lometrexol and Neoplasms

Topics: Antineoplastic Agents; Benzamides; Benzoquinones; Boronic Acids; Bortezomib; Clinical Trials as Topic; Dioxoles; Enzyme Inhibitors; Humans; Hydroxamic Acids; Imatinib Mesylate; Isoquinolines; Lactams, Macrocyclic; Neoplasms; Piperazines; Pyrazines; Pyrimidines; Rifabutin; Stilbenes; Tetrahydrofolates; Tetrahydroisoquinolines; Trabectedin; Vorinostat

A number of promising new antifolates have been entered in clinical trials in recent years. These agents have been rationally designed based on the current understanding of folate transport and metabolism and of the mechanisms by which cells become resistant to methotrexate. Methotrexate-resistant cell lines are generally sensitive to one or more of the newer antifolates, which differ from methotrexate by being either more lipid soluble, more extensively polyglutamated, or by inhibiting folate-requiring enzymes other than dihydrofolate reductase. Five of the agents furthest along in clinical testing, trimetrexate, piritrexim, edatrexate, lometrexol, and D1694, are discussed. These drugs offer exciting opportunities to expand the role of antifolates in cancer chemotherapy, as well as in antimicrobial and antirheumatic therapy.

Topics: Aminopterin; Animals; Antineoplastic Agents; Chemistry, Pharmaceutical; Clinical Trials as Topic; Drug Evaluation; Folic Acid Antagonists; Forecasting; Humans; Neoplasms; Pyrimidines; Quinazolines; Tetrahydrofolates; Thiophenes; Trimetrexate

Lometrexol [(6R)-5,10-dideaza-5,6,7,8-tetrahydrofolate] is the prototype folate antimetabolite that targets the de novo purine synthesis pathway. Early phase I trials were confounded by cumulative myelosuppression that prevented repetitive administration. Subsequent preclinical and clinical studies suggested that coadministration of folic acid might favorably modulate lometrexol toxicity without eliminating potential antitumor activity. We set out to determine if concurrent folic acid would allow administration of lometrexol on a weekly schedule, and, if so, to identify an appropriate dose combination for phase II trials. Pharmacokinetic and metabolism studies were undertaken in an attempt to improve our understanding of lometrexol pharmacodynamics.. Patients with advanced cancer received daily oral folic acid beginning 7 days before lometrexol and continuing for 7 days beyond the last lometrexol dose. Lometrexol was administered by short i.v. infusion weekly for 8 weeks. Scheduled lometrexol doses were omitted for toxicity of more than grade 2 present on the day of treatment, and dose-limiting toxicity was prospectively defined in terms of frequency of dose omission as well as the occurrence of severe toxic events. Plasma and whole blood total lometrexol contents (lometrexol plus lometrexol polyglutamates) were measured in samples taken just prior to each lometrexol dose.. A total of 18 patients were treated at five lometrexol dose levels. The maximum tolerated dose was identified by frequent dose omission due to thrombocytopenia and mucositis. The recommended phase II dose combination is lometrexol 10.4 mg/m(2) per week i.v. with folic acid 3 mg/m(2) per day orally. One patient with melanoma experienced a partial response, and three patients, two with melanoma and one with renal cell carcinoma, experienced stable disease. Lometrexol was not detectable in any predose plasma sample tested. The total red blood cell content of lometrexol increased over several weeks and then appeared to plateau.. Weekly administration of lometrexol is feasible and well-tolerated when coadministered with daily oral folic acid. The nature of the interaction between natural folates and lometrexol that renders this schedule feasible remains unclear. A definition of dose-limiting toxicity that incorporated attention to dose omissions allowed efficient identification of a recommended phase II dose that reflects the maximum feasible dose intensity for a weekly schedule. Lometrexol is a promising, anticancer agent.

Topics: Administration, Oral; Adult; Aged; Anemia; Drug Administration Schedule; Drug Evaluation; Erythrocyte Count; Female; Folic Acid; Folic Acid Antagonists; Hematinics; Humans; Infusions, Intravenous; Lymphoma; Male; Middle Aged; Neoplasms; Tetrahydrofolates

Topics: Antimetabolites, Antineoplastic; Drug Administration Schedule; Female; Folic Acid; Folic Acid Antagonists; Humans; Infusions, Intravenous; Male; Neoplasms; Pancytopenia; Stomatitis; Tetrahydrofolates; Treatment Failure

