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PubMed1994

Trimetrexate with leucovorin versus trimethoprim-sulfamethoxazole for moderate to severe episodes of Pneumocystis carinii pneumonia in patients with AIDS: a prospective, controlled multicenter investigation of the AIDS Clinical Trials Group Protocol 029/031.

Trimetrexate is a powerful inhibitor of the dihydrofolate reductase of Pneumocystis carinii. AIDS patients (n = 215) with moderate to severe P. carinii pneumonia were enrolled in a double-blind study of trimetrexate plus leucovorin versus trimethoprim-sulfamethoxazole (TMP-SMZ) for 21 days. By study day 10, study therapy failed because of lack of efficacy in 16% of patients assigned to TMP-SMZ and 27% assigned to trimetrexate (P = .064), and the PAO2-PaO2 improved significantly faster with TMP-SMZ. By study day 21, failure rates were 20% with TMP-SMZ and 38% with trimetrexate (P = .008), with respective mortality rates of 12% and 20% (P = .088). By study day 49, the difference in mortality (16% vs. 31%) was significant (P = .028). The cumulative incidence of serious and treatment-terminating adverse events including hematologic toxicities was less with trimetrexate (P < .001). Thus, trimetrexate plus leucovorin was effective, albeit inferior to TMP-SMZ, for moderately severe P. carinii pneumonia but was better tolerated than TMP-SMZ.

AIDS-Related Opportunistic Infections↗

PubMed1987

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

Trimetrexate, a highly lipid-soluble quinazoline antifolate now undergoing trials as an anticancer agent, was found to be a potent inhibitor of the dihydrofolate reductase (DHFR) isolated from Toxoplasma gondii. The concentration required for 50% inhibition of protozoal DHFR was 1.4 nM. As an inhibitor of this enzyme, trimetrexate was almost 600-fold (amount of antifolate required to inhibit catalytic reaction by 50%) and 750-fold (inhibition constant) more potent than pyrimethamine, the DHFR inhibitor currently used to treat toxoplasma infection. When the protozoan was incubated with 1 microM trimetrexate, the drug rapidly reached high intracellular concentrations. Since toxoplasma organisms lack a transmembrane transport system for physiologic folates, host toxicity can be prevented by co-administration of the reduced folate, leucovorin, without reversing the antiprotozoal effect. The effectiveness of trimetrexate against toxoplasma was demonstrated both in vitro and vivo. Proliferation of toxoplasma in murine macrophages in vitro was completely inhibited by exposure of these cells to 10(-7) M trimetrexate for 18 h. When used alone, trimetrexate was able to extend the survival of T. gondii-infected mice.

Animals↗

PubMed1988

Efficacy of trimetrexate, a potent lipid-soluble antifolate, in the treatment of rodent Pneumocystis carinii pneumonia.

Trimetrexate is a lipid-soluble antifolate that has been shown in vitro to be a much more potent inhibitor of Pneumocystis carinii dihydrofolate reductase than the conventionally used inhibitor trimethoprim. To evaluate the in vivo efficacy of trimetrexate, steroid-treated rats which spontaneously develop P. carinii pneumonia were used. Rats treated with trimetrexate (25 mg/kg/d) plus sulfamethoxazole (250 mg/kg/d) orally responded at least as well as rats treated with trimethoprim (50 mg/kg/d) plus sulfamethoxazole. Trimetrexate alone administered orally was ineffective in treating P. carinii infection, but subcutaneous (sc) trimetrexate (7 mg/kg/d) significantly decreased the intensity of infection compared to controls. Trimetrexate is a potent antifolate that may provide an effective alternative to pentamidine and trimethoprim-sulfamethoxazole for treatment of P. carinii pneumonia in humans.

Administration, Oral↗

PubMed1990

Role of substrate depletion in the inhibition of thymidylate biosynthesis by the dihydrofolate reductase inhibitor trimetrexate in cultured hepatoma cells.

