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1.
Cancer Res ; 51(12): 3171-6, 1991 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-1710167

RESUMO

Because the initial evaluation of N,N',N''-triethylenethiophosphoramide (thioTEPA) preceded the standardized approach to the Phase I trials, uncertainty surrounds the recommended dose. Since it has recently been demonstrated that an almost 100-fold increase in dose can be administered in bone marrow transplant regimens, we conducted a Phase I reevaluation of thioTEPA. ThioTEPA was administered i.v. in 50 ml 5% dextrose in water over 10 min. Twenty-seven patients were entered at doses ranging from 30 to 75 mg/m2. The major toxic effect was myelosuppression; thrombocytopenia greater than or equal to grade 3 occurred in four of seven patients, and leukopenia greater than or equal to grade 3 in two of seven patients at 75 mg/m2. Among eight patients at 65 mg/m2 only two had greater than or equal to grade 3 myelosuppression making this the recommended new phase II dose for the majority of patients. Moderate (grade 2) easily controlled nausea and vomiting was the only other major side effect. There was no alopecia or mucosal or neurological toxicity. Three partial remissions were observed among nine previously treated ovarian cancer patients. Plasma concentrations of thioTEPA and its major active metabolite triethylenephosphoramide (TEPA) were measured by gas chromatography. The half-life of thioTEPA ranged from 51.6 to 211.8 min, and its pharmacokinetics was dose dependent; total body thioTEPA clearance decreased with increasing dose. The half-life of TEPA was considerably longer than that of the parent compound (3.0 to 21.1 h); as a result, the area under the plasma concentration-time curve (AUC) of TEPA was severalfold greater than that of the parent compound. The ratio of TEPA AUC to thioTEPA AUC decreased with increasing dose, suggesting that formation of TEPA is a saturable step in elimination. The AUC and total body clearance of thioTEPA, but not of TEPA, were closely correlated with neutrophil but not platelet toxicity.


Assuntos
Tiotepa/toxicidade , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Feminino , Humanos , Contagem de Leucócitos/efeitos dos fármacos , Leucopenia/induzido quimicamente , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neutrófilos/efeitos dos fármacos , Tiotepa/farmacocinética , Tiotepa/uso terapêutico , Trombocitopenia/induzido quimicamente , Trietilenofosforamida/sangue
2.
Biochim Biophys Acta ; 418(3): 257-65, 1976 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-174724

RESUMO

A method is described for the preparation of 125I-labelled SV40 DNA. Using this method, SV40 DNA can be routinely labelled to 15 - 10(6) dpm per mug; much higher specific activities are easily obtained by minor modifications of the method. Once incorporated, the radioactive label dissociates from DNA exceedingly slowly at 4 degrees C or at 68 degrees C. Iodinated SV40 DNA is shown to be useful in the quantitation of viral nucleic acid sequences in SV40-transformed 3T3 cells by DNA - DNA reassociation kinetics.


Assuntos
DNA Viral , Vírus 40 dos Símios , Sequência de Bases , Linhagem Celular , Transformação Celular Neoplásica , Radioisótopos do Iodo , Cinética , Métodos , Renaturação de Ácido Nucleico
3.
Clin Cancer Res ; 2(9): 1475-80, 1996 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9816323

