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Annals of Oncology : Official Journal... May 2007The prognosis for any patient with progressive or recurrent invasive transitional cell carcinoma remains poor. In this context, the focus of clinical research in these... (Review)
Review
The prognosis for any patient with progressive or recurrent invasive transitional cell carcinoma remains poor. In this context, the focus of clinical research in these invasive cancers concentrates on identifying systemic treatment options and new agents in order to improve survival of patients. Cisplatin-based chemotherapy is standard treatment of patients with metastatic urothelial cancer; however, despite regimens as the cisplatin-gemcitabine combination, the overall response rates vary between 40% and 65%, with complete response in 15%-25% with survivals up to 16 months. This survival is frequently achieved with severe and life-threatening side effects. None the less, almost all responding patients relapse within the first year; therefore, the need for development of new and tolerable agents is urgent. This review highlights some new active chemotherapeutic as new platinum compounds (oxaliplatin, lobaplatin), gallium nitrate, ifosfamide, the antifolates piritrexim and pemetrexed (Alimta, LY231514), vinflunine and molecular targeting agents such as farnesyltransferase inhibitors (lonafarnib, R115777, SCH66336), ribozyme (RPI.4610), histone deacetylase inhibitor (CI-994) and monoclonal antibodies (epidermal growth factor receptor, Her 2/neu).
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Clinical Trials as Topic; Enzyme Inhibitors; Humans; Multicenter Studies as Topic; Neoplasm Metastasis; Neoplasm Recurrence, Local
PubMed: 17018703
DOI: 10.1093/annonc/mdl331 -
Cancer Chemotherapy and Pharmacology Dec 2006Cellular uptake of hydrophilic antifolates proceeds via the reduced folate carrier whereas lipophilic antifolates enter cells by diffusion. Recently we have shown that...
Cellular uptake of hydrophilic antifolates proceeds via the reduced folate carrier whereas lipophilic antifolates enter cells by diffusion. Recently we have shown that transfectant cells overexpressing the mutant G482 ABCG2 displayed 120-6,250-fold resistance to hydrophilic antifolates than untransfected cells upon 4 h drug exposure, but lost almost all their antifolate resistance upon 72 h drug exposure (Shafran et al. in Cancer Res 65:8414-8422, 2005). Here we explored the ability of the wild type (WT) R482-as well as the mutant G482-and T482 ABCG2 to confer resistance to lipophilic antifolate inhibitors of dihydrofolate reductase (trimetrexate, piritrexim, metoprine and pyrimethamine) and thymidylate synthase (AG337, AG377 and AG331). Lipophilic antifolate resistance was determined using growth inhibition assays upon 72 h drug exposure. Cells overexpressing these mutant efflux transporters displayed up to 106-fold resistance to lipophilic antifolates relative to untransfected cells; this resistance was reversed by the specific and potent ABCG2 efflux inhibitor Ko143. In contrast, cells overexpressing the WT R482 ABCG2 exhibited either no or only a low-level of lipophilic antifolate resistance. These results provide the first evidence that overexpression of the mutant G482- and T482 but not the WT R482 ABCG2 confers a high-level of resistance to lipophilic antifolates. The high membrane partitioning of lipophilic antifolates along with the large confinement of ABCG2 to the plasma membrane suggest that these mutant ABCG2 transporters may possibly recognize and extrude lipophilic antifolates from the lipid bilayer. The potential implications to cancer chemotherapy as well as the mechanism of anticancer drug extrusion by these mutant exporters are discussed.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Antineoplastic Agents; Biological Transport; Cell Line; Cell Proliferation; Cell Survival; Cisplatin; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Neoplasm; Fluorouracil; Folic Acid Antagonists; Heterocyclic Compounds, 3-Ring; Humans; Indoles; Lipids; Molecular Structure; Mutation; Neoplasm Proteins; Paclitaxel; Pyrimethamine; Pyrimidines; Quinazolines; Rhodamines; Transfection; Trimetrexate
PubMed: 16612649
DOI: 10.1007/s00280-006-0230-9 -
American Journal of Clinical Oncology Dec 2005In this phase I study, the combination of piritrexim and gemcitabine was given to establish the maximum tolerated dose and the recommended phase II dose, and to... (Comparative Study)
Comparative Study
OBJECTIVES
In this phase I study, the combination of piritrexim and gemcitabine was given to establish the maximum tolerated dose and the recommended phase II dose, and to determine a toxicity and efficacy profile.