The effects of the lipid-soluble dihydrofolate reductase inhibitor, trimetrexate, on the inhibition of thymidylate biosynthesis as a result of perturbation in cellular folate pools in H35 hepatoma cells in vitro has been investigated. Exposure of the cultures to increasing concentrations of trimetrexate between 2 and 20 nM causes a marked reduction in de novo thymidylate biosynthesis and a concomitant decrease in (6R)5,10-methylenetetrahydropteroylpolyglutamate (5,10-CH2H4PteGlun) from 2.0-0.2 microM, respectively. This is accompanied by an increase in H2PteGlun from 1.2 microM in control cultures to 4.7 microM in cultures exposed to 20 nM trimetrexate. The dependency of de novo thymidylate biosynthesis on intracellular 5,10-CH2H4PteGlun in trimetrexate-treated cells is compared with (a) the relationship of thymidylate biosynthesis on intracellular levels of 5,10-CH2H4PteGlun in folate-depleted cells supplemented with increments of folic acid and (b) the substrate (5,10-CH2H4PteGlun) dependence of purified thymidylate synthase from the same source. All three results are nearly identical demonstrating that trimetrexate-dependent inhibition of de novo thymidylate biosynthesis is primarily a result of substrate depletion. These results coupled with the weak inhibitory properties of H2PteGlun for thymidylate synthase Ki = 5.0 microM) suggest that H2PteGlun accumulation is not the major determinant in inhibiting thymidylate synthase following trimetrexate inhibition but under certain conditions has the potential to enhance the inhibition caused by substrate depletion.

Carcinoma, Hepatocellular↗

PubMed1987

Phase I and clinical pharmacology study of trimetrexate administered weekly for three weeks.

Trimetrexate, a new antifolate compound, was administered by 30-min infusions weekly for 3 weeks to 29 patients with solid tumors in a Phase I study. Thrombocytopenia was dose limiting, but highly variable among patients at a given dose level; other toxicity was mild and uncommon. Twenty-three patients participated in pharmacokinetic studies and five patients participated in a study of the effects of trimetrexate on [6-3H]-deoxyuridine incorporation into hematopoietic cell DNA. The median total body clearance of trimetrexate for each dose level was independent of dose but the total body clearance varied widely among patients at a given dose level. The magnitude of the fall in platelet count in individual patients correlated well with the amount of exposure to trimetrexate, but not with the extent of prior therapy. The amount of [6-3H]deoxyuridine incorporation into hematopoietic cell DNA at 72 h after drug administration correlated with the total body clearance of trimetrexate. The total body clearance of trimetrexate was reduced in patients with impaired hepatic synthetic function, as judged by low pretreatment serum albumin concentrations. The recommended Phase II starting dose on this schedule is 130 mg/m2 weekly for 3 weeks; patients with hypoalbuminemia should be treated at lower doses.

Adenocarcinoma↗

PubMed1998

A randomized phase II trial of echinomycin, trimetrexate, and cisplatin plus etoposide in patients with metastatic nonsmall cell lung carcinoma: an Eastern Cooperative Oncology Group Study (E1587).

BACKGROUND: Patients with metastatic nonsmall cell lung carcinoma (NSCLC) usually have a poor prognosis. A chemotherapy regimen containing cisplatin is commonly used for symptom palliation. Echinomycin is a potent bifunctional intercalator of double-strand DNA; trimetrexate is a new derivative of methotrexate and is active against methotrexate-resistant tumor cells in vitro. METHODS: The Eastern Cooperative Oncology Group conducted a randomized Phase II study. Eligible patients were assigned to receive echinomycin 1200 microg/m2 by intravenous (i.v.) infusion over 30-60 minutes once a week for 4 weeks, repeated every 6 weeks; trimetrexate 12 mg/m2 i.v. bolus on Days 1-5 every 3 weeks, or 8 mg/m2 i.v. bolus on Days 1-5 for patients who had prior radiation to greater than 30% of their bone marrow; or cisplatin 60 mg/m2 i.v. on Day 1 and etoposide 120 mg/m2 i.v. on Days 1-3 every 4 weeks. Patients were evaluated before each cycle for tumor response, toxicity, and quality-of-life measurements. RESULTS: One hundred thirty-six patients were entered on the study, and 118 were evaluable for toxicity and response. The response rates were 16%, 5%, and 5% in patients treated with cisplatin and etoposide, echinomycin, and trimetrexate, respectively. There were no complete responses. The median survival was 37.9, 24.3, and 28.0 weeks for patients who received cisplatin and etoposide, echinomycin, and trimetrexate, respectively. Although cisplatin and etoposide appeared to give better therapeutic results, the response rate or survival did not reach statistical significance. This may have been due to inadequate sample size. Neither did quality-of-life measurement show any significant differences among treatments. CONCLUSIONS: Echinomycin and trimetrexate had minimal antitumor activity in patients with metastatic NSCLC: Response rate and survival remained poor in all three treatment arms. Patients should be encouraged to participate in clinical trials so that more effective therapy can be identified.