RESUMO

Multiple studies have shown that leucovorin-fluorouracil regimens are modestly superior to fluorouracil alone in the treatment of advanced colorectal cancer. Laboratory data suggest that iododeoxyuridine could further enhance the efficacy of leucovorin-fluorouracil regimens. This report describes the Phase I clinical evaluation of a leucovorin-fluorouracil-iododeoxyuridine chemotherapy regimen. Twenty-four patients received treatment with leucovorin (500 mg/m2), fluorouracil (500 mg/m2), and iododeoxyuridine (escalating doses) on days 1 and 8 of a 21-day cycle. The maximum tolerated dose of iododeoxyuridine was 1200 mg/m2, with a recommended Phase II dose of 1000 mg/m2. Myelosuppression (leukopenia) was dose limiting; other commonly observed treatment toxicities were nausea/vomiting, mucositis, and hyperlacrimation. Although the 1200 mg/m2 dose was tolerated during the initial few cycles of therapy, chronic administration could not be maintained secondary to dose-limiting neutropenia. Since neutropenia was dose limiting, in a follow-up study, 10 patients received a modified regimen (treatment on days 1 and 6 instead of days 1 and 8) with the addition of granulocyte colony-stimulating factor (days 8-19). The addition of granulocyte colony-stimulating factor, however, did not permit further escalation of the iododeoxyuridine dose. Three partial responses and six minor responses were observed. Phase II studies of this regimen are ongoing in advanced colorectal and advanced pancreatic cancer to determine response rates in these diseases.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Antídotos/administração & dosagem , Antídotos/efeitos adversos , Antídotos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Relação Dose-Resposta a Droga , Estudos de Avaliação como Assunto , Fadiga/induzido quimicamente , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Idoxuridina/administração & dosagem , Idoxuridina/efeitos adversos , Idoxuridina/uso terapêutico , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neutropenia/induzido quimicamente , Vômito/induzido quimicamente
4.
Clin Cancer Res ; 3(12 Pt 1): 2347-54, 1997 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9815633

RESUMO

Tumor angiogenesis is critically important to tumor growth and metastasis. We have shown that pentosan polysulfate (PPS) is an effective inhibitor of heparin-binding growth factors in vitro and can effectively inhibit the establishment and growth of tumors in nude mice. Following completion of our Phase I trial of s.c. administered PPS, we performed a Phase I trial of p.o. administered PPS in patients with advanced cancer to determine the maximum tolerated dose (MTD) and toxicity profile and to search for any evidence for biological activity in vivo. Patients diagnosed with advanced, incurable malignancies who met standard Phase I criteria and who did not have a history of bleeding complications were enrolled, in cohorts of three, to receive PPS p.o. t.i.d., at planned doses of 180, 270, 400, 600, and 800 mg/m2. Patients were monitored at least every 2 weeks with physical exams and weekly with hematological, chemistry, stool hemoccult, and coagulation blood studies, and serum and urine samples for PPS and basic fibroblastic growth factor (bFGF) levels were also taken. The PPS dose was escalated in an attempt to reach the MTD. Eight additional patients were enrolled at the highest dose to further characterize the toxicity profile and biological in vivo effects of PPS. A total of 21 patients were enrolled in the three cohorts of doses 180 (n = 4), 270 (n = 3), and 400 (n = 14) mg/m2. The most severe toxicities seen were grade 3 proctitis and grade 4 diarrhea; however, 20 of the 21 patients had evidence of grade 1 or 2 gastrointestinal (GI) bleeding. These toxicities became evident at a much earlier time point as the dose was increased, but their severities were similar at all dose levels. There were no objective responses, although three patients had prolonged stabilization of previously progressing disease. Pharmacokinetic analysis suggested marked accumulation of PPS upon chronic administration. Serum and urine bFGF levels failed to show a consistent, interpretable pattern; however the data suggested an inverse relationship between PPS and bFGF levels in vivo. A MTD could not be determined using the daily t.i.d. dosing schedule due to the development of grade 3/4 GI toxicity (proctitis) at all dose levels studied. PPS, administered p.o. at doses of 400 mg/m2 t.i.d., did not cause significant systemic toxicity, but most patients developed moderate-to-severe GI toxicity within 1-2 months. The cause of the GI toxicity was unclear, but it was readily reversible upon cessation of the agent. The suggestion of an inverse relationship between PPS and bFGF supports further study of PPS as an antiangiogenic agent. The tested doses and schedule cannot be recommended for further study. Subsequent murine experiments showed PPS to be more effective as an anticancer agent when it is given intermittently. We propose a study of PPS given on a weekly schedule in further clinical trials.


Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Neoplasias/tratamento farmacológico , Poliéster Sulfúrico de Pentosana/efeitos adversos , Poliéster Sulfúrico de Pentosana/farmacocinética , Administração Oral , Adulto , Idoso , Animais , Antineoplásicos/administração & dosagem , Diarreia/induzido quimicamente , Relação Dose-Resposta a Droga , Feminino , Fator 2 de Crescimento de Fibroblastos/sangue , Fator 2 de Crescimento de Fibroblastos/urina , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Masculino , Taxa de Depuração Metabólica , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/patologia , Neoplasias/urina , Poliéster Sulfúrico de Pentosana/administração & dosagem , Proctite/induzido quimicamente
5.
Clin Pharmacokinet ; 26(3): 190-200, 1994 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8194282

RESUMO

Trimetrexate represents one of a number of new antimetabolites that have been studied in malignant, rheumatological and infectious disease. Methotrexate, the classical antifolate agent, is active in a broad spectrum of clinical settings, but its use is limited ny pre-existing or acquired cellular resistance. Trimetrexate is an agent that does not require uptake by the folate carrier transport system, a major mechanism of cellular resistance both in vitro and in vivo. Both dihydrofolate reductase inhibition and high performance liquid chromatography (HPLC) assays can be used to determine drug concentrations. Clearance of trimetrexate has been reported to follow biphasic or triphasic patterns. Elimination is primarily by biotransformation with less than 5% of the drug excreted renally in an unchanged form. Both active and inactive metabolites have been found, but the precise metabolic pathways have yet to be defined. The role of trimetrexate in the treatment of Pneumocystis carinii pneumonia is limited to compassionate use, as clinical studies have shown cotrimoxazole (trimethoprim-sulfamethoxazole) to be superior to trimetrexate. However, in a wide spectrum of malignant processes, trimetrexate appears to have a role either as a high-dose single agent, with calcium folinate (leucovorin calcium) rescue, or in combination with other antineoplastic agents. However, further trials are needed to fully establish the efficacy of trimetrexate in these settings. Increased knowledge of the pattern of resistance for individual tumours and tumour types may result in trimetrexate becoming more widely used clinically.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Trimetrexato/farmacologia , Trimetrexato/farmacocinética , Animais , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Hospedeiro Imunocomprometido , Estudos Multicêntricos como Assunto , Infecções por Pneumocystis/tratamento farmacológico , Distribuição Tecidual , Toxoplasmose/tratamento farmacológico , Trimetrexato/efeitos adversos , Trimetrexato/uso terapêutico
6.
Ann N Y Acad Sci ; 949: 341-4, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11795373

RESUMO

The Federal Food, Drug, and Cosmetic Act and related regulations (21 U.S.C. 301 et seq.) give FDA staff the legal authority and responsibility to review the safety and effectiveness of drugs and biological products (including products used in cancer treatment), from preclinical testing through all phases of clinical research and marketing. FDA review activities in the oncology arena can be divided into five major categories: (1) initial review of investigational new drug (IND) applications; (2) ongoing review of premarketing research (including new research protocols submitted to existing INDs and IND safety reports describing adverse events with the new drug); (3) discussions with commercial sponsors regarding their clinical development plans, including the design and conduct of key studies that are intended to support initial marketing approval for a new product or to support the addition of new indications to the prescribing information for currently marketed products; (4) review of submitted new drug applications (NDAs) or biological licensing applications (BLAs); and (5) continuing review of the safety and effectiveness of marketed products. Through these review activities, FDA staff work to ensure that products approved for marketing for cancer treatment are effective and adequately safe for their intended uses and to ensure that the quality, effectiveness, and safety of products on the market are preserved or enhanced, so patients and physicians may use these products with confidence and with adequate safety. Because these review activities generally fall into a chronologic sequence, the following discussion parallels the development course of a typical new drug.


Assuntos
Antineoplásicos/normas , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , United States Food and Drug Administration , Humanos , Marketing de Serviços de Saúde/normas , Projetos de Pesquisa , Estados Unidos
7.
Cancer Chemother Pharmacol ; 24(2): 117-22, 1989.
Artigo em Inglês | MEDLINE | ID: mdl-2525077

