levoleucovorin and metoprine

DDMP, a diaminopyrimidine folate antagonist, was given to 26 tumor patients in a dosage of 50 mg/m2 per week orally, simultaneously with 3 mg CF i.m. or i.v. The CF dose was increased to 30 mg in patients showing evidence of toxicity, and withdrawn in the absence of toxicity. The dose-limiting toxicity was seen in myelosuppression, particularly thrombopenia and skin rashes. At the 3 mg CF level, 18 out of 26 patients developed toxicity. No toxicity was seen at the 30 mg CF level in 11 patients. After cessation of CF, toxicity occurred in five out of seven patients. After the onset of toxicity, CF was added as a delayed rescue, in a dosage of 15 mg every 8 h or 30-60 mg daily. One patient died of sepsis with agranulocytosis. All other patients recovered from myelosuppression within 1 or 2 weeks. Objective responses were observed in seven patients, four of the ten with epidermoid cancer of the head and neck, two out of eight with epidermoid cancer of the lung, and one out of three with melanoma.

Topics: Adult; Aged; Antineoplastic Agents; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Pyrimethamine

We describe the characterization of an antitumor drug resistance following multiple step selection of hamster cells to the 2,4-diaminopyrimidines (DAP) metoprine, pyrimethamine (Pyr), and trimethoprim (Tmp). Pyr and Tmp are DAP lipophilic antifolates currently used as antiparasitic and antibacterial antibiotics, respectively. Dihydrofolate reductase (DHFR) from hamster cells bore a low or poor affinity to these DAP as compared to the hydrophilic folate antagonist methotrexate (MTX). Metoprine-resistant cells over-expressed DHFR enzyme and consequently displayed a high level of resistance to both hydrophilic and lipophilic antifolates including DAP but maintained wild type sensitivity to pleiotropic drugs involved in multi-drug resistance (MDR). In contrast, although Pyr- and Tmp-resistant cells expressed parental levels of wild type DHFR, they displayed a high degree of resistance to DAP and, surprisingly, to the lipophilic MTX analogs piritrexim (PTX) and trimetrexate (TMTX), while maintaining sensitivity to MTX. These drug-resistant cells maintained wild type mRNA levels of the MDR gene product P-glycoprotein and showed collateral hypersensitivity to pleiotropic drugs. To study the underlying mechanism of this apparently new resistance phenotype, we have employed fluorescein-methotrexate (F-MTX) labeling of cells and its displacement by different antifolates. Parental AA8 and Pyr-resistant cells showed a similar level of F-MTX labeling, however, while DAP, TMTX, and PTX showed an efficient competitive displacement of F-MTX from AA8 cells, Pyr-resistant cells displayed a persistent retention of F-MTX labeling in the presence of high concentrations of these lipophilic antifolates. Pyr-resistant cells showed a wild type displacement of F-MTX with MTX. This DAP resistance phenotype was unstable as it was rapidly lost upon growth under nonselective conditions. Furthermore, when the antifolate resistance levels of Pyr-resistant cells were plotted versus the ratios of the 50% F-MTX displacement values obtained with resistant and parental AA8 cells, a good correlation (r2 > 0.98) was obtained. We conclude that Pyr-resistant cells possess a novel phenotype that derives its resistance to lipophilic antifolates solely from a predominant decrease in the accumulation of DAP and lipid-soluble analogs of MTX.

Topics: Animals; Cell Survival; CHO Cells; Cricetinae; Drug Resistance; Flow Cytometry; Folic Acid Antagonists; Leucovorin; Pyrimethamine; RNA, Messenger; Tetrahydrofolate Dehydrogenase; Trimethoprim

We have used a microtiter assay to study the toxicity of various folate analogs in a series of cultured human cell lines that exhibit different degrees of resistance to methotrexate, an inhibitor of dihydrofolate reductase. These cells retain their sensitivity to the lipophilic antifolate BW301U despite the amplification of dihydrofolate reductase genes. Because the cell lines under investigation grow very slowly and have poor plating efficiencies in unconditioned medium, an assay was developed that relies on cell proliferation rather than colony formation as a measure of toxicity. This approach is easily generalized to provide a rapid and inexpensive assay of drug competition. Two-dimensional studies indicate that methotrexate and BW301U show differences in patterns of toxicity, competition, and rescue by folinic acid, suggesting that the two drugs act on different targets. Further applications of the microtiter assay to the analysis of multidrug interactions are discussed.