Lometrexol (5,10-dideazatetrahydrofolic acid) is a new antifolate that is highly selective in inhibiting the key enzyme of purine synthesis glycinamide ribonucleotide formyltransferase. The most promising preclinical features of lometrexol in animal models were its significant activity against a broad panel of solid tumors, the schedule dependency of its antitumor activity, and the availability of a rescue regimen with folinic or folic acid. In the present study, lometrexol was first given daily for 3 consecutive days, repeated every 4 weeks (part I). The occurrence of delayed myelotoxicity prompted the development of a rescue regimen with lometrexol given in a single dose on day 1, followed by oral folinic acid, 15 mg four times a day, from day 3 to day 5 (part II). Longer time intervals between administration of lometrexol and start of rescue were then evaluated (part III), and in the last part of the study (part IV), the maximum tolerated dose of single intermittent doses of lometrexol with folinic acid given from day 7 to day 9 was established. Sixty adult patients entered the study. In part I, the highest daily dose that could be safely given was 4 mg/m2, for a total dose of 12 mg/m2. Cumulative early stomatitis and delayed thrombocytopenia were dose limiting. The use of oral folinic acid made it possible to escalate the dose up to 60 mg/m2, and the maximum tolerated dose was reached at this dose when folinic was given from day 7 to day 9, with anemia being the dose-limiting toxicity. A shorter time interval between lometrexol and folinic acid administrations (from day 5 to day 7) is recommended for Phase II evaluations to optimize the antitumor effect. Anemia was normochromic and macrocytic, possibly due to a deficiency of folic acid. One partial response of 8 months' duration was reported in a patient with epithelial cancer of the ovary, relapsing after cisplatin and alkylating agents. The use of folic acid as rescue, proposed on the basis of experimental data and pharmacological considerations, has also allowed the repeated administration of lometrexol at doses higher than in the previous studies. The advantages of rescue with folinic acid over supplementation with folic acid, however, are difficult to define.

Topics: Adult; Bone Marrow; Folic Acid Antagonists; Humans; Leucovorin; Neoplasms; Tetrahydrofolates

(6R)-5,10-Dideaza-5,6,7,8-tetrahydrofolic acid (lometrexol) is an antipurine antifolate which selectively inhibits glycinamide ribonucleotide formyltransferase. Lometrexol pharmacokinetics were evaluated in 17 patients (32 courses) as part of a Phase I study in which folic acid supplementation was used to improve tolerance to the drug, its clinical utility being previously limited by severe cumulative toxicity. Lometrexol was administered as an i.v. bolus every 4 weeks at a starting dose of 12 mg/m2, with subsequent interpatient dose escalation to 16, 30, and 45 mg/m2. p.o. folic acid (5 mg/day) was given for 7 days before and 7 days after lometrexol administration. The disposition of total lometrexol in plasma was best described by a biexponential model for data acquired up to 12 h after drug administration, although triexponential plasma pharmacokinetics were often found to give a more adequate description when data were available at later time intervals (24 h and greater). Mean plasma half-lives (+ SD) for model-dependent analysis were t1/2alpha 19 +/- 7 min, t1/2beta 256 +/- 96 min, and t1/2gamma (where measurable) 1170 +/- 435 min. Lometrexol area under plasma concentration versus time curve was proportional to the dose administered. Moderate plasma protein binding of lometrexol was evident (78 +/- 3%) with an inverse linear relationship between fraction of unbound lometrexol and the concentration of serum albumin. The volume of distribution of lometrexol at steady state was between 4.7 and 15.8 l/m2. Renal elimination of lometrexol, studied in 19 patients (21 courses), was considerable, accounting for 56 +/- 17% of the total dose administered within 6 h of treatment, and 85 +/- 16% within 24 h of treatment. These recoveries of unchanged lometrexol indicate that the drug does not appear to undergo appreciable systemic metabolism at the range of concentrations studied. Lometrexol pharmacokinetics were also examined in seven patients who received 45 or 60 mg/m2 lometrexol as part of a separate study of the drug given with folinic acid rescue 5-7 days after treatment. No marked differences were evident in lometrexol plasma half-lives, plasma clearance, or the extent of plasma protein binding, indicating that there is not a pronounced pharmacokinetic interaction between lometrexol and folic acid.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Area Under Curve; Blood Proteins; Female; Folic Acid; Humans; Male; Middle Aged; Neoplasms; Tetrahydrofolates