RESUMO

Based on the synergy of sequential methotrexate (MTX) and 5-fluorouracil (5-FU) in vitro and in vivo and the superior antitumor activity of trimetrexate (TMTX) compared with MTX in preclinical models, we carried out a phase I trial of TMTX and 5-FU (fixed dose, 400 mg/m2 per day), both given as 10-min i.v. infusions daily x 5 days, every 28 days. The TMTX dose was escalated from 3.0 to 14.0 mg/m2 per day. In all, 92 evaluable courses were given to 34 patients, half of whom were heavily pretreated with radiation or cytotoxics. Myelosuppression and mucositis were the dose-limiting toxicities but were not different in heavily or minimally pretreated patients; there were five episodes of moderate to severe mucositis. Rash, fatigue, and diarrhea were mild toxicities. Plasma TMTX elimination was biexponential, with a mean t.1/2 alpha of 0.23 h and a t.1/2 beta of 16.7 h. The area under the plasma TMTX concentration versus time curve increased linearly with dose, suggesting first-order elimination. Total plasma TMTX clearance (mean +/- SD) was 14.3 +/- 5.9 ml/min per m2. Renal clearance accounted for approximately 7% of total clearance, indicating biotransformation as the major route of elimination. TMTX was highly protein-bound (97%). Thus, TMTX can be given with 5-FU (400 mg/m2) on a daily x 5-day bolus schedule at the 12 mg/m2 per day dose level, which was the recommended dose of TMTX as a single agent for phase II studies using the 5-day bolus schedule.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Proteínas Sanguíneas/metabolismo , Cromatografia Líquida de Alta Pressão , Esquema de Medicação , Avaliação de Medicamentos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Meia-Vida , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Mucosa Bucal , Neoplasias/metabolismo , Neutropenia/induzido quimicamente , Ligação Proteica , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Estomatite/induzido quimicamente , Trombocitopenia/induzido quimicamente , Trimetrexato
9.
10.
Yale J Biol Med ; 61(1): 23-34, 1988.
Artigo em Inglês | MEDLINE | ID: mdl-3284210

RESUMO

Fluorouracil has been in clinical use as an anticancer drug for 30 years. Although this drug has a broad spectrum of anticancer activity, including significant activity against the common solid tumors of the gastrointestinal system, only a minority of patients treated with fluorouracil experience an objective response to therapy. Furthermore, in randomized clinical trials completed to date, it has not been possible to demonstrate that fluorouracil therapy significantly prolongs the life span of patients with advanced cancer. Recent laboratory studies have indicated that leucovorin can enhance the cytotoxicity of fluorouracil in vitro, evidently by enhancing inhibition of the key enzyme, thymidylate synthetase, by the fluorouracil metabolite, FdUMP (fluorodeoxyuridine monophosphate; a stable inactive FdUMP-reduced folate-thymidylate synthetase complex is formed). Pilot, uncontrolled studies of leucovorin-fluorouracil combinations have suggested that leucovorin may significantly increase both the clinical efficacy and the clinical toxicity of fluorouracil in cancer patients. These findings have led to the initiation of several randomized, controlled studies of leucovorin plus fluorouracil versus fluorouracil alone in the treatment of patients with advanced colorectal cancer. Three of these studies have recently completed patient accrual, and the preliminary results of each of the three studies indicate that leucovorin-fluorouracil combinations will have a better therapeutic index than fluorouracil used alone in this disease. Further follow-up of these studies will be needed to determine whether leucovorin-fluorouracil combination therapy will prolong the life span of patients with colorectal cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluoruracila/administração & dosagem , Leucovorina/administração & dosagem , Neoplasias/tratamento farmacológico , Ensaios Clínicos como Assunto , Sinergismo Farmacológico , Humanos , Distribuição Aleatória
11.
Proc Natl Acad Sci U S A ; 75(12): 5855-9, 1978 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-282606

RESUMO

Small circular DNAs ranging in contour length from 0.06 to 3.5 micrometers have been isolated from bursas of 19-day chicken embryos and 4- to 5-week-old chickens. Small circular DNA is present in bursas of 19-day embryos at approximately 0.2 molecules per cell and is very heterogeneous, lacking distinct size classes; most molecules have contour lengths of less than 0.04 micrometers. In contrast, small circular DNA is present in bursas of 4- to 5-week old chickens at about 4 molecules per cell, and although this DNA is still heterogeneous, it contains a major distinct class of molecules 0.8 micrometers in size. These small circular DNAs may be products of developmental gene rearrangements occurring in the chromosomal DNA of lymphocytes in the bursa.


Assuntos
Bolsa de Fabricius/crescimento & desenvolvimento , DNA Circular/metabolismo , Animais