Topics: Animals; Cell Division; Cell Line; Drug Interactions; Drug Resistance; Gene Amplification; Humans; Leucovorin; Methotrexate; Mice; Pyrimethamine; Pyrimidines; Tetrahydrofolate Dehydrogenase; Xeroderma Pigmentosum

Escalating doses of DDMP (metoprine) (15-280 mg/m2) were administered as single oral doses 24 h before a fixed leucovorin (CF) rescue (15 mg IM every 6 h for 72 h). CNS toxicity was dose-limiting and cumulative when the drug was given more frequently than at 3-week intervals. DDMP has a very long half-life (150 h) and is extensively bound to serum proteins (88%). It diffuses into the CSF and concentrates in brain tumours and normal brain tissue (brainserum ratio 3.8-5.3). DDMP is a potentially useful drug against brain tumors. Tumor regressions were seen in two patients with epidermoid carcinomas.

Topics: Antineoplastic Agents; Drug Evaluation; Humans; Kinetics; Leucovorin; Neoplasms; Protein Binding; Pyrimethamine

DDMP, a 2-4 diaminopyrimidine folate antagonist was administered PO once every 3 weeks at a fixed dose level (90 mg/m2), 24 h before a single IM injection of folinic acid (CF), to 77 patients with advanced solid tumors. CF doses were escalated in sequential sets of patients from 9-108 mg/m2. Therapeutic activity was documented against epidermoid tumors of head and neck and lung only at the lower CF doses (9 and 15 mg/m2). Increasing CF resulted in the absence of hematologic toxicity and therapeutic activity. There was no evidence of selective bone marrow protection in this clinical study.

Topics: Antineoplastic Agents; Bone Marrow Diseases; Drug Evaluation; Humans; Leucovorin; Neoplasms; Pyrimethamine

A phase II study of metoprine in low dose and in high dose with citrovorum rescue was conducted in patients with non-small-cell lung carcinoma. There were no responses observed in the 36 patients studied, yielding a predicted true response rate of less than 9%. Thrombocytopenia was the dose-limiting toxicity of the low-dose regimen; there was also one episode of leukopenia and sepsis in this group. Although citrovorum rescue obviated hematologic toxicity in the high-dose regimen, mild to moderate neurological toxicity occurred at this dose. Metoprine does not appear to be a useful agent in non-small-cell lung carcinoma when used in the dose schedule employed in this study.

Topics: Adult; Aged; Antineoplastic Agents; Drug Evaluation; Female; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Pyrimethamine

In a phase II trial 24 patients with measurable metastatic colorectal carcinoma were treated every 2 weeks with high-dose metoprine at 175 mg/m2 and leucovorin rescue. Hematologic toxicity was mild; the limiting toxicity was CNS, occurring in 54% of the patients. No responses were observed, but four patients had disease stabilization. High-dose metoprine with leucovorin rescue appears ineffective in previously treated patients with colorectal carcinoma in the dose and schedule used in this study.

