the in vivo activity of the alpha-monoamides might be related to in vivo transformation to methotrexate was studied by HPLC analysis of mice serum after administration of the alpha- and gamma-propylamides.

Animals↗

PubMed1989

Transport of methotrexate by the in vitro isolated rabbit proximal tubule.

The tubular transport of [3H]methotrexate was studied in isolated nonperfused and perfused superficial proximal tubular segments of rabbit kidneys. Reabsorption represented only 5% of perfused methotrexate, and appeared to be mostly of passive nature inasmuch as it was not modified by reducing the temperature or by ouabain. Cellular accumulation in nonperfused segments and secretion in perfused tubules were highest in the S2 segment and lower in the S3 and S1 segments. Secretion against a bath-to-lumen concentration gradient was observed only in S2 segments (with a maximum methotrexate secretory rate of 478 +/- 48 fmol/mm.min and an apparent Km of transport of 363 +/- 32 microM), and was inhibited by probenecid and folate. The low capacity for methotrexate secretion may be explained by a low capacity of transport across the basolateral membrane of the proximal cell as methotrexate was accumulated only to a low extent in nonperfused tubules (tissue water to medium concentration ratio of 8.2 +/- 1 in S2 segments). During secretion a small amount of methotrexate was metabolized; the nature of the metabolite(s) remains to be defined.

Absorption↗

PubMed1987

Methotrexate efflux in L1210 cells. Kinetic and specificity properties of the efflux system sensitive to bromosulfophthalein and its possible identity with a system which mediates the efflux of 3',5'-cyclic AMP.

Methotrexate exits L1210 mouse leukemia cells via multiple routes that include a unidirectional efflux component which is sensitive to bromosulfophthalein. This efflux component has been characterized in the present study after eliminating the contribution from the other efflux routes by treatment of the cells with an active ester of methotrexate and by reducing the assay pH to 6.2. The remaining efflux at pH 6.2 was greater than 90% sensitive to bromosulfophthalein. This route was also inhibited by probenecid, prostaglandin A1, diamide, 1-methyl-3-isobutylxanthine, various metabolic inhibitors, and by transfer of the cells to a buffer containing high concentrations of KCl. The inhibition by prostaglandin A1 was exceptionally potent and reached 50% at a concentration of 0.5 microM. An enhancement in efflux occurred upon the addition of glucose or by transfer of the cells to a non-saline buffer. When parameters relating to cellular energetics were measured, a reduction in ATP level was associated with the inhibition of efflux by probenecid, carbonylcyanide m-chlorophenylhydrazone, valinomycin, and antimycin A, whereas the increase in efflux by glucose was accompanied by an increase in intracellular ATP. Changes in ATP, however, were not associated with the inhibition by various other compounds or additions or with the enhancement in efflux by the non-anionic buffer. When the relative sensitivity of methotrexate efflux to bromosulfophthalein, 4,4'-diisothiocyanostilbene-2,2'-disulfonate, and lactic anhydride was compared with other anion transport systems, differences in specificity indicated that methotrexate was not exiting the cells via the bicarbonate/chloride exchange carrier, the lactate/H+ co-transport system, or a system which mediates the efflux of phthalate. However, a correlation was apparent between the sensitivity of methotrexate efflux to inhibition by prostaglandin A1, probenecid, and certain metabolic inhibitors and the ability of these same compounds to inhibit the unidirectional efflux of 3',5'-cyclic AMP in other cell lines, suggesting that methotrexate may share a common efflux route with cyclic nucleotides.

Adenosine Triphosphate↗

PubMed1989

Toxicity of methotrexate compared with azathioprine in the treatment of rheumatoid arthritis. A case-control study of 131 patients.

One hundred thirty-one patients with rheumatoid arthritis treated with either azathioprine sodium (n = 37, 102.7 +/- 32.9 mg/d) or methotrexate sodium (n = 94, 8.4 +/- 3.0 mg/wk) were followed up for 38 +/- 23.3 months to determine the nature, frequency, and potential predictors of "major" toxic reactions. Thirty-one methotrexate-treated patients (33%) and 11 patients (30%) receiving azathioprine experienced a major toxic reaction during the study period. With the case-control method, no predictors of major toxic reactions secondary to azathioprine therapy were found. Sex, drug dosage, response to prior slow-acting antirheumatic drug therapy, concurrent use of salicylates, and age did not predict major toxic reactions secondary to methotrexate treatment, but the methotrexate-treated patients who experienced a major toxic reaction had a significantly greater mean level of blood urea nitrogen at the time of their reaction compared with the control group. Life-table analysis suggested toxic reactions posed a greater risk of treatment termination in methotrexate-treated patients compared with the lack or loss of efficacy. This trend was not apparent in the azathioprine group. The majority of patients in each treatment group (79 for methotrexate and 29 for azathioprine) experienced one or more "minor" toxic reactions during the follow-up period.

