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Clinical Genitourinary Cancer Mar 2008Piritrexim is reported to have a response rate of 38% in patients with chemotherapy-naive disease and 23% for second-line therapy after chemotherapy failure. We report...
BACKGROUND
Piritrexim is reported to have a response rate of 38% in patients with chemotherapy-naive disease and 23% for second-line therapy after chemotherapy failure. We report the results of a multiinstitutional, open-label, 2-stage, phase II study that further evaluates oral piritrexim in patients with urothelial carcinoma and who proved nonresponsive to standard chemotherapy.
PATIENTS AND METHODS
Eligible patients included those with bi-dimensionally measurable disease and an Eastern Cooperative Oncology Group performance status of 0-2, transitional cell carcinoma or adenocarcinoma of the urothelium, and nonresponse to > or = 1 previous standard chemotherapy regimen. Patients received piritrexim orally at 25 mg 3 times daily (every 8 hours regularly) for 5 consecutive days each week for 3 weeks, followed by a 1-week rest period. Treatment was continued until disease progression, unacceptable toxicity, or patient refusal.
RESULTS
Of the 23 patients enrolled, 19 patients and 22 patients were assessable for toxicity and response, respectively. Two patients required dose reduction because of toxicity, 2 patients discontinued study because of toxicity, and 6 patients had > or = 1 serious adverse event. Except for grade 1/2 pain and fatigue, gastrointestinal toxicities were the most commonly reported events, followed by fever, delirium, and myelosuppression. No objective responses were observed, with 2 patients demonstrating stable disease after 2-4 cycles. By the statistical design of the trial, further enrollment was halted because of lack of activity.
CONCLUSION
Regardless of modest side effects, oral piritrexim in heavily pretreated patients is inactive at this dose and schedule, confirming the results of a recent cooperative group trial.
Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Folic Acid Antagonists; Humans; Middle Aged; Pyrimidines; Treatment Outcome; Urologic Neoplasms
PubMed: 18501080
DOI: 10.3816/CGC.2008.n.005 -
Journal of Medicinal Chemistry Mar 19962,4-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...
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.
Topics: Animals; Anti-Infective Agents; Folic Acid Antagonists; Opportunistic Infections; Pneumocystis; Pneumonia, Pneumocystis; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase; Toxoplasma; Toxoplasmosis; Trimetrexate
PubMed: 8632434
DOI: 10.1021/jm950760y -
Cancer Feb 1992Piritrexim (PTX) is a newly developed lipid-soluble folate antagonist that crosses the cell membrane by a simple, rapid, carrier-independent diffusion process. A Phase... (Clinical Trial)
Clinical Trial
Piritrexim (PTX) is a newly developed lipid-soluble folate antagonist that crosses the cell membrane by a simple, rapid, carrier-independent diffusion process. A Phase II study was conducted to evaluate the activity of PTX in 34 patients with previously chemotherapy-naive squamous cell cancer of the head and neck area (SCCHN). Among them, 30 patients had received previous radiation therapy and/or surgery. Of 33 patients who could be examined, 3 had a complete response (CR), 6 had a partial response (PR), 11 had no change, and 13 had disease progression. The overall response rate (CR + PR) was 27% (9 of 33; 95% confidence interval, 13% to 46%). The response duration ranged from 36 to 360 + days (median, 162) and was similar to the best studies reported with methotrexate. The three most severe side effects (Grades 3 and 4 by World Health Organization criteria) were leukopenia, thrombocytopenia, and mucositis. These occurred in 41%, 26%, and 15% of the 34 patients, respectively. This study established PTX as an agent with some activity in SCCHN. The use of PTX in combination chemotherapeutic regimens needs to be explored.
Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Drug Evaluation; Female; Head and Neck Neoplasms; Humans; Male; Methotrexate; Middle Aged; Pyrimidines
PubMed: 1735068
DOI: 10.1002/1097-0142(19920215)69:4<1008::aid-cncr2820690430>3.0.co;2-h -
Molecular Pharmacology Dec 1986The lipid-soluble folate antagonist, 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidin e (piritrexim; BW301U), induced misincorporation of dUMP in human...