Cancer chemotherapy with folate antimetabolites has been traditionally targeted at the enzyme dihydrofolate reductase and is based on the requirement of dividing tumor cells for a supply of thymidylate and purines. However, a new compound, 5,10-dideazatetrahydrofolate (DDATHF, whose 6R diastereomer is also known as Lometrexol), has become available that prevents tumor cell growth by inhibiting the first of the folate-dependent enzymes involved in de novo purine synthesis, glycinamide ribonucleotide formyltransferase.. We investigated the toxicity and therapeutic activity of DDATHF in a phase I clinical trial.. DDATHF was given at one of the following dose levels to 33 patients (16 females and 17 males) with malignant solid tumors: 3.0 mg/m2 per week (level A) to 10 patients, 4.5 mg/m2 per week (level B) to 13 patients, or 6.0 mg/m2 per week (level C) to 10 patients. Each drug cycle consisted of three weekly injections of DDATHF followed by a 2-week rest prior to redosing in the next cycle.. Of 33 patients, 27 received at least one full cycle of DDATHF. Thrombocytopenia was the major dose-limiting toxicity, and it was severe in one of 10 patients during the first cycle and in two of four patients during the second cycle. Because of cumulative toxicity at 6.0 mg/m2, second or later cycles were abbreviated to two weekly doses. Stomatitis was generally mild, but it was dose-limiting in one patient. Neutropenia was infrequent and mild, and normocytic anemia requiring blood transfusion was common with repeat dosing. Leucovorin was given for grade 2 or greater thrombocytopenia and resulted in hematologic recovery within 1 week in all eight patients so treated. Without leucovorin, the thrombocytopenia lasted from 7 to 49 days in three patients. A partial response was noted in one patient with non-small-cell lung cancer and a minor response in one patient with breast cancer. Three patients with colorectal cancer achieved stable disease for greater than 3 months with improvement in carcinoembryonic antigen levels in one patient.. DDATHF has an unusual pattern of toxicity with repetitive dosing, and humans with advanced cancer are considerably more sensitive than would be predicted from previous animal studies. Although doses of 6.0 mg/m2 per week on our schedule have been determined to be safe, repeated cycles require careful monitoring because of cumulative toxic effects.. Additional phase I studies of DDATHF that relate toxicity to folate intake and tissue folate pools appear warranted.

Topics: Adult; Aged; Drug Administration Schedule; Female; Folic Acid Antagonists; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Purines; Tetrahydrofolates; Treatment Outcome

The inosine monophosphate cyclohydrolase (IMPCH) component (residues 1-199) of the bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase (AICAR Tfase, residues 200-593)/IMPCH (ATIC) catalyzes the final step in the de novo purine biosynthesis pathway that produces IMP. As a potential target for antineoplastic intervention, we designed IMPCH inhibitors, 1,5-dihydroimidazo[4,5-c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide (heterocycle, 1), the corresponding nucleoside (2), and the nucleoside monophosphate (nucleotide) (3), as mimics of the tetrahedral intermediate in the cyclization reaction. All compounds are competitive inhibitors against IMPCH (K(i) values = 0.13-0.23 microm) with the simple heterocycle 1 exhibiting the most potent inhibition (K(i) = 0.13 microm). Crystal structures of bifunctional ATIC in complex with nucleoside 2 and nucleotide 3 revealed IMPCH binding modes similar to that of the IMPCH feedback inhibitor, xanthosine 5'-monophosphate. Surprisingly, the simpler heterocycle 1 had a completely different IMPCH binding mode and was relocated to the phosphate binding pocket that was identified from previous xanthosine 5'-monophosphate structures. The aromatic imidazole ring interacts with a helix dipole, similar to the interaction with the phosphate moiety of 3. The crystal structures not only revealed the mechanism of inhibition of these compounds, but they now serve as a platform for future inhibitor improvements. Importantly, the nucleoside-complexed structure supports the notion that inhibitors lacking a negatively charged phosphate can still inhibit IMPCH activity with comparable potency to phosphate-containing inhibitors. Provocatively, the nucleotide inhibitor 3 also binds to the AICAR Tfase domain of ATIC, which now provides a lead compound for the design of inhibitors that simultaneously target both active sites of this bifunctional enzyme.

Topics: Animals; Avian Proteins; Binding Sites; Birds; Enzyme Inhibitors; Humans; Neoplasm Proteins; Neoplasms; Nucleosides; Nucleotides; Phosphoribosylaminoimidazolecarboxamide Formyltransferase; Protein Binding; Protein Structure, Tertiary; Purines

The class of folate antimetabolites typified by (6R)-dideazatetrahydrofolate (lometrexol, DDATHF) are specific inhibitors of de novo purine synthesis because of potent inhibition of glycinamide ribonucleotide formyltransferase (GART) but do not induce detectable levels of DNA strand breaks. As such, they are a test case of the concept that ribonucleotide depletion can be sensed by p53, resulting in a G(1) cell cycle block. The GART inhibitors have been proposed previously to be cytotoxic in tumor cells lacking p53 function but only cytostatic in p53 wild-type tumor cells. We have investigated this concept. Cell cycle progression into and through S phase was slowed by DDATHF, but both p53 +/+ and -/- human colon carcinoma cells entered and completed one S phase in the presence of drug. This inability of p53 to initiate a G(1) arrest after DDATHF treatment was mirrored by an independence of the cytotoxicity of DDATHF on p53 function. We conclude that carcinoma cells are killed equally well by DDATHF and related compounds whether or not the p53 pathway is intact and that the utility of GART inhibitors would not be limited to p53-negative tumors.