Actuarial Analysis↗

PubMed1988

Cyclosporine v methotrexate for graft-v-host disease prevention in patients given marrow grafts for leukemia: long-term follow-up of three controlled trials.

One hundred seventy-nine patients with acute nonlymphoblastic leukemia in first remission (n = 75), chronic myelocytic leukemia in chronic or accelerated phase (n = 48) or leukemia in advanced stage (n = 56) were given HLA-identical marrow grafts and randomized to receive methotrexate or cyclosporine for prevention of graft-v-host disease (GVHD). The current report updates the three prospective trials with follow-ups ranging from 3.2 to 6.2 years after marrow grafting. Results were analyzed separately for each individual study and for all three studies combined. Overall, 40% of patients given cyclosporine and 55% of those given methotrexate developed acute GVHD (P = .13); the incidence of chronic GVHD was 42% and 48%, respectively (P = .67). Twenty-two percent of cyclosporine-treated patients and 30% of methotrexate-treated patients developed interstitial pneumonia of any etiology (P = .25), and the figures for cytomegalovirus pneumonia were 18% and 20%, respectively (P = .41). The overall incidence of leukemic relapse was 31% in cyclosporine-treated patients and 36% in methotrexate-treated patients (P = .75). The probabilities of survival for cyclosporine-v methotrexate-treated patients were comparable for all three study groups: 52% v 48% in patients with acute nonlymphoblastic leukemia (P = .42), 55% v 60% for those with chronic myelocytic leukemia (P = .61), 12% and 12% for those with advanced leukemia (P = .93), and 39% v 38% overall (P = .72). We conclude that cyclosporine and methotrexate are comparable regarding the likelihood of acute/chronic GVHD, interstitial pneumonia, leukemic relapse, and long-term survival.

Acute Disease↗

PubMed1977

High-dose methotrexate with folinic acid rescue.

A brief review of the pharmacology of methotrexate is presented, and the rationale for the administration of high-dose methotrexate and the necessity of a folinic acid rescue to prevent methotrexate toxicity are discussed. Critical factors concenrning the use of this therapy, as well as unusual toxicities associated with the use of high-dose methotrexate, are presented. Several drug-and patient-related variables which may affect the toxicity of this dual drug administration are discussed to better enable pharmacists to monitor patients receiving this form of therapy. High-dose methotrexate with folinic acid rescue has improved the therapeutic index of methotrexate. The optimal dosage and duration of the two agents are yet to be determined.

Absorption↗

PubMed1987

Inhibition of methotrexate-induced differentiation of cultured human choriocarcinoma (BeWo) cells by thymidine.

During exposure to methotrexate, cultured human choriocarcinoma (BeWo) cells stop proliferating, enlarge, and undergo a complex differentiative response that resembles in utero development of quiescent syncytiotrophoblasts. In the present work, complete inhibition of proliferation and maximal cell enlargement required exposure to 1 microM methotrexate, whereas colony-forming ability, determined after transfer of cells to drug-free medium, was unaffected over a wide range of concentrations (10(-12)-10(-5) M). BeWo cells were sensitive to the antifolate effects of methotrexate since thymidylate synthase activity and incorporation of [14C]formate into DNA, RNA, and protein were reduced by greater than 90% after short drug exposures, and progression of cells through S phase of the cell cycle was blocked by prolonged drug exposures. When methotrexate was coadministered with hypoxanthine and thymidine or leucovorin, its antiproliferative and differentiative effects were blocked. When methotrexate was coadministered with either hypoxanthine or thymidine, its antiproliferative activity was unaffected, whereas expression of syncytiotrophoblastic markers was blocked in the presence of thymidine but not in the presence of hypoxanthine. Exposure of BeWo cells to fluorodeoxyuridine also stimulated cell enlargement and expression of syncytiotrophoblastic markers, and these effects were blocked by coadministration of thymidine. Thus BeWo cells, which were sensitive to the antifolate effects of methotrexate, were not killed during cytostasis but instead entered a reversible differentiated state, apparently resulting from thymidylate starvation and consequent inhibition of DNA synthesis.

Cell Differentiation↗