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PubMed1982

Phase I study of high-dose methotrexate with thymidine and low-dose leucovorin.

A total of 15 patients with advanced neoplastic disease, 13 with different solid tumors, one with lymphoma, and one with acute lymphocytic leukemia, underwent treatment consisting of continuous infusion of methotrexate (2 g/sq m/day) with concomitant thymidine (8 g/sq m/day) and leucovorin (1 mg/sq m/day). The dose of methotrexate was increased progressively by lengthening the methotrexate infusion from 2 to 7 days. After cessation of methotrexate infusion, thymidine and leucovorin were continued until the plasma level of methotrexate decreased to 2 X 10(-8) M. Toxicity was mucositis (23 of 27 evaluable courses), leukopenia (15 of 26 evaluable courses), thrombocytopenia (10 of 26 evaluable courses), renal and hepatic toxicity and diarrhea. Plateau levels of plasma methotrexate or methotrexate plasma half-life did not correlate with toxicity.

Adult↗

PubMed1982

Methotrexate and etretinate as concurrent therapies in severe psoriasis.

A patient with pustular psoriasis, which was inadequately controlled by high-dose methotrexate and potent topical corticosteroid therapy, was treated with oral methotrexate and the aromatic retinoid etretinate. The patient's psoriasis improved with sustained maximal etretinate therapy and continued high-dose methotrexate therapy. Subsequently, the methotrexate dose was tapered and used of this drug was discontinued. Previously unattainable success in controlling the psoriasis was achieved with continued etretinate treatment. There were no recognizable adverse effects from concurrent therapy. As the methotrexate dose was tapered, the patient noted increased psoriatic arthritic pain, unrelieved at maximal etretinate levels, but improved with indomethacin treatment. Combination therapy with methotrexate and etretinate may be useful in the treatment of severe psoriasis by providing a controlled transition from methotrexate to etretinate therapy alone.

Drug Therapy, Combination↗

PubMed1994

Increased methotrexate resistance and dhfr gene amplification as a consequence of induced Ha-ras expression in NIH 3T3 cells.

Oncogene activation and loss of tumor suppressor genes are known to play a role in tumor initiation as well as its progression. The potential roles of these genes in perturbation of genome stability has become a major interest. To better understand the relationship between expression of an oncogene and genetic instability, we have studied a cell line expressing an activated human Ha-ras under the control of bacterial lactose operon regulatory elements for changes in methotrexate resistance and dihydrofolate reductase (dhfr) gene amplification following mutant Ha-ras induction. In these cells mutant Ha-ras is directed by an inducible SV40 promoter containing a bacterial lac operator sequence which is repressed due to constitutive expression of bacterial lac repressor gene. The expression of this Ha-ras is specifically induced by the addition of isopropyl-1-thio-beta-D-galactopyranoside (IPTG), a lactose analogue, to the culture medium. During single-step methotrexate selection, these cells showed an increased frequency of methotrexate resistance in the presence of IPTG. More than 60% of the methotrexate-resistant colonies showed a 2-6-fold amplification of the dhfr gene. One clone with rearranged dhfr had about 100-fold amplification of the gene. The increased capacity to amplify DNA in response to mutant Ha-ras induction was not locus specific since cells also displayed an increased frequency of resistance to N-(phosphonacetyl)-L-aspartic acid in the presence of ITPG. Four of the methotrexate-resistant clones with amplified dhfr gene were cultured further in the presence or absence of IPTG and subsequently compared for their ability to grow in soft agar as a measure of transformation. In medium containing methotrexate but no IPTG, the clones were unable to grow in soft agar, indicating that methotrexate resistance due to gene amplification is separable from transformation.

3T3 Cells↗

PubMed1993

Methotrexate for the treatment of chronic corticosteroid-dependent asthma.

The role and adverse effects of methotrexate in the treatment of chronic corticosteroid-dependent asthma are discussed. Methotrexate is a folic acid antagonist that has been used as an anti-inflammatory agent in the treatment of arthritis. It also appears to be effective in reducing the corticosteroid requirements in patients with chronic corticosteroid-dependent asthma, a use that was first reported in 1986. Studies of this use of methotrexate in adults support a trial of methotrexate in patients with severe asthma who have been unable to discontinue corticosteroid use despite aggressive management of their asthma and who are experiencing severe corticosteroid toxicity. Experience with methotrexate in children with asthma is limited to case series. Adverse effects associated with the use of methotrexate for treatment of corticosteroid-dependent asthma include nausea, elevated serum aminotransferase, diarrhea, and thinning of hair. While methotrexate appears to reduce corticosteroid requirements in patients with chronic corticosteroid-dependent asthma, its role in asthma therapy still needs to be clarified.