The lipid-soluble folate antagonist, 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidin e (piritrexim; BW301U), induced misincorporation of dUMP in human B (SB)- and T (MOLT-4)-lymphoblastoid cells, and in human promyelocytic leukemia cells (HL-60). Analysis by alkaline sucrose gradients and alkaline elution indicated that 3H-DNA that had been labeled for 15 min distributed into progressively smaller DNA fragment sizes in a drug concentration-dependent manner from 0 microM to 50 microM piritrexim. This phenomenon was observed regardless of the labeled nucleotide precursor employed for detection of newly synthesized DNA [( 3H]deoxyuridine, [3H]deoxyadenosine, or [3H]deoxycytidine). In contrast, formaldehyde denaturation and sedimentation of DNA in neutral denaturing sucrose gradients released only 3-4% of the newly synthesized DNA as 3S-6S fragments (80-200 nucleotides), whereas the remaining population of newly synthesized DNA pelleted to the bottom of the tube. Failure to detect DNA fragmentation under neutral conditions to the extent observed under alkaline conditions indicated the presence of apurinic and apyrimidinic sites in DNA--lesions which would be expected in DNA undergoing excision-repair of misincorporated dUMP. Cytotoxicity resulting from dUMP misincorporation was consistent with the enhanced toxicity of piritrexim which was observed when HL-60 cells or MOLT-4 cells were exposed concurrently to exogenous deoxyuridine. Deoxyuridine-enhanced toxicity was demonstrated to be concentration dependent for both cell lines when piritrexim concentrations were marginally toxic. The cytotoxic effect of dUMP misincorporation was further substantiated by the observation that MOLT-4 cells treated with 0.5 microM piritrexim alone eventually developed resistance to the drug, whereas treatment with both piritrexim and 10 microM deoxyuridine prevented the selection of piritrexim-resistant cells.
Topics: B-Lymphocytes; Cell Line; DNA Damage; DNA Replication; Deoxyribonucleosides; Folic Acid Antagonists; Humans; Kinetics; Pyrimidines; T-Lymphocytes; Tritium
PubMed: 3491287
DOI: No ID Found -
Investigational New Drugs 1997Oral piritrexim (PTX), a second generation antimetabolite, has been shown to be an active agent against methotrexate refractory transitional cell cancer (TCC) of the... (Clinical Trial)
Clinical Trial
UNLABELLED
Oral piritrexim (PTX), a second generation antimetabolite, has been shown to be an active agent against methotrexate refractory transitional cell cancer (TCC) of the bladder in phase I trials. We conducted a phase II trial of this drug in patients with TCC of the bladder who failed a first line chemotherapy regimen.
METHODS
Oral PTX was started at the dose of 25 mg three times per day for 5 days weekly for 3 weeks followed by one week of rest. If this was tolerated the dose was increased to 50 mg three times a day. Patients were monitored for response rate and toxicity.
RESULTS
Seventeen patients were entered into the trial. Two patients did not complete the required 2 courses of treatment to be evaluable. There were 13 evaluable patients. Among the 13 no one achieved a complete response (CR), however, there were 3 partial responses (PRs = RR: 23%) and 5 stable diseases (SDs). The responses lasted 2, 8 and 14 months. The major dose-limiting toxicity was myelosuppression. Two patients died on treatment. One death was due to neutropenic fever and the cause of death in the second patient is thought to be a cerebral vascular accident (CVA).
CONCLUSION
PTX is an active drug in the treatment of TCC of the bladder. Bone marrow suppression is the most common dose-limiting toxicity. In view of the observed responses and toxicities in this study and other studies, we suggest that the role of PTX be further investigated in the following clinical settings: 1. Palliative initial treatment in patients with TCC of the bladder who are not candidates for more aggressive chemotherapy. 2. As first line chemotherapy in combination with other active drugs.
Topics: Administration, Oral; Aged; Antimetabolites, Antineoplastic; Carcinoma, Transitional Cell; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Pyrimidines; Urinary Bladder Neoplasms
PubMed: 9220296
DOI: 10.1023/a:1005860806635 -
Oncology (Williston Park, N.Y.) Jul 1995Numerous new antifolate drugs have been developed in an attempt to overcome the potential mechanisms of tumor cell resistance to methotrexate, which can include... (Review)
Review
Numerous new antifolate drugs have been developed in an attempt to overcome the potential mechanisms of tumor cell resistance to methotrexate, which can include decreased drug transport into cells; decreased polyglutamation, leading to increased drug efflux from cells; decreased drug affinity for folate-dependent enzymes; mutations of dihydrofolate reductase (DHFR), a key enzyme required for the maintenance of adequate intracellular reduced folate levels that is inhibited by methotrexate; and increased expression of the DHFR protein. Promising antifolate compounds undergoing clinical testing as anticancer agents include trimetrexate (which was recently approved by the FDA for the treatment of Pneumocystis carinii pneumonia), edatrexate, piritrexim, Tomudex, and lometrexol. The mechanisms of action, dosage, pharmacokinetics, clinical toxicity, and antitumor activity of these drugs are profiled.