METHODS
Fifty-two patients with normal and impaired renal function were enrolled on this phase I study. The starting dose was piritrexim 10 mg 3 times daily (5 days of the week for 3 weeks and 1 week off each 28-day cycle) and gemcitabine 1000 mg/m2 on days 1, 8, and 15. The piritrexim was escalated in a stepwise fashion with this dose of gemcitabine and then with gemcitabine 1000 mg/m2 for days 1 and 15.
RESULTS
The recommended phase II dose of this combination was felt to be piritrexim 50 mg/day (10 mg every morning, 20 mg every noon, and 20 mg every evening) with gemcitabine 1000 mg/m2 on days 1, 8, and 15, and piritrexim 75 mg/day (25 mg thrice daily) with gemcitabine 1000 mg/m2 on days 1 and 15. Neutropenia and thrombocytopenia were the most often reported toxicity. Dose-limiting toxicity was thrombocytopenia in both groups. The number of renal-impaired patients enrolled was too small to establish a maximum tolerated dose for this group (piritrexim became unavailable), but the combination was tolerated in the patients with impaired renal dysfunction. There was 1 complete response, 1 partial response, and 1 minimal response.
CONCLUSION
The combination of piritrexim and gemcitabine was determined to be tolerable in heavily pretreated patients for use in solid tumors.
Topics: Administration, Oral; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Deoxycytidine; Drug Synergism; Female; Folic Acid Antagonists; Gastrointestinal Diseases; Hematologic Diseases; Humans; Kidney; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Pyrimidines; Salvage Therapy; Treatment Outcome; Gemcitabine
PubMed: 16317274
DOI: 10.1097/01.coc.0000171281.13541.90 -
IDrugs : the Investigational Drugs... Nov 1999ILEX Oncology is developing the dihydrofolate reductase inhibitor, piritrexim (discovered originally by Burroughs Wellcome), for the potential treatment of cancer. It is...
ILEX Oncology is developing the dihydrofolate reductase inhibitor, piritrexim (discovered originally by Burroughs Wellcome), for the potential treatment of cancer. It is in phase II clinical trials for malignant fibrous histiocytoma. ILEX conducted phase II clinical trials in the US and Europe with piritrexim in bladder cancer patients; however, development for this indication was discontinued in the third quarter of 1998 due to lack of efficacy. The company also initiated phase III trials in early 1997 for the treatment of AIDS-related Kaposi's sarcoma, but no further development for this indication has been reported since that time. Piritrexim was discovered by Burroughs Wellcome, which conducted phase I and II clinical trials in more than 700 patients. Due to its potentially superior properties to those of methotrexate, it was expected that piritrexim would be active in certain methotrexate-resistant tumors. Tumor responses were noted in patients with advanced bladder cancer, Kaposi's sarcoma, colon cancer, melanoma, head and neck cancer and other cancer types. In published phase II studies, piritrexim demonstrated objective response rates ranging from 23 to 75% in patients with advanced bladder cancer who failed a standard first-line chemotherapy regimen. In March 1995, ILEX acquired an exclusive, worldwide license to patents held by Burroughs Wellcome covering the composition and use of piritrexim for all cancer indications. Under the terms of the agreement, ILEX paid a licensing fee and is obligated to pay Wellcome royalties on net sales of piritrexim. In December 1996, ILEX formed a joint venture with MPI Enterprises for the manufacture and marketing of piritrexim.
PubMed: 16113990
DOI: No ID Found -
Journal of Medicinal Chemistry Jun 2005As part of a search for dihydrofolate reductase (DHFR) inhibitors combining the high potency of piritrexim (PTX) with the high antiparasitic vs mammalian selectivity of...
Design, synthesis, and antifolate activity of new analogues of piritrexim and other diaminopyrimidine dihydrofolate reductase inhibitors with omega-carboxyalkoxy or omega-carboxy-1-alkynyl substitution in the side chain.