Adrenal Cortex Hormones↗

PubMed1993

Mechanism of the discrepant effect of a combination of methotrexate plus dipyridamole on human hematologic cell lines.

Mechanisms of the discrepant effect of methotrexate and dipyridamole on human hematologic cultured cell lines were investigated by analyzing intracellular methotrexate levels and thymidine incorporation through the salvage pathway, since the combination of methotrexate and dipyridamole has different effects according to cell type: additive effects on ML-1 and THP-1 (myelo-monocytoid cells); reduced effects on MOLT-3, SKW-3, P32/ish and BL-TH (lymphoid cells). Dipyridamole reduced the toxicity of methotrexate by diminishing intracellular methotrexate levels in MOLT-3 and BL-TH (lymphoid cells), in which the reduction of intracellular methotrexate affected more than just the blocking of the salvage pathway required for growth by dipyridamole. On the other hand, dipyridamole enhanced the toxicity of the combination by blocking the salvage pathway in an ML-1 (myelo-monocytoid cell) and in a methotrexate-resistant subline of BL-TH/MTX (lymphoid cell), in which the salvage pathways were considered activated. Dipyridamole could prove to be a useful drug for reversing the drug resistance caused by the activation of the salvage pathway.

Adult↗

PubMed1996

In vitro and in vivo protein binding of methotrexate assessed by microdialysis.

The purpose of the study was firstly to estimate methotrexate protein binding using microdialysis, and secondly to determine the influence of the protein content in the dialyzed medium on the dialysis membrane recovery. In vitro recovery was estimated by both water recovery method and concentration difference method. The relative recovery was independent of methotrexate concentration: 39.3% +/- 2.86% and 39.2 +/- 1.27% for 50 microM and 300 microM, respectively. A significant influence of the presence of proteins on the dialysis membrane recovery was observed: 55.9% +/- 2.7%, 42.3% +/- 7.5% and 45.5% +/- 0.1% for buffer, human serum albumin (HSA) (600 microM) and human plasma, respectively. Methotrexate binding to human and rat plasma proteins showed a nonsaturable phenomenon. The bound percentages and corresponding total binding capacities were 58.7% +/- 3.13% and 1.44 +/- 0.033 mM-1 and 71.7% +/- 4.38% and 2.18 +/- 0.09 mM-1 for the human and rat plasma, respectively. For HSA this binding was saturable with an affinity constant of 4.75 +/- 0.66 mM-1. After intravenous administration (250 mg/kg) the in vivo rat plasma binding of methotrexate was roughly 20% higher (93.6%) than the in vitro methotrexate plasma binding. The in vivo relative recovery of methotrexate was found to be 12.6% +/- 1.8% versus 25.4% +/- 3.3% in vitro. This study showed that the protein content can directly affect microdialysis probe recovery. However, by taking into account this recovery, microdialysis allows to measure the protein binding of methotrexate.

Animals↗

PubMed1996

Methotrexate bound to carbon particles used for treating cancers with lymph node metastases in animal experiments and a clinical pilot study.

BACKGROUND: A new dosage formulation, methotrexate adsorbed onto activated carbon particles (MTX-CH), was developed for treating cancer patients with lymph node metastases. METHODS: MTX-CH injected subcutaneously into the left hind foot pad of rats delivered greater amounts of methotrexate selectively to the regional lymph nodes and to the injection site for longer periods than did the same dose of methotrexate in aqueous solution. Seven days after mice received a subcutaneous inoculation with 5 x 10(5) P388 leukemia cells in the left hind foot pad, when metastasis had occurred in the left popliteal lymph node, methotrexate was injected subcutaneously into the left hind foot pad in the form of either MTX-CH or methotrexate aqueous solution. In clinical trials, patients with cancers in relatively early stages (5 patients with gastric cancer and 1 with esophageal cancer) each received local injections of MTX-CH doses of 250 to 500 mg under fiberscope. RESULTS: MTX-CH extended the survival time better than did methotrexate aqueous solution. In mice who received an inoculation of P388 leukemia cells and drug treatment using the same procedures, the treatment effects on metastases to the regional lymph nodes were significantly greater in mice treated with the MTX-CH than in those given methotrexate aqueous solution. MTX-CH controlled the disease well for 25 to 35 months. CONCLUSIONS: Local injection of MTX-CH is apparently useful for treating digestive cancers with lymph node metastases in patients who have difficulty tolerating surgery.