Topics: Alleles; Animals; Cell Division; Colonic Neoplasms; Folic Acid Antagonists; G1 Phase; Glutamates; HeLa Cells; Humans; Hydroxymethyl and Formyl Transferases; Leukemia L1210; Mice; Mitosis; Neoplasms; Phosphoribosylglycinamide Formyltransferase; Purines; Pyrimidines; S Phase; Tetrahydrofolates; Tumor Cells, Cultured; Tumor Suppressor Protein p53

We have studied the molecular effects of a LFD in a murine model in order to better define the biochemical changes associated with folate deficiency. In addition, we have demonstrated the effect of a LFD on the pharmacokinetic profile and therapeutic activity and toxicity of lometrexol. These studies showed increased density of FR in tumors implanted in LFD mice and a decrease in the affinity of these receptors for folic acid. The results suggest that tumors can compensate for low folate bioavailability by up-regulation of a second FR with slightly lower affinity for folic acid. The higher density of this FR would provide greater capacity for garnering serum folate. FPGS activity increased in several tumors and liver and kidney of LFD mice. The increase in this enzyme activity would result in enhanced polyglutamation of folates and classical antifolates and thus increased cellular retention. Consistent with these changes in liver FPGS, mice injected i.v. with a single dose of lometrexol accumulated significantly more drug in liver and tumors of LFD animals compared to SD mice. Also, higher liver concentrations of lometrexol persisted longer in LFD mice. Polyglutamate analysis showed that longer polyglutamate forms appeared earlier in liver of LFD mice. After 7 days, longer polyglutamyl forms were recovered from liver of LFD mice (octa- and hepta-glutamyl lometrexol) compared to those on SD. A comparison of the efficacy and toxicity of lometrexol in C3H mammary tumor-bearing mice showed that in mice on LFD, lometrexol treatment produced a delayed toxicity with an LD50 of 0.1-0.3 mg/kg, a 3000-fold increase in lethality compared to SD mice. Supplementation of mice with folic acid restored anti-tumor activity and increased the therapeutic dose-range over which efficacy could be assessed. These studies support the use of folic acid supplementation for cancer patients treated with antifolate therapy in order to prevent the biochemical changes in FR and FPGS associated with folate deficiency, prevent delayed toxicity to GARFT inhibitors and enhance the therapeutic potential of this class of drugs.

Topics: Acyltransferases; Animals; Carrier Proteins; Diet; Enzyme Inhibitors; Folate Receptors, GPI-Anchored; Folic Acid; Hydroxymethyl and Formyl Transferases; Kidney; Liver; Mice; Neoplasms; Peptide Synthases; Phosphoribosylglycinamide Formyltransferase; Polyglutamic Acid; Protein Binding; Receptors, Cell Surface; Tetrahydrofolates; Tumor Cells, Cultured

A competitive particle concentration fluorescence immunoassay (PCFIA) is described for measuring 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (lometrexol; Lilly) in human serum. b-Phycoerythrin-labeled lometrexol competes with free lometrexol for binding to a limiting concentration of lometrexol-specific antibodies immobilized by a second antibody to submicrometer-diameter polystyrene particles in specially designed 96-well plates. Reaction particles are washed and concentrated onto filter membranes in the wells of the plates and the fluorescence is measured at 575 nm. The method, including sample preparation and data reduction, is automated and can be completed in less than 2 h. The assay has a standard curve maximum measurable concentration of 1000 micrograms/L and a minimum detectable concentration of 0.1 microgram/L. Analytical recovery of lometrexol in serum is quantitative at concentrations greater than 1 micrograms/L. Intra- and interassay coefficients of variation at 50 micrograms/L in serum are 7.1% (n = 9) and 7.5% (n = 33), respectively. The cross-reactivity of naturally occurring folates, folic acid analogs, and the anti-cancer agent methotrexate is minimal. We report the use of the PCFIA during Phase I clinical studies designed to evaluate the pharmacokinetics of lomextrexol after intravenous administration to cancer patients.

Topics: Adult; Antineoplastic Agents; Fluoroimmunoassay; Humans; Middle Aged; Neoplasms; Tetrahydrofolates