As part of a search for dihydrofolate reductase (DHFR) inhibitors combining the high potency of piritrexim (PTX) with the high antiparasitic vs mammalian selectivity of trimethoprim (TMP), the heretofore undescribed 2,4-diamino-6-(2',5'-disubstituted benzyl)pyrido[2,3-d]pyrimidines 6-14 with O-(omega-carboxyalkyl) or omega-carboxy-1-alkynyl groups on the benzyl moiety were synthesized and tested against Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium DHFR vs rat DHFR. Three N-(2,4-diaminopteridin-6-yl)methyl)-2'-(omega-carboxy-1-alkynyl)dibenz[b,f]azepines (19-21) were also synthesized and tested. The pyridopyrimidine with the best combination of potency and selectivity was 2,4-diamino-5-methyl-6-[2'-(5-carboxy-1-butynyl)-5'-methoxy]benzyl]pyrimidine (13), with an IC(50) value of 0.65 nM against P. carinii DHFR, 0.57 nM against M. avium DHFR, and 55 nM against rat DHFR. The potency of 13 against P. carinii DHFR was 20-fold greater than that of PTX (IC(50) = 13 nM), and its selectivity index (SI) relative to rat DHFR was 85, whereas PTX was nonselective. The activity of 13 against P. carinii DHFR was 20 000 times greater than that of TMP, with an SI of 96, whereas that of TMP was only 14. However 13 was no more potent than PTX against M. avium DHFR, and its SI was no better than that of TMP. Molecular modeling dynamics studies using compounds 10 and 13 indicated a slight binding preference for the latter, in qualitative agreement with the IC(50) data. Among the pteridines, the most potent against P. carinii DHFR and M. avium DHFR was the 2'-(5-carboxy-1-butynyl)dibenz[b,f]azepinyl derivative 20 (IC(50) = 2.9 nM), whereas the most selective was the 2'-(5-carboxy-1-pentynyl) analogue 21, with SI values of >100 against both P. carinii and M. avium DHFR relative to rat DHFR. The final compound, 2,4-diamino-5-[3'-(4-carboxy-1-butynyl)-4'-bromo-5'-methoxybenzyl]pyrimidine (22), was both potent and selective against M. avium DHFR (IC(50) = 0.47 nM, SI = 1300) but was not potent or selective against either P. carinii or T. gondii DHFR.
Topics: Animals; Anti-Infective Agents; Drug Design; Folic Acid Antagonists; Models, Molecular; Molecular Structure; Mycobacterium avium; Pneumocystis carinii; Pyrimidines; Rats; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase; Toxoplasma
PubMed: 15974594
DOI: 10.1021/jm0581718 -
The Journal of Organic Chemistry Feb 2005[reaction: see text] A regiospecific and convergent route the lipophilic antifolate piritrexim (PTX) is described in which a key step is a Pd(0)-catalyzed cross-coupling...
[reaction: see text] A regiospecific and convergent route the lipophilic antifolate piritrexim (PTX) is described in which a key step is a Pd(0)-catalyzed cross-coupling reaction between 2-amino-3-cyano-4-methyl-5-bromopyridine and 2,5-dimethoxybenzylzinc chloride to form 2-amino-4-methyl-5-(2,5-dimethoxybenzyl)nicotinonitrile. To complete the synthesis, the amino group is replaced by a more reactive bromine atom via nonaqueous diazotization with tert-butyl nitrite, and the resultant bromo nitrile is cyclized with guanidine.
Topics: Catalysis; Folic Acid Antagonists; Molecular Structure; Palladium; Pyrimidines
PubMed: 15704971
DOI: 10.1021/jo040268z -
European Journal of Medicinal Chemistry Dec 2004Piritrexim (PTX) (1), a lipophilic inhibitor of the human dihydrofolate reductase, has been evaluated as an anticancer agent. The synthesis of four structural variations...
Piritrexim (PTX) (1), a lipophilic inhibitor of the human dihydrofolate reductase, has been evaluated as an anticancer agent. The synthesis of four structural variations (2-5) of PTX is reported. The PTX analogues 2-5 were obtained by reaction of suitable C3-building blocks with pyrimidine-2,4,6-triamine (14) or with cyanacetamide (7) and guanidine (10). The evaluation of 2-4 for antitumor activity against a panel of 60 human cancer cell lines showed inhibitory effects on the growth of the cell lines. These data are supported by molecular modeling and docking studies, which show that compounds 2-4 share the same binding mode within the DHFR active site. Moreover, the estimated ligand binding energies are in good agreement with the experimental activity data.