Aged↗

PubMed1996

[In vivo effect of etoposide on the pharmacokinetics of methotrexate].

High dose (5 g/m2/24 h) methotrexate therapy was combined two times with etoposide (100 mg/m2/1h) infusions as a part of the Medulloblastoma protocol developed in our Department Vepesid therapy was administered in two different schedules. The first group of the patients have received etoposide immediately before and at the end (24th h) of methotrexate treatment. The second group was treated with etoposide at 24 h and at 48 hour after starting methotrexate infusion. In this latter group treatment related grade 3-4 toxicity developed more frequently than in the first group (58.6% vs 33.3%). The authors observed that after the second dose of etoposide given at 48 h (second group) both total and unbound serum methotrexate levels (determined by high performance liquid chromatography) were elevated by 53.14-109.19%, and 25.86-64.95%, respectively by the third hour after completion of Vepesid infusion. This effect was detectable for 6 hours. All the liver and kidney functions of the patients were in the normal range. These results suggest the possibility of partial recirculation of extra/intracellular methotrexate into the blood after etoposide administration. Based on these results the therapeutic protocol has been modified and Vepesid is given prior to and at the end (24 h) of high dose methotrexate treatment. Under these conditions only a slight decrease of methotrexate elimination has been detected between the 25-28th h. These results emphasize the role of possible schedule dependent interactions of cytostatic drugs.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1997

[High-dose methotrexate and cerebral neurotoxicity. Apropos of a case of arachnoiditis].

BACKGROUND: High-dose methotrexate has been used as a therapeutic strategy in osteosarcoma for 20 years. Cerebral neurotoxicity is frequent. CASE REPORT: A 21-year-old patient with non-metastatic osteosarcoma was given high-dose methotrexate prior to surgery. He developed subacute encephalitis and arachnoiditis after intravenous injection of methotrexate. COMMENTS: Although pharmacokinetic monitoring and leucovorin rescue is helpful in controlling systemic toxicity, cerebral toxicity with acute, subacute or delayed reactions may occur, depending on the administration route and use of the folate antagonist. Generally, acute arachnoiditis and subacute encephalitis are reversible and occur respectively after intrathecal methotrexate and intravenous high-dose methotrexate, while the chronic delayed leukoencephalopathy usually begins several months after a combination regime using intrathecal methotrexate, intravenous methotrexate and cerebral irradiation.

Adult↗

PubMed1998

Reproductive outcome after methotrexate treatment of tubal pregnancies.

OBJECTIVE: To evaluate subsequent pregnancy outcomes in women who have been treated with methotrexate for tubal pregnancies. METHODS: Descriptive study of subsequent pregnancy outcomes in 170 women who were treated with methotrexate for tubal pregnancy at Brigham and Women's Hospital during 1989-1994. Patients who agreed to participate were administered a telephone interview. Fertility rates and outcomes were calculated for patients who tried to conceive after receiving methotrexate. RESULTS: One hundred four of the 170 women with tubal pregnancies identified during the study period returned their consent forms. The other 66 patients were either unable to be reached by phone, and/or their consent form was returned without a forwarding address. Ninety-four patients (90%) agreed to participate in the study. Eighty-two (87%) women tried to conceive after receiving methotrexate for their tubal pregnancies, and 57 (70%) were successful. Forty-six (81%) of the 57 women experienced intrauterine pregnancies, and 11 (19%) had recurrent tubal pregnancies. When the first subsequent postmethotrexate outcome was examined, there were 26 (46%) term births, 5 (9%) preterm births, 11 (19%) recurrent ectopics and 15 (26%) spontaneous abortions. Over the six-year study period, 42 (74%) women had at least one live birth. There were no congenital anomalies or stillbirths in the subsequent pregnancies. CONCLUSION: Pregnancy outcomes after methotrexate treatment for tubal pregnancy are comparable to reported experience with surgical therapy. Patients who are treated with methotrexate for tubal pregnancies can be assured that their methotrexate exposure should have no untoward effects on subsequent pregnancies.