Topics: Aminopterin; Antimetabolites, Antineoplastic; Antineoplastic Agents; Drugs, Investigational; Folic Acid Antagonists; Humans; Neoplasms; Pyrimidines; Quinazolines; Thiophenes; Trimetrexate
PubMed: 8924375
DOI: No ID Found -
Cancer Research Feb 1992Piritrexim, an orally administered, lipid-soluble antifolate, was evaluated in a multi-institutional phase I trial in children. The starting dose was 10 mg/m2/dose... (Clinical Trial)
Clinical Trial
Piritrexim, an orally administered, lipid-soluble antifolate, was evaluated in a multi-institutional phase I trial in children. The starting dose was 10 mg/m2/dose administered every 8 h daily for 5 days for 3 consecutive weeks, with dose escalations in increments of 5 mg/m2/dose. Eighteen patients (16 with metastatic sarcoma, 1 with acute lymphoblastic leukemia, and 1 with a brainstem glioma), 3.5-20 years of age, with malignancy refractory to therapy, were entered into the study. The dose-limiting toxicities (DLTs), which were myelosuppression and mucositis, occurred in 4 of 4 patients treated at the 25-mg/m2/dose level but in none of the patients treated at the 15- and 20-mg/m2/dose levels. The recommended dose for phase II trials is 20 mg/m2/dose. Pharmacokinetic monitoring was performed in 15 of the 18 children. The area under the concentration-time curve (AUC) was linearly related to the dose administered. Piritrexim was rapidly absorbed, with the median time to peak level occurring 1.5 h after an oral dose. The terminal half-life of piritrexim ranged from 1.5 to 4.5 h. A limited sampling strategy developed earlier, capable of predicting the AUC based on the plasma concentrations at 3 and 6 h after an oral dose, was prospectively tested in this trial and proved to be highly predictive of the AUC (r = 0.98, P = 0.0001). Pharmacodynamic-pharmacokinetic correlations were obtained after combining data from this and the prior phase I pediatric trial. Trough plasma piritrexim concentration strongly correlated with DLT (P = 0.0016). A trough plasma piritrexim concentration greater than 0.5 microM appeared to be predictive of toxicity. Eleven of 15 patients with trough concentrations exceeding this threshold experienced DLTs. Therapeutic drug monitoring may thus play an important role in adjusting the dose and schedule of piritrexim in future trials.
Topics: Adolescent; Adult; Antineoplastic Agents; Brain Neoplasms; Child; Child, Preschool; Drug Administration Schedule; Drug Evaluation; Female; Glioma; Humans; Leukocyte Count; Male; Neoplasms; Platelet Count; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Sarcoma
PubMed: 1732038
DOI: No ID Found -
Acta Biochimica Polonica 2001Dihydrofolate reductase (DHFR, EC 1.5.1.3) is one of the enzymes active in the folate cycle which plays an important role in DNA synthesis. Inhibition of DHFR is a key...
Dihydrofolate reductase (DHFR, EC 1.5.1.3) is one of the enzymes active in the folate cycle which plays an important role in DNA synthesis. Inhibition of DHFR is a key element in the treatment of many diseases, including cancer and AIDS related infections. A search for new selective inhibitors is motivated by the resistance to common drugs observed in the course of treatment. In this paper, results of a detailed computer analysis of human DHFR interactions with the lipophilic inhibitor piritrexim (PTX) are presented. It was found that the NADPH cofactor contributes 30% of the total PTX-enzyme interaction energy. Substitution of the highly conserved Glu30 with alanine does not lead to the release of the inhibitor from the hDHFR pocket. The important L22F point mutation does affect PTX orientation but does not changethe binding energy. Simulations of the dynamics of binary hDHFR-PTX complexes were performed with the use of Extensible Systematic Force Field (ESFF) and the results indicate structural changes in the enzyme induced by NADPH binding.