Topics: Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Drug Screening Assays, Antitumor; Folic Acid Antagonists; Humans; Models, Molecular; Molecular Structure; Protein Binding; Protein Conformation; Pyridines; Pyrimidines; Tetrahydrofolate Dehydrogenase
PubMed: 15571870
DOI: 10.1016/j.ejmech.2004.09.001 -
Journal of Medicinal Chemistry May 2004Six previously undescribed N-(2,4-diaminopteridin-6-yl)methyldibenz[b,f]azepines with water-solubilizing O-carboxyalkyloxy or O-carboxybenzyloxy side chains at the...
Synthesis of 2,4-diamino-6-[2'-O-(omega-carboxyalkyl)oxydibenz[b,f]azepin-5-yl]methylpteridines as potent and selective inhibitors of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductase.
Six previously undescribed N-(2,4-diaminopteridin-6-yl)methyldibenz[b,f]azepines with water-solubilizing O-carboxyalkyloxy or O-carboxybenzyloxy side chains at the 2'-position were synthesized and compared with trimethoprim (TMP) and piritrexim (PTX) as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), and Mycobacterium avium (Ma), three of the opportunistic organisms known to cause significant morbidity and mortality in patients with AIDS and other disorders of the immune system. The ability of the new analogues to inhibit reduction of dihydrofolate to tetrahydrofolate by Pc, Tg, Ma, and rat DHFR was determined, and the selectivity index (SI) was calculated from the ratio IC(50)(rat DHFR)/IC(50)(Pc, Tg, or Ma DHFR). The IC(50) values of the 2'-O-carboxypropyl analogue (10), with SI values in parentheses, were 1.1 nM (1300) against Pc DHFR, 9.9 nM (120) against Tg DHFR, and 2.0 nM (600) against Ma DHFR. The corresponding values for the 2'-O-(4-carboxybenzyloxy) analogue (12) were 1.0 nM (560), 22 nM (21), and 0.75 nM (630). By comparison, the IC(50) and SI values for TMP were Pc, 13 000 nM (14); Tg, 2800 nM (65); and Ma, 300 nM (610). For the prototypical potent but nonselective inhibitors PTX and TMX, respectively, these values were Pc, 13 nM (0.26) and 47 nM (0.17); Tg, 4.3 nM (0.76) and 16 nM (0.50); Ma, 0.61 nM (5.4) and 1.5 nM (5.3). Thus 10 and 12 met the criterion for DHFR inhibitors that combine the high selectivity of TMP with the high potency of PTX and TMX.
Topics: Animals; Azepines; Benzazepines; Folic Acid Antagonists; Models, Molecular; Mycobacterium avium; Pneumocystis carinii; Pteridines; Rats; Solubility; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase; Toxoplasma; Water
PubMed: 15115391
DOI: 10.1021/jm030599o -
Journal of Medicinal Chemistry Mar 2004In a continuing effort to design small-molecule inhibitors of dihydrofolate reductase (DHFR) that combine the enzyme-binding selectivity of...
New 2,4-diamino-5-(2',5'-substituted benzyl)pyrimidines as potential drugs against opportunistic infections of AIDS and other immune disorders. Synthesis and species-dependent antifolate activity.