Adult↗

PubMed1993

A randomized phase II trial of amonafide or trimetrexate in patients with advanced non-small cell lung cancer. A trial of the North Central Cancer Treatment Group.

BACKGROUND: In an effort to identify new active chemotherapeutic agents against non-small cell lung cancer (NSCLC), the authors conducted a randomized Phase II trial to evaluate the efficacy of amonafide or trimetrexate in patients with Stage IV disease. METHODS: This was a multicenter Cooperative Oncology Group trial. All patients had advanced NSCLC and were previously untreated with chemotherapy. Patients were randomized to treatment after enrollment. Amonafide was administered as a 24-hour continuous infusion (1600 mg/m2) every 21 days. Trimetrexate (150 mg/m2) was administered intravenously over 30 minutes every 2 weeks. The primary endpoints of the study were clinical response and toxic effects. All patients were observed for survival. RESULTS: Thirty-five patients received amonafide and were assessable. There were no complete responses and two partial responses (6%). Thirty-seven patients were treated with trimetrexate. There were no complete responses and five (14%) partial responses. Myelosuppression was the primary toxic effect observed with amonafide treatment. Trimetrexate was associated infrequently with clinically significant side effects. CONCLUSIONS: Amonafide is inactive against NSCLC, and no additional studies with this agent are planned. Trimetrexate has some activity against NSCLC, but its role in the future therapy of this disease is questionable.

Adenine↗

PubMed1990

Treatment of metastatic malignant melanoma with trimetrexate: a phase II study.

Trimetrexate glucuronate, a nonclassical antifolate, was administered to 14 patients with recurrent and progressive metastatic malignant melanoma. Thirteen patients were evaluable for response and toxicity. Five patients had received prior treatment consisting of immunotherapy (one patient), immunotherapy plus radiotherapy (one patient), radiotherapy (one patient), chemotherapy (one patient), or radiotherapy and chemotherapy (one patient). The starting dose of trimetrexate was 8 mg/m2 given as an intravenous bolus daily for 5 consecutive days of a 21-day cycle. Subsequent cycles of therapy were escalated by 25% based on individual patient tolerance. A median of two courses of trimetrexate was administered (range 1-4). No patient demonstrated a measurable objective response to this treatment regimen. Trimetrexate was well-tolerated; toxicity was mild and consisted primarily of myelosuppression or nausea and vomiting. At the dose level and schedule used in this study, trimetrexate was not effective for the treatment of disseminated malignant melanoma.

Adult↗

PubMed1989

A fluorescein-methotrexate-based flow cytometric bioassay for measurement of plasma methotrexate and trimetrexate levels.

We describe a bioassay for the quantitation of plasma methotrexate and trimetrexate levels employing intact cells. This assay is based on the intracellular saturation of dihydrofolate reductase with fluorescein-methotrexate (F-MTX) and its dose-dependent displacement by methotrexate or trimetrexate as monitored by flow cytometry. Serially diluted methotrexate-containing plasma, representing a wide chemotherapeutic range, produces F-MTX displacement curves similar to those of standard methotrexate solutions. There is no interference by normal plasma components such as folate and its reduced forms. Plasma methotrexate or trimetrexate concentration is the product of the 50% displacing concentration of standard antifolate (IC50) and the reciprocal of the plasma dilution which yields the same displacement. F-MTX competition with standard methotrexate displayed linear displacement from 18.0 +/- 3.1 to 33.7 +/- 1.5 nM (n = 10). The standard trimetrexate calibration curve was linear from 0.28 +/- 0.03 to 1.5 +/- 0.33 nM (n = 8). Thus, the bioassay sensitivities for methotrexate and trimetrexate are at least 18 and 0.3 nM, respectively. Comparison of methotrexate levels in 10 plasma specimens from cancer patients determined by the clinical enzyme inhibition assay and by our bioassay showed a high degree of correlation (r = 0.987).

Flow Cytometry↗

PubMed1986

Determination of plasma trimetrexate levels using gas chromatography-mass spectrometry with selected-ion monitoring.

Trimetrexate is a potent inhibitor of dihydrofolate reductase and has demonstrated significant antitumor activity against murine and human cell lines both in vitro and against several murine transplanted tumors. The importance of antifolate concentration and exposure time in determining toxic and therapeutic effects necessitates an assay of suitable sensitivity, accuracy and specificity for investigation of trimetrexate pharmacokinetics. This paper describes a gas chromatographic-mass spectrometric (GC-MS) procedure using selected-ion monitoring (SIM) for the determination of plasma trimetrexate levels. Using the C18 Bond-Elut extraction columns, the drug and internal standard are removed from plasma, derivatized to their bis(trimethylsilyl) derivatives and analysed by GC-SIM-MS. The reproducibility of the daily standard curves had coefficients of variation ranging from 4.9 to 11.4%. The precision of the assay yielded a coefficient of variation ranging from 5.6 to 10.1%, and the concentration means for the seeded control samples were found to be within -3.7 to +0.7% of the theoretical values for trimetrexate. No interfering peaks have been observed in application of the procedure on patient samples. The minimum detectable level under the conditions described was 0.005-0.014 microM trimetrexate.

Folic Acid Antagonists↗

PubMed1996

Lipophilic antifolates as agents against opportunistic infections. 1. Agents superior to trimetrexate and piritrexim against Toxoplasma gondii and Pneumocystis carinii in in vitro evaluations.

2,4-Diaminopteridines (21 compounds) and 2,4-diamino-5-methyl-5-deazapteridines (34 compounds) along with three 2,4-diamino-5-unsubstituted-5-deazapteridines and four 2,4-diaminoquinazolines, each with an aryl groups attached to the 6-position of the heterocyclic moiety through a two-atom bridge (either CH2NH, CH2N(CH3),CH2S, or CH2CH2), were synthesized and evaluated as inhibitors of the growth of Toxoplasma gondii in culture and as inhibitors of dihydrofolate reductase enzymes from T. gondii, Pneumocystis carinii, and rat liver. Exceptionally high levels of combined potency and selectivity as growth inhibitors of T. gondii and as inhibitors of the microbial enzymes relative to the mammalian enzyme were found among the 5-methyl-5-deazapteridines but not for the other heterocyclic types. Thirty of the 34 5-methyl-5-deaza compounds gave growth inhibition IC50 values lower than that of pyrimethamine (0.4 microM) with 14 compounds below 0.1 microM, values that compare favorably with those for piritrexim and trimetrexate (both near 0.02 microM). As inhibitors of T gondii DHFR, all but three of the 34 5-methyl-5-deaza compounds gave IC50 values in the order of magnitude with those of piritrexim (0.017 microM) and trimetrexate (0.010 microM), and 17 compounds of this group gave IC50 values versus P. carinii DHFR similarly comparable with those of piritrexim (0.031 microM) and trimetrexate (0.042 microM). Thirteen of these congeners gave both T. gondii growth inhibition and DHFR inhibition IC50 values of 0.10 microM or less, thus indicating facile penetration of the cell membrane. Eleven of these inhibitors of both T. gondii growth and DHFR have selectivity ratios (IC50 rat liver divided by IC50 T. gondii) of 5 or greater for the parasite DHFR. The highest selectivity ratio of nearly 100 belongs to the 5-methyl-5-deaza compound whose 6-substituent is CH2CH2C6H3(OCH3)2-2,5. This compound is over 10(3)-fold more selective for T. gondii DHFR than bridge homologue piritrexim (selectivity ratio 0.088), a compound now in clinical trials. The candidate with CH2NHC6H3(CH3)2-2,5 in the 6-position gave the highest P. carinii DHFR selectivity ratio of 4.0, which is about 60-fold more selective than trimetrexate (0.071) and 80-fold more selective than piritrexim (0.048) toward this enzyme. The 10 best compounds with respect to potency and selectivity includes six compounds bearing 2,5-disubstituted phenyl groups in the side chain (with little, if any, difference in effects of methyl, methoxy, or ethoxy), two side chains bearing 1-naphthyl groups, and two with 5,6,7,8-tetrahydro-1-naphthyl groups. Bridge groups represented in the 10 choice compounds are CH2NH, CH2N(CH3), CH2CH2, and CH2S. The high levels of both potency and selectivity among these agents suggest that in vivo studies now underway may lead to agents that could replace trimetrexate and piritrexim in treatment of toxoplasmosis and P. carinii pneumonia.

Animals↗

PubMed1996

Trimetrexate glucuronate associated with anti-Kaposi sarcoma effect.

Trimetrexate glucuronate, a dihydrofolate reductase inhibitor related to methotrexate, was developed by Parke-Davis as an alternative antineoplastic agent for tumors, especially sarcomas, that had developed resistance to methotrexate. This is a report on a patient with AIDS who developed Pneumocystis carinii pneumonia, which was treated with trimethoprim sulfamethoxazole (Bactrim) with poor response, then with pentamidine with poor response, and finally with trimetrexate glucuronate (Neutrexin) and leucovorin rescue, with good response. The patient also suffered from cutaneous and visceral Kaposi's sarcoma (KS), which had been treated with high- dose HCG1 and well recognized chemotherapeutic protocols. Both HCG and chemotherapy resulted in tumor regression. The patient's KS flared, however, when he developed pneumocystis pneumonia. When trimetrexate glucuronate and leucovorin rescue were administered, his tumor burden decreased significantly, suggesting that trimetrexate glucuronate may have some activity against KS. The regression of KS in this anecdotal observation may be secondary to a delayed response from HCG and/or chemotherapy, or secondary to a spontaneous partial regression. Such regression may only be of the decreased edema around the KS lesions and not the neoplastic tissue itself. If other clinicians see this same phenomenon, however, it is possible that trimetrexate glucuronate may have an anti-KS effect. Such future clinical observations would warrant further testing at the basic science level.

AIDS-Related Opportunistic Infections↗

PubMed1987

Potent effect of trimetrexate, a lipid-soluble antifolate, on Toxoplasma gondii.

Trimetrexate, a lipid-soluble antifolate, has considerably greater activity in inhibiting the dihydrofolate reductase of Toxoplasma gondii than do the conventional antifolates pyrimethamine and trimethoprim. In an investigation of the effect of trimetrexate on T. gondii, in vitro and in vivo studies were undertaken with peritoneal macrophage cultures and acutely infected mice. Against T. gondii cultured in mouse peritoneal macrophages, 10(-7) M trimetrexate inhibited replication of the organism compared with 10(-6) M pyrimethamine and 10(-4) M trimethoprim. In acutely infected mice, trimetrexate alone prolonged survival and, when combined with sulfadiazine, allowed 93%-100% of mice to survive. These studies suggest that trimetrexate alone or combined with a sulfonamide may provide a safe and effective alternative to pyrimethamine plus sulfonamide for the treatment of T. gondii diseases.

Animals↗

PubMed1988

Clinical response to trimetrexate as sole therapy for nonsmall cell lung cancer.

Trimetrexate glucuronate was evaluated in 70 nonsmall cell lung cancer patients with incurable disease and/or demonstrated progression following surgery/radiotherapy and no prior cytotoxic chemotherapy. Trimetrexate was initially administered at 8 mg/m2 intravenously (IV) daily for 5 days and repeated every 3 to 4 weeks with dose adjustments depending on patient tolerance. A median of two courses of trimetrexate therapy was administered (range 1 to 12). Fifty-nine (84%) patients were evaluable for response. Eleven patients (19%) achieved a partial response with a median duration of 15.3 weeks. The median time to response was 4.6 weeks. Twenty-three patients (39%) had stable disease with a median time to progression of 15.7 weeks. The median survival for evaluable patients was 26.4 weeks. Trimetrexate was well tolerated with manageable myelosuppression as the dose limiting toxicity. Trimetrexate was shown to have activity in nonsmall cell lung cancer.

Adolescent↗

PubMed1999

Microsatellite instability and clonal heterogeneity of MDR1 messenger RNA expression in trimetrexate-resistant human leukemia MOLT-3 cells developed in thymidine.

Various gene alterations are involved in the drug resistance of leukemia cells. To understand the mechanism that underlies the emergence of cells with such gene alterations in human leukemia, we performed clonal analysis of the gene expression of mutant dihydrofolate reductase (DHFR) and mdr1 in trimetrexate-resistant human leukemia MOLT-3 cells. Trimetrexate-resistant (70- and 60-fold) sublines were developed in the presence or absence of an exogenous supply of thymidine (MOLT-3/TMQ70/Th+, MOLT-3/TMQ60/Th-, respectively). Ten clonal lines were isolated by methyl cellulose cloning from each of the 2 trimetrexate-resistant MOLT-3 sublines. All the clonal lines from the 2 sublines expressed mutated DHFR mRNA, with a base change (T --> C) at the second position of codon 31, as well as the wild-type mRNA, in accordance with cross-resistance to methotrexate. On the other hand, mdr1 mRNA expression was demonstrated by reverse-transcription polymerase chain reaction only in clonal lines from MOLT-3/TMQ70/Th+ cells. mdr1 mRNA expression in clonal lines from MOLT-3/TMQ70/Th+ cells and subclonal lines subsequently obtained from the 3 clonal lines with different mdr1 mRNA expression levels was heterogeneous, and its high expression levels were correlated with acquisition of the multidrug resistance (MDR) phenotype. Polymerase chain reaction-based assay for separate microsatellites, mfd27 and mfd41, demonstrated genomic instability among clonal and subclonal lines of MOLT-3. The clonal analysis of polymorphic microsatellites also suggested that emergence of MDR in trimetrexate-resistant MOLT-3 cells in thymidine was not only heterogeneous but also progressively expanding among clones. Genomic instability may play a role in the establishment and clonal evolution of drug resistance in leukemia cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

An Eastern Cooperative Oncology Group phase II trial of trimetrexate in the treatment of advanced urothelial carcinoma.

BACKGROUND: Trimetrexate is an antifol that differs from methotrexate in ways that may be clinically important. Because methotrexate has activity in advanced bladder cancer, this trial was initiated. METHODS: Ambulatory patients with advanced urothelial carcinoma were treated with the nonclassic antifol trimetrexate at the intravenous dose of 8 mg/m2 daily for 5 consecutive days every 3 weeks (4 mg/m2 daily for 5 consecutive days for patients with creatinine levels greater than 1.6 mg/dl). RESULTS: Of the 48 patients in the study, one had a complete response and seven had partial responses, for an overall response rate of 17% (exact 95% confidence interval, 7-30%). The response rate in patients who had received prior methotrexate was 18%, suggesting lack of complete cross-resistance. Toxicity was manageable and primarily mucosal, gastrointestinal, and myelosuppressive. CONCLUSIONS: Trimetrexate has as much activity as other single agents in advanced urothelial carcinoma. Combination therapy, possibly with cisplatin, platinum analogs, or other antifols, using trimetrexate should be studied.

Adult↗

PubMed1991

Phase II trial of trimetrexate in patients with advanced soft-tissue sarcoma.

Trimetrexate, a lipophilic, 2,4-diaminoquinazoline derivative of methotrexate, enters cells by passive diffusion rather than via a transport system. Trimetrexate has shown promising activity in animal model systems. A total of 16 patients with metastatic soft-tissue sarcoma who had received only one prior chemotherapy regimen were treated with trimetrexate (8 mg/m2 given intravenously daily for 5 days) every 3 weeks. Treatment-related toxicity included greater than or equal to grade 2 neutropenia (8/16), thrombocytopenia (3/16), mucositis (4/16) and skin rash (3/16). No partial or complete responses were observed in 15 evaluable patients (95% confidence interval for true response rate, 0-22%) Six subjects showed stabilization of disease for periods ranging from 2 to 9 months. At this dose and on this schedule, trimetrexate appears to have little activity against refractory soft-tissue sarcomas.

Antineoplastic Agents↗

PubMed1992

Chronic toxicity of the anticancer agent trimetrexate in rats.

Trimetrexate was administered to rats in an interrupted treatment regimen comparable to proposed human clinical treatment. Forty-five rats of each sex were dosed intravenously with trimetrexate at 0, 1, 10, or 30 mg/kg (0, 6, 60, or 180 mg/m2), once daily for 5 consecutive days, followed by a 23-day recovery period. This cycle of dosing and recovery was repeated for a total of six cycles. Hematology, urinalysis, clinical chemistry, and gross and microscopic pathology examinations were conducted for animals euthanatized 3 and 21 days after dosing cycles 1, 3, and 6. Additional rats in each group were maintained without dosing for an additional 56 days (77 days after the last trimetrexate dose) to assess the long-term reversibility of pathologic changes. Target organs were typical for an antifolate and included gastrointestinal tract, lymphoid tissues, and the hematopoietic and male reproductive systems. No toxicity was observed at 1 mg/kg. Treatment-related changes in hematology parameters following 10 and 30 mg/kg were fully reversible within 3 weeks of each dosing cycle. Except for testis and cecum, histopathological changes were also reversible within 21 days of dosing. Trimetrexate-induced testicular changes persisting during the course of multiple cycles of dosing were not reversible within 21 days, but required an additional 56 days for essentially complete recovery.

Animals↗