Female↗

PubMed1998

Lymphoproliferative disorders in rheumatoid arthritis patients on low-dose methotrexate.

Methotrexate is the most widely used second-line treatment in rheumatoid arthritis because of its excellent efficacy and safety profile. However, since 1991, about 100 cases of lymphoproliferative disorders have been reported in rheumatoid arthritis patients under methotrexate therapy. Four characteristics similar to those in lymphomas associated with immunodeficiency were identified during a review of the 48 cases for which detailed information is available. (1) Most cases were non-Hodgkin's B-cell lymphomas of the large cell or diffuse mixed type. (2) Extranodal involvement (55% of cases) was unusually common. (3) Evidence of Epstein-Barr infection was found in 46% of tested patients. (4) Of the 14 patients treated by methotrexate withdrawal alone, eight achieved a full remission, with follow-ups ranging from one to five years. These characteristics suggest a role for two factors: (1) the abnormalities in cell-mediated immunity seen in rheumatoid arthritis may promote latent Epstein-Barr virus infection, which may in turn lead to proliferation of malignant lymphoid cells; (2) the immunomodulatory effects of methotrexate may promote the development not only of opportunistic infections but also of Epstein-Barr virus-related lymphoproliferative disorders. There is no firm evidence to date that methotrexate has a direct oncogenic effect and no excess in malignant diseases has been reported with this drug. In conclusion, the rate of occurrence of lymphoproliferative disorders induced by low-dose methotrexate therapy remains controversial, although the characteristics of the malignancies and the possibility of a complete remission after methotrexate withdrawal militate against a chance association. Epidemiologic and other studies are needed to clarify this issue.

Adolescent↗

PubMed1998

Can collagen type II sustain a methotrexate-induced therapeutic effect in patients with long-standing rheumatoid arthritis? A double-blind, randomized trial.

OBJECTIVE: Based on the results of two recently published, randomized, double-blind and placebo-controlled studies, a possible improvement in rheumatoid arthritis disease activity after oral tolerization with triple helical collagen type II has been suggested. The goal of this study was to go one step further and ask the question whether collagen type II can sustain the therapeutic effect induced by methotrexate, the most widely accepted disease-modifying anti-rheumatic drug in patients with long-standing rheumatoid arthritis. METHODS: Ninety-two patients with rheumatoid arthritis on stable therapy with methotrexate were enrolled in a 3 month double-blind, randomized and comparative study to examine the efficacy of oral triple helical collagen type II as compared to continuing methotrexate. The dose of methotrexate (or the respective placebo drug) and of concomitant corticosteroids was not changed and intra-articular corticosteroids were not allowed during the 3 months. The primary study endpoint was disease activity as measured by physician and patients. RESULTS: While patients under ongoing therapy with methotrexate had, as expected, no change in disease activity, almost all parameters of disease activity and outcome in patients under a daily oral dose of 0.5 mg triple helical collagen type II worsened significantly (highly significant difference in swollen joints, between the two groups, P < 0.0001). No significant differences in side-effects between the two groups during the study period could be demonstrated. CONCLUSIONS: Substitution of methotrexate with daily 0.5 mg of triple helical collagen type II in patients with rheumatoid arthritis leads to a significant increase in disease activity, suggesting that oral collagen type II at the given dose is not capable of sustaining the methotrexate-induced anti-inflammatory effect in patients with long-standing rheumatoid arthritis.

Administration, Oral↗

PubMed1992

Simultaneous changes in various mechanisms that mediate the cell incorporation of folate compounds account for low levels of resistance to methotrexate.

Changes in the mechanisms of folate incorporation were studied in cells treated with low concentrations of methotrexate in order to evaluate their contribution to the development of resistance to antifolate drugs. The uptake of methotrexate via reduced-folate system, the membrane-associated high-affinity folate binding capacity and the activity, levels and affinity for methotrexate of dihydrofolate reductase were measured in L5178 murine leukemic lymphoblasts and in a subline, MTX/R16, 16 times more resistant to methotrexate which was isolated after a short exposure to the antifolate. Various simultaneous changes were characterized in MTX/R16 cells which co-participated in the development of resistance: a decreased affinity of the carrier for methotrexate uptake via the reduced-folate system of entry, the increase of dihydrofolate reductase activity and levels and a two-fold increased expression of a membrane-associated high-affinity folate-binding protein (mFBP). The increase of the mFBP expression, besides ensuring the growth of resistant cells by its contribution to the reduced folate intake, also participates in the methotrexate resistance by the internalization of folate cofactor which would compete with methotrexate hindering the effective inhibition of dihydrofolate reductase by the antifolate.

