levoleucovorin and edatrexate

Combinations of active antineoplastic agents have been the most effective treatment for metastatic breast cancer. Criteria for an effective combination include use of drugs with different mechanisms of action, nonoverlapping toxic effects, and synergistic, or at least additive, antitumor activity. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), with its unique mechanism of action, offers an excellent opportunity for development of effective combination therapy against breast cancer. However, a number of problems have hindered the rapid development of effective combinations. The most obvious problem is the lack of a defined optimal dose and schedule of administration. The second problem has been the demonstration of unexpected interactions between paclitaxel and the other component(s) of the combination, often resulting in unusual and serious toxic effects. This review will focus on the phase I and II trials of paclitaxel in combination with established antineoplastic drugs (except doxorubicin and congeners, which is covered elsewhere in this issue) for breast cancer: cisplatin, 5-fluorouracil with or without folinic acid, cyclophosphamide, radiation therapy, as well as novel investigational agents or strategies, edatrexate, monoclonal antibodies to oncogenes, growth factors, and gene therapy with insertion of multidrug resistance gene into blood stem cells. Combination therapy offers exciting possibilities of enhanced antitumor efficacy. However, given the unexpected and serious toxic effects observed, only proven combinations should be used outside the context of a clinical trial. Additionally, the burden of proof will be to show that these combinations have increased antitumor activity, decreased toxicity, or both compared with single-agent paclitaxel.

Topics: Aminopterin; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cisplatin; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Drug Synergism; Drugs, Investigational; Female; Fluorouracil; Genetic Therapy; Humans; Leucovorin; Neoplasm Metastasis; Oncogenes; Paclitaxel; Radiotherapy, Adjuvant

The Cancer and Leukemia Group B (CALGB) conducted sequential Phase II multicenter trials to evaluate the activity of edatrexate alone (E) or with leucovorin rescue (EL) in patients with malignant pleural mesothelioma (CALGB Protocol 9131).. Twenty patients were accrued to the E portion of the study and received edatrexate, 80 mg/m(2), intravenously over 20-30 minutes weekly. After a protocol amendment precipitated by excessive toxic events with E, 40 patients were enrolled in the EL arm and received the same dose of edatrexate with leucovorin, 15 mg orally, every 6 hours for 4 doses beginning 24 hours after edatrexate. Eligibility criteria included a CALGB performance status of 0-2 and no prior chemotherapy. A central pathology review was performed. Of the 58 patients included in this analysis (20 receiving E and 38 receiving EL), 36 had epithelial cell type and 22 had mixed or sarcomatous cell types. There were 31 patients with measurable disease and 27 with evaluable disease.. The overall response rate was 25% for E (95% confidence interval [95% CI], 9-49%) and 16% for EL (95% CI, 6-31%). There was a 5% complete response [CR] rate, a 10% partial response [PR] rate, and a 10% regression [R] rate for E and a 0% CR rate, a 3% PR rate, and a 13% R rate for EL. The median survival duration from study entry was 9.6 months and 6.6 months, respectively, for E and EL; 1-year survival was 50% and 32%, respectively, for E and EL. There were four early deaths with the E regimen (including two from neutropenic sepsis) and one early death with the EL regimen (from progressive disease). Principal toxicities included mu cositis, myelosuppression, and rash, which were less frequent with leucovorin rescue.. Moderate antitumor activity has been observed with both regimens. Leucovorin rescue ameliorated the mucosal, hematologic, and dermatologic toxicities of edatrexate, but also may have reduced its efficacy.

Topics: Aminopterin; Antineoplastic Agents; Dose-Response Relationship, Drug; Female; Humans; Leucovorin; Leukemia; Male; Mesothelioma; Middle Aged; Pleural Neoplasms; Survival Rate; Treatment Failure

Our objective was to determine the maximum tolerated dose and toxicity of i.v. edatrexate with p.o. leucovorin. Thirty-one adults with advanced solid tumors received edatrexate as a 2-h infusion, once a week for 3 weeks, recycled every 28 days. p.o. leucovorin (10 mg/m2, every 6 h for 10 doses) began 24 h later. All had urinary alkalinization and p.o. hydration. Nine dosage levels ranging from 120 to 3750 mg/m2 were explored. Fatigue, epistaxis, nausea/emesis, mucositis, rash, myalgias, leukopenia, thrombocytopenia, and transient elevations of serum aspartate transferase were observed. Leukoencephalopathy with clinical manifestations occurred in two patients (one had prior cranial irradiation). Pharmacokinetic studies carried out at the 120- and 1080-mg/m2 dose levels revealed no significant difference in the elimination half-life at the two dose levels studied and no significant intrapatient variability between day 1 and day 8 edatrexate administration. Serum edatrexate levels measured using a dihydrofolate reductase inhibition assay correlated with those by high-performance liquid chromatography. Three major and two minor antitumor responses occurred. The maximum tolerated dose was 3750 mg/m2, with grade 3 or 4 leukopenia (one patient), stomatitis (one patient), and leukoencephalopathy (one patient). Because of the occurrence of leukoencephalopathy, further study of high-dose edatrexate with leucovorin rescue is not recommended.

Topics: Administration, Oral; Adult; Aged; Aminopterin; Antineoplastic Agents; Drug Interactions; Drug Monitoring; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasms

Recurrent squamous cell carcinoma of the head and neck is poorly responsive to chemotherapy in most patients; therefore, the development of new approaches is essential. Edatrexate is a new antifolate with improved preclinical antitumor activity when compared to methotrexate. The purpose of this study was to define the feasibility and efficacy of combining edatrexate with another active single agent, carboplatin in chemotherapy-naive recurrent disease. Carboplatin was given as an outpatient on day 1 at a dosage based on the formula: Dose (mg/m2) = (0.091) (creatinine clearance) (body surface area) (desired percentage change in platelet count) + 86. Edatrexate (80 mg/m2) was given on days 1, 8, and 15 of a 21 day cycle. Calcium leucovorin 15 mg was given orally every 6 h for 4 doses after edatrexate. Of the 26 patients entered on the study, 1 was invaluable for toxicity or response and 3 patients were evaluable for toxicity only. Grade 3 or 4 neutropenia occurred in 2 patients each, and grade 3 or 4 thrombocytopenia occurred in 2 and 4 patients, respectively. Grade 3 stomatitis occurred in only two patients. Overall, major responses occurred in 2 of 22 evaluable patients (9%). The combination of carboplatin and edatrexate was not superior to the results expected with either agent alone.

Topics: Adult; Aged; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Squamous Cell; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local

The role of a membrane-associated folate binding protein (mFBP) in transport of folate analogues was investigated in three epithelial cell lines that were grown in high folate medium and folate-conditioned medium and express different levels of mFBP: human nasopharyngeal KB cells, monkey kidney MA104 cells, and IGROV-I ovarian carcinoma cells. Folate analogues were selected for which mFBP exhibits a low affinity, i.e., methotrexate (MTX) and 10-ethyl-10-deazaaminopterin (10-EdAM) or a (moderately) high affinity as compared to folic acid, i.e., N-(5[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl(-N-m ethylamino]-2-theonyl)-L-glutamic acid (ZD1694), N10-propargyl-5,8-dideazafolic acid (CB3717), and 5,10-dideazatetrahydrofolic acid. Regardless of the medium folate status, growth inhibition studies with IGROV-I and MA104 cells demonstrated a lack of correlation between the affinity of mFBP for the antifolate drugs and their sensitivity profile; both cell lines were highly sensitive to growth inhibition by MTX, 10-EdAM, ZD1694 and 5,10-dideazatetrahydrofolic acid, but were insensitive for CB3717. The same drug sensitivity profile was observed for KB cells, with the exception that these cells were also sensitive to growth inhibition by CB3717 but only in folate-conditioned medium. This overall drug sensitivity profile appeared to correlate with the differential efficiency of drug transport via the "classical" reduced folate/MTX carrier (RFC), rather than by mFBP. Characteristics that further supported functional RFC activity in KB, IGROV-I, and MA104 cells included: (a) the growth inhibitory effects of the drugs could be prevented by the reduced folate leucovorin rather than by folic acid; (b) rates for uptake of [3H]10-EdAM were 2-4-fold higher than for [3H]MTX at 1 microM extracellular concentrations and coincided with the affinity of the RFC for these drugs, rather than those of the mFBP; (c) uptake of [3H]10-EdAM and [3H]leucovorin was markedly inhibited by leucovorin and 10-EdAM, respectively, or by an N-hydroxysuccinimide ester of MTX (irreversibly labeling RFC) but only to a minor extent by folic acid or an N-hydroxysuccinimide ester of folic acid (irreversibly labeling mFBP); and, finally, (d) labeling with an N-hydroxysuccinimide ester of [3H]MTX identified a protein with a molecular weight within the range of that reported for the RFC in human leukemic cells. Altogether, these results indicate that both RFC and mFBP are coexpressed in three epithe

Topics: Aminopterin; Animals; Carrier Proteins; Cell Division; Female; Folate Receptors, GPI-Anchored; Folic Acid; Folic Acid Antagonists; Glutamates; Haplorhini; Humans; Kidney; Leucovorin; Methotrexate; Nasopharyngeal Neoplasms; Ovarian Neoplasms; Quinazolines; Receptors, Cell Surface; Tetrahydrofolates; Thiophenes; Tumor Cells, Cultured

We have examined the cytotoxic activities of edatrexate (EDX) and methotrexate (MTX) and their reversal by leucovorin in nine human cancer cell lines and in human bone marrow CFU-GM cells. EDX was 3.7- to 123-fold more toxic than MTX against the cancer cell lines and 25-fold against the bone marrow cells. Lower EDX concentrates generally were needed to inhibit cancer cell growth relative to bone marrow cells, however, whereas bone marrow and cancer cell growth were more often susceptible to the same MTX concentrations. The new antifolate was metabolized to long-chain polyglutamates to a greater extent than MTX in seven cell lines. Leucovorin at 0.2 microM rescued two breast cancer and two non-small cell lung cancer cell lines to a lesser extent following EDX than MTX, but significant rescue was observed in two head and neck cancer cell lines that formed large amounts of polyglutamates. These cell lines also accumulated reduced folates to a greater extent than the other cell lines following leucovorin exposure. Leucovorin rescued bone marrow cells following MTX but only partially following the highest EDX concentrations. EDX may enjoy a better therapeutic index than MTX against some cancer cell lines relative to bone marrow precursor cells, especially after leucovorin rescue.

Topics: Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cell Division; Folic Acid; Humans; Leucovorin; Methotrexate; Polyglutamic Acid; Tumor Cells, Cultured

Topics: Aminopterin; Biological Transport; Carrier Proteins; Cell Division; Cell Membrane; Folate Receptors, GPI-Anchored; Folic Acid; Folic Acid Antagonists; Humans; KB Cells; Kinetics; Leucovorin; Methotrexate; Quinazolines; Receptors, Cell Surface; Structure-Activity Relationship

10-Ethyl-10-deazaaminopterin (EDX, edatrexate) exhibits therapeutic activity against methotrexate (MTX)-resistant tumors in animals and patients. In an effort to improve its efficacy among more chemoresistant tumors, studies were initiated in murine models of advanced metastatic disease comparing EDX and MTX at their maximum tolerated dose alone and in a high-dose regimen incorporating low-dose, delayed Ca leucovorin (LCV) rescue. Both twice-weekly x 3 and weekly x 3 schedules of administration were used with LCV given 16, 20, and 24 h after EDX. The LCV dose required to protect mice was 1/40 and 1/20 of the EDX or MTX dose, respectively, on either schedule. Therapy was initiated 5 or 6 days following i.v. implant of 5 x 10(5) cells of the E0771 mammary adenocarcinoma, T241 fibrosarcoma, Lewis lung carcinoma, B16 melanoma, or C38 colon carcinoma. MTX was essentially ineffective (increase in life span = < 30%) when given alone and either ineffective or only modestly effective (increase in life span = 20-80%) in increasing survival when given in the high-dose regimen to tumor-bearing mice. EDX alone was more effective than MTX when it was given in either regimen of therapy. Also, EDX given in the high-dose regimen (either twice-weekly or weekly x 3) was markedly more effective than EDX alone. Increased survival with this regimen was 2-3-fold greater than EDX alone against all 5 tumors, and long-term survivors were obtained with E0771 (20%), T241 (30-40%), Lewis lung (10-15%), B16 (20%), and C38 (40%) tumors. The administration of 6 doses rather than 3 doses on the twice-weekly schedule against T241 and Lewis lung tumors required a modest increase in the LCV dose but substantially improved efficacy, with as much as 70% long-term survivors (T241 tumor). We conclude that the use of a high-dose regimen with delayed LCV rescue markedly improved the therapeutic effectiveness of EDX against advanced metastatic disease in tumor-bearing mice. These studies should provide a framework for further clinical work with EDX, using this modality of therapy.

Topics: Adenocarcinoma; Aminopterin; Animals; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fibrosarcoma; Leucovorin; Lung Neoplasms; Mammary Neoplasms, Experimental; Melanoma, Experimental; Methotrexate; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Salvage Therapy

Edatrexate (10-ethyl-10-deaza-aminopterin; CGP 30 694) is a methotrexate (MTX) analogue that shows promise against non-small-cell lung cancer (NSCLC) and other tumors. Since edatrexate's mechanism of action is the same as that of MTX, we used leucovorin in an attempt to alleviate its dose-limiting toxicity, stomatitis. In four patients with NSCLC who had experienced significant stomatitis after treatment with edatrexate, cyclophosphamide, and cisplatin, we observed a remarkable reduction in stomatitis following the administration of low-dose leucovorin. On the basis of the results obtained in these individuals, we treated 15 additional patients with this three-drug regimen plus leucovorin rescue. These subjects could tolerate the treatment with lesser degrees of stomatitis and received higher edatrexate doses in subsequent courses as compared with the patients who previously received this regimen without leucovorin rescue. This approach is expected to improve the therapeutic indices of edatrexate and edatrexate-containing chemotherapy regimens by modifying the dose-limiting toxicity of this antineoplastic agent.

Topics: Aminopterin; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Evaluation; Drug Tolerance; Female; Folic Acid Antagonists; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Stomatitis

A methylcholanthrene-induced rat sarcoma that can be propagated in vitro or in vivo was evaluated for resistance to antifolates and was found to be relatively resistant to methotrexate and 10-ethyl-10-deazaaminopterin but sensitive to trimetrexate. Rat sarcoma cell extracts contained low levels of dihydrofolate reductase activity, the target enzyme of methotrexate, and inhibition of this enzyme by these three antifolates was similar. Transport studies showed poor uptake of both methotrexate and 10-ethyl-10-deazaaminopterin. In contrast, trimetrexate achieved high intracellular levels. The poor uptake of methotrexate was not due to lack of polyglutamylation. Thus, the basis for natural resistance to methotrexate and 10-ethyl-10-deazaaminopterin, compared with trimetrexate, in this rat sarcoma cell line was due to decreased transport of these drugs.

Topics: Aminopterin; Animals; Drug Resistance; Folic Acid Antagonists; Leucovorin; Methotrexate; Methylcholanthrene; Polyglutamic Acid; Rats; Sarcoma, Experimental; Tetrahydrofolate Dehydrogenase; Trimetrexate; Tumor Cells, Cultured

Administration i.p. of 10-ethyl-10-deazaaminopterin (10EDAM) with cis-diamminedichloroplatinum(II) (cis-Pt) had significant antitumor activity against the murine ovarian tumor. This tumor is a teratoma originating in the ovary with pathogenesis and metastatic properties similar to those of human ovarian cancer. Drug was given on a schedule of once every 3 days for 3 doses 1 or 2 days after i.p. implant of 10(7) tumor cells. Despite the 2-fold attenuation of dosage required, antitumor activity of the combination (increased life span, 161%) was approximately twice that obtained with maximum tolerated doses of either agent alone and tumor-free, long-term survivors were obtained. Incorporation of s.c. calcium leucovorin administration 16 h after each dose of 10EDAM and cis-Pt allowed a 4-fold increase in dosage of 10-EDAM without an increase in toxicity, increased median survival by an additional 120%, and quadrupled the number of tumor-free, long-term survivors to 40% of treated animals. By comparison, methotrexate was only modestly active against this tumor model either as a single agent, with cis-Pt, or with delayed s.c. calcium leucovorin administration. These results appear to suggest that 10EDAM with cis-Pt may have considerable potential for intracavitary therapy of human cancer, including ovarian carcinoma, particularly when incorporating delayed systemic calcium leucovorin administration.

Topics: Aminopterin; Animals; Cisplatin; Drug Evaluation, Preclinical; Female; Folic Acid Antagonists; Injections, Intraperitoneal; Injections, Subcutaneous; Leucovorin; Male; Methotrexate; Mice; Mice, Inbred C3H; Ovarian Neoplasms