Topics: Antineoplastic Agents; Binding Sites; Humans; Models, Molecular; Mutation; NADP; Point Mutation; Protein Binding; Pyrimidines; Software; Tetrahydrofolate Dehydrogenase
PubMed: 11996001
DOI: No ID Found -
Journal of Clinical Oncology : Official... Mar 1991A phase II trial of piritrexim (2,4-diamino-6[2,5-dimethoxybenzyl]-5-methyl pyrido-[2,3d] pyrimidine, 301U74; PTX) was conducted for patients with metastatic malignant... (Clinical Trial)
Clinical Trial
A phase II trial of piritrexim (2,4-diamino-6[2,5-dimethoxybenzyl]-5-methyl pyrido-[2,3d] pyrimidine, 301U74; PTX) was conducted for patients with metastatic malignant melanoma using an intermittent, low-dose oral administration schedule. PTX was administered at a starting dose of 25 mg orally three times per day for 5 days weekly for 3 weeks followed by 1 week of rest. Thirty-one patients were entered onto the study. Among 31 patients assessable for response, there were two complete responses (CRs) and five partial responses (PRs) for a response rate (CR plus PR) of 23% (95% confidence limit, 10% to 42%). Five responses occurred in soft tissue lesions, and two responses occurred in lung lesions. The initial dose schedule was well tolerated. The dose-limiting toxicity was myelosuppression. PTX administered in this schedule appears to be active against malignant melanoma. Further clinical trials to confirm these results are underway.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Drug Administration Schedule; Drug Evaluation; Female; Humans; Leukopenia; Male; Melanoma; Middle Aged; Pyrimidines; Thrombocytopenia
PubMed: 1999717
DOI: 10.1200/JCO.1991.9.3.464 -
Journal of Medicinal Chemistry Jan 2002A series of previously undescribed 2,4-diamino-5-[2-methoxy-5-alkoxybenzyl]pyrimidines (3a-e) and 2,4-diamino-5-[2-methoxy-5-(omega-carboxyalkyloxy)benzyl]pyrimidines... (Comparative Study)
Comparative Study
Inhibition of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductases by 2,4-diamino-5-[2-methoxy-5-(omega-carboxyalkyloxy)benzyl]pyrimidines: marked improvement in potency relative to trimethoprim and species selectivity relative to piritrexim.
A series of previously undescribed 2,4-diamino-5-[2-methoxy-5-alkoxybenzyl]pyrimidines (3a-e) and 2,4-diamino-5-[2-methoxy-5-(omega-carboxyalkyloxy)benzyl]pyrimidines (3f-k) with up to eight CH2 groups in the alkoxy or omega-carboxyalkyloxy side chain were synthesized and tested for the ability to inhibit partially purified dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), Mycobacterium avium (Ma), and rat liver in comparison with two standard inhibitors, trimethoprim (1) and piritrexim (2). The latter drug is known to be extremely potent but shows a marked preference for binding to mammalian DHFR, whereas the former is very selective for the parasite enzymes but is a much weaker inhibitor. The underlying strategy for the synthesis of compounds 3a-k was that a hybrid structure embodying some features of both 1 and 2 might possess a more favorable combination of potency and selectivity than either parent drug. The choice of analogues 3f-k was based on the idea that the acidic omega-carboxyl group might interact preferentially with a basic center in the active site of DHFR from any of the parasite species relative to the active site of mammalian DHFR. In addition, the omega-carboxyl group was expected to improve water solubility relative to 1 or 2. In standardized spectrophotometric assays with dihydrofolate as the substrate and NADPH as the cofactor, 2,4-diamino-5-[(2-methoxy-4-carboxybutyloxy)benzyl]pyrimidine (3g) inhibited Pc DHFR with an IC(50) of 0.049 microM and rat DHFR with IC(50) of 3.9 microM. Its potency against Pc DHFR was 140-fold greater than that of 1 and close to that of 2, and its selectivity index, defined as the ratio IC(50)(rat liver)/IC(50)(P. carinii), was 8-fold higher than that of 1 and >10(4)-fold higher than that of 2. Although it was less potent and less selective against Tg than Pc DHFR, it was very potent as well as highly selective against Ma DHFR, with an IC(50) of 0.0058 microM and an IC(50)(rat liver)/IC(50)(M. avium) ratio of >600. Because of this favorable combination of potency and selectivity relative to 1 and 2, compound 3g may be viewed as a promising lead in the search for new antifolates with potential clinical activity against P. carinii and other opportunistic pathogens in patients with AIDS.
Topics: Animals; Folic Acid Antagonists; Liver; Mycobacterium avium; Pneumocystis; Pyrimidines; Rats; Species Specificity; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase; Toxoplasma; Trimethoprim
PubMed: 11754594
DOI: 10.1021/jm010407u