Animals↗

PubMed2003

Fistula response to methotrexate in Crohn's disease: a case series.

BACKGROUND: Controlled trials have demonstrated the efficacy of methotrexate in the induction and maintenance of remission in luminal Crohn's disease; however, its effect on fistulizing disease is unknown. AIM: To describe the response to methotrexate therapy in a series of patients with fistulizing Crohn's disease. METHODS: A retrospective chart review was conducted of all patients with Crohn's disease receiving methotrexate in one practice. The response of patients with fistulizing and luminal disease was assessed using clinical and laboratory criteria. Fistula response was categorized as either complete or partial closure. RESULTS: Thirty-seven courses of methotrexate therapy were given to 33 patients with luminal and/or fistulizing Crohn's disease. In 16 patients with fistulas, four (25%) had complete closure, five (31%) had partial closure and all had failed or were intolerant to 6-mercaptopurine therapy. Overall, response to methotrexate was seen in 23 of 37 (62%) treatment courses in patients with luminal and/or fistulizing Crohn's disease. Two of the 33 patients (6%) had a significant adverse event. CONCLUSIONS: In this case series, 56% of patients with Crohn's fistulas on methotrexate showed a complete or partial response to therapy. Further studies are needed to confirm the role of methotrexate alone, and in combination with other therapies, for the treatment of fistulizing Crohn's disease.

Abdominal Wall↗

PubMed1999

Urinary adenosine and aminoimidazolecarboxamide excretion in methotrexate-treated patients with psoriasis.

BACKGROUND: We hypothesized that low-dose methotrexate treatment for patients with psoriasis would block purine biosynthesis at the step catalyzed by aminoimidazolecarboxamide (AICA) ribotide transformylase and would inhibit adenosine metabolism as evidenced by increased urinary levels of AICA and adenosine, respectively. Eight patients collected a 24-hour urine specimen on the day before their methotrexate dose and the next day during their methotrexate dose. Eight age- and sex-matched controls also collected a 24-hour urine sample. Urinary AICA and adenosine were assayed by spectrophotometric and radioimmune assays, respectively; means are reported as micromole per millimole of creatinine and were compared by the paired t test (1-tailed). OBSERVATIONS: Mean AICA excretion increased from 1.30 micromol/mmol on the day before to 1.85 micromol/mmol on the day during methotrexate dosing (P<.01). Mean adenosine values increased from 0.68 to 1.07 micromol/mmol, (P<.03). Controls had mean AICA and adenosine levels of 1.29 and 0.50 micromol/mmol, respectively. During the day of methotrexate dosing, patients had higher mean AICA and adenosine levels when compared with controls (P<.01). Mean AICA levels increased from 1.36 to 2.06 micromol/mmol (P<.025), and mean adenosine levels increased from 0.72 to 1.25 micromol/mmol (P<.025) in 5 patients showing improvement in clinical disease activity. In contrast, 3 patients with no change or worsening in clinical disease activity had smaller increases. CONCLUSIONS: Methotrexate treatment of patients with psoriasis inhibits AICA ribotide transformylase and adenosine metabolism. Since adenosine is a T-lymphocyte toxin, it may be partially responsible for the immunosuppressive effect.

Adenosine↗

PubMed2003

Phase 1/2 pilot study of methotrexate-laurocapram topical gel for the treatment of patients with early-stage mycosis fungoides.