Topics: Adult; Aged; Antineoplastic Agents; Colonic Neoplasms; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pyrimethamine; Rectal Neoplasms

Topics: Antineoplastic Agents; Bone Marrow Diseases; Drug Administration Schedule; Drug Therapy, Combination; Humans; Leucovorin; Neoplasms; Pyrimethamine

Topics: Animals; Cell Survival; Cells, Cultured; Deoxyuridine; Dose-Response Relationship, Drug; Drug Resistance; Folic Acid Antagonists; Leucovorin; Leukemia L1210; Methotrexate; Mice; Purines; Pyrimethamine; Pyrimidines; Thymidine

Topics: Adenocarcinoma; Carcinoma, Squamous Cell; Child; Drug Evaluation; Drug Therapy, Combination; Folic Acid Antagonists; Head and Neck Neoplasms; Humans; Leucovorin; Leukocyte Count; Melanoma; Neoplasms; Platelet Count; Pyrimethamine; Sarcoma

In this study, three methods are utilized to analyze toxicity produced by methotrexate and the lipid-soluble antifolate, 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine, in human lymphoblasts (WIL-2) and leukemic cells. These methods detect increasingly severe metabolic damage; inhibition of deoxyuridine incorporation into DNA, the reversibility of inhibition of deoxyuridine incorporation by supplementation with formyltetrahydrofolate as Ca2+ leucovorin, and the ability of cells to form clones in soft agarose. The critical dose and exposure time for establishing and maintaining the metabolic toxicity of methotrexate is examined in detail. It is shown that, if an initial loading dose of methotrexate is of high enough concentration or is maintained for a sufficient period to achieve greater than 98% inhibition of deoxyuridine incorporation, this inhibition can be sustained by low concentrations of 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine or methotrexate. Concentrations of methotrexate or 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine that equal or exceed 0.1 microM are sufficient for maintenance of inhibition by an initial loading dose of methotrexate but escape from inhibition that occurs if lower levels of drug are used. The possible implications of these observations for in vivo protocols are discussed.

Topics: Cell Line; Cell Survival; Deoxyuridine; Dose-Response Relationship, Drug; Folic Acid Antagonists; Humans; Leucovorin; Leukemia; Methotrexate; Pyrimethamine; Time Factors

Topics: Antineoplastic Agents; Drug Administration Schedule; Drug Therapy, Combination; Folic Acid; Hematologic Diseases; Humans; Leucovorin; Middle Aged; Pyrimethamine

On the basis of activity against experimental tumors and potency as inhibitors of human dihydrofolate reductase, two compounds were selected for pharmacokinetic evaluation: metoprine ((2,4-diamino-5-(3',4'-dichlorophenyl)-6-methyl pyrimidine, DDMP, B.W. 197U) and etoprine, the corresponding 6-ethyl analog (DDEP, B.W. 276U). These lipid-soluble compounds readily cross the blood-brain barrier and penetrate rapidly into brain and brain tumors induced in rats by ethylnitrosourea. Both compounds are extensively bound to human plasma protein and their slow elimination from plasma and tissues contrasts with the kinetics of methotrexate. Cerebrospinal fluid levels of "folate" were elevated following oral administration of citrovorum factor to rats but not following equivalent doses of folic acid. The balance between selective action of the drug and selective protection by the vitamin is discussed with regard to differential distribution into separate compartments.

Topics: Administration, Oral; Animals; Brain; Brain Neoplasms; Dogs; Folic Acid; Folic Acid Antagonists; Half-Life; Humans; Leucovorin; Lipid Metabolism; Male; Models, Biological; Pyrimethamine; Pyrimidines; Rats; Solubility; Species Specificity

Topics: Bone Marrow; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Neoplasms; Pyrimethamine; Remission, Spontaneous

Methodichlorophen was given to 26 patients with terminal malignant disease. Eight patients received adequate doses, and five of them showed objective evidence of tumour regression while three failed to respond. Those who responded included four out of five patients with lung cancer (three with squamous-cell carcinoma and one with oat-cell carcinoma) and a patient with hypernephroma. Two patients with testicular teratomas and one with acute myeloid leukemia failed to respond. The drug may be given safely by mouth to outpatients if certain precautions are taken.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Bone Marrow Diseases; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Chlorobenzenes; Drug Therapy, Combination; Erythema; Headache; Humans; Kidney Neoplasms; Leucovorin; Leukemia, Myeloid, Acute; Lung Neoplasms; Male; Middle Aged; Neoplasms; Pyrimethamine; Pyrimidines; Teratoma; Testicular Neoplasms