In a continuing effort to design small-molecule inhibitors of dihydrofolate reductase (DHFR) that combine the enzyme-binding selectivity of 2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine (trimethoprim, TMP) with the potency of 2,4-diamino-5-methyl-6-(2',5'-dimethoxybenzyl)pyrido[2,3-d]pyrimidine (piritrexim, PTX), seven previously undescribed 2,4-diamino-5-[2'-methoxy-5'-(substituted benzyl)]pyrimidines were synthesized in which the substituent at the 5'-position was a carboxyphenyl group linked to the benzyl moiety by a bridge of two or four atoms in length. The new analogues were all obtained from 2,4-diamino-5-(5'-iodo-2'-methoxybenzyl)pyrimidine via a Sonogashira reaction, followed, where appropriate, by catalytic hydrogenation. The new analogues were tested as inhibitors of DHFR from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), and Mycobacterium avium (Ma), three life-threatening pathogens often found in AIDS patients and individuals whose immune system is impaired as a result of treatment with immunosuppressive chemotherapy or radiation. The selectivity index (SI) of each compound was obtained by dividing its 50% inhibitory concentration (IC(50)) against Pc, Tg, or Ma DHFR by its IC(50) against rat DHFR. 2,4-Diamino-[2'-methoxy-5'-(3-carboxyphenyl)ethynylbenzyl]pyrimidine (28), with an IC(50) of 23 nM and an SI of 28 in the Pc DHFR assay, had about the same potency as PTX and was 520 times more potent than TMP. As an inhibitor of Tg DHFR, 28 had an IC(50) of 5.5 nM (510-fold lower than that of TMP and similar to that of PTX) and an SI value of 120 (2-fold better than TMP and vastly superior to PTX). Against Ma DHFR, 28 had IC(50) and SI values of 1.5 nM and 430, respectively, compared with 300 nM and 610 for TMP. Although it had 2.5-fold lower potency than 28 against Ma DHFR (IC(50) = 3.7 nM) and was substantially weaker against Pc and Tg DHFR, 2,4-diamino-[2'-methoxy-5'-(4-carboxyphenyl)ethynylbenzyl]pyrimidine (29), with the carboxy group at the para rather than the meta position, displayed 2200-fold selectivity against the Ma enzyme and was the most selective 2,4-diamino-5-(5'-substituted benzyl)pyrimidine inhibitor of this enzyme we have encountered to date. Additional bioassay data for these compounds are also reported.
Topics: AIDS-Related Opportunistic Infections; Animals; Folic Acid Antagonists; Humans; Inhibitory Concentration 50; Liver; Microbial Sensitivity Tests; Mycobacterium avium; Opportunistic Infections; Pneumocystis carinii; Pyrimidines; Rats; Recombinant Proteins; Species Specificity; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase; Toxoplasma
PubMed: 14998335
DOI: 10.1021/jm030438k -
The International Journal of... Mar 2004Amido phosphoribosyltransferase (APRT) catalyzes the first step of the de novo biosynthesis of purine nucleotides, the conversion of 5-phosphoribosyl-1-pyrophosphate... (Comparative Study)
Comparative Study
Amido phosphoribosyltransferase (APRT) catalyzes the first step of the de novo biosynthesis of purine nucleotides, the conversion of 5-phosphoribosyl-1-pyrophosphate (PRPP) into 5-phosphoribosylamine (PRA). APRT is a valid target for development of inhibitors as anticancer drugs. We have developed a thin layer chromatographic assay for PRPP extracted from cells. Using coupling enzymes, PRPP with excess [2-14C]orotate (OA) is quantitatively converted to [2-14C]OMP and then [2-14C]UMP with hydrolysis of the PPi. The reaction products are isolated on poly(ethyleneimine)-cellulose (PEI-C) chromatograms. Human CCRF-CEM leukaemia cells growing in culture have been exposed to a number of antifolates and their effects upon cellular levels of PRPP determined. The steady-state level of PRPP measured in CCRF-CEM cells was 102+/-11 microM. Following addition of an antifolate to a culture, accumulation of PRPP in cells indicates the degree of inhibition of APRT. In human CCRF-CEM leukaemia cells, lometrexol (LTX), 2,4-diamino-6-(3,4,5-trimethoxybenzyl)-5,6,7,8-tetrahydro-quinazoline (PY899), methotrexate (MTX), N(alpha)(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine (PT523), piritrexim (PTX), metoprine, 2,4-diamino-6-(3,4,5-trimethoxyanilino)-methylpyrido[3,2-d]pyrimidine (PY873) and multitargeted antifolate, N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid (MTA) directly or indirectly induce inhibition of APRT indicated by time-courses for accumulation of PRPP to maximum values of 3-12-fold. These data indicate that LTX induces the most potent inhibition of APRT.
Topics: Amidophosphoribosyltransferase; Antineoplastic Agents; Cell Line, Tumor; Enzyme Inhibitors; Folic Acid Antagonists; Humans; Leukemia; Molecular Structure; Phosphoribosyl Pyrophosphate; Pyrimethamine
PubMed: 14687931
DOI: 10.1016/j.biocel.2003.08.014