OBJECTIVES: To assess the safety and tolerability of a topical gel formulation combining methotrexate and laurocapram and to obtain preliminary information on the therapeutic potential of methotrexate-laurocapram in patients with early-stage mycosis fungoides (stage IA or IB). DESIGN: An open-label, phase 1/2 pilot study. SETTING: Two academic referral centers. PATIENTS: Ten patients 18 years or older with histologically confirmed stage IA or IB mycosis fungoides. Intervention The gel formulation of methotrexate-laurocapram was applied to the total body surface, excluding genital, perianal areas, nipples, face, and skin under the breasts, on an every-other-day basis for 24 consecutive weeks. MAIN OUTCOME MEASURES: The safety of methotrexate-laurocapram was assessed in this study by reviewing adverse events and laboratory data. Efficacy outcomes included changes in lesion condition and severity assessments, reduction in area of sample lesions, and the investigator's global evaluation. RESULTS: Adverse events consisted of skin reactions of mild severity. No clinically significant laboratory abnormalities were observed. Based on the investigator's global evaluation at the end of the treatment phase (week 24), 7 (78%) of 9 patients demonstrated a slight-to-moderate response to treatment with methotrexate-laurocapram. Statistical significance (P =.049) was reached for induration and pruritus, a trend (P =.10) was observed for erythema, and no change was found for scaling (P =.37). CONCLUSIONS: These findings indicate that the topical administration of methotrexate-laurocapram is safe and in general well tolerated. This treatment may represent a new therapeutic potential for patients with mycosis fungoides.

Administration, Topical↗

PubMed2003

Treatment of corticosteroid-responsive autoimmune inner ear disease with methotrexate: a randomized controlled trial.

CONTEXT: A number of therapies have been proposed for the long-term management of corticosteroid-responsive, rapidly progressive, bilateral sensorineural hearing loss (autoimmune inner ear disease [AIED]). Methotrexate has emerged as the benchmark agent but has not been rigorously evaluated for hearing improvement in patients with AIED. OBJECTIVE: To assess the efficacy of long-term methotrexate in maintaining hearing improvements achieved with glucocorticoid (prednisone) therapy in patients with AIED. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled trial conducted from February 3, 1998, to November 5, 2001, of 67 patients with rapidly progressive, bilateral sensorineural hearing loss at 10 tertiary care centers in the United States. INTERVENTION: Randomization to either oral methotrexate (15 to 20 mg/wk; n = 33) or placebo (n = 34), in combination with an 18-week prednisone taper. Follow-up examinations, including audiometric evaluation, were performed at 4, 8, 12, 24, 36, 48, and 52 weeks, or until hearing loss was documented. MAIN OUTCOME MEASURE: Maintenance of hearing improvement achieved from prednisone treatment. RESULTS: Sixty-seven patients (57.8%) enrolled in the prednisone challenge experienced hearing improvement. Twenty-five patients (37%) experienced hearing improvements in both ears. Of the individuals who reached study end points, 24 (80%) of 30 end points were because of measured hearing loss in the methotrexate group and 29 (93.5%) of 31 end points were because of measured hearing loss in the placebo group (P =.15). Methotrexate was no more effective than placebo in maintaining the hearing improvement achieved with prednisone treatment (hazard ratio, 1.31; 95% confidence interval, 0.79-2.17; P =.30). CONCLUSION: Methotrexate does not appear to be effective in maintaining the hearing improvement achieved with prednisone therapy in patients with AIED.

Audiometry↗

PubMed1998

In vitro mutations in dihydrofolate reductase that confer resistance to methotrexate: potential for clinical application.

Mammalian cells cultured in the presence of the chemotherapeutic agent, methotrexate, develop resistance to this drug. Sometimes this is due to mutations in the gene for dihydrofolate reductase, the primary target of methotrexate. However, it has not been possible to link such polymorphism to resistance of neoplastic disease to therapy with methotrexate. Nevertheless, interest in this possibility lead to the introduction of many mutations into the cDNA for human DHFR by mutagenesis. Most of the corresponding enzyme variants have been expressed in Escherichia coli and characterized. Many mutations in codons for hydrophobic residues at the active site greatly decrease inhibition by methotrexate, and by the related substrate analogue, trimetrexate, while allowing the retention of considerable catalytic efficiency. Introduction of some of these mutants into mammalian cells by retroviral transfer provides substantial protection from toxic effects of the inhibitors, and has promise for the myeloprotection of patients receiving therapy with methotrexate or trimetrexate. Another potential use is in therapy for inherited disorders of hematopoiesis, where genetic modification of enough cells is a perennial problem. After transplantation of bone marrow that has been transduced with a bicistronic vector encoding both the mutant DHFR and a therapeutic gene, subsequent administration of methotrexate or trimetrexate should permit selection and enrichment of genetically modified hematopoietic cells.

Bone Marrow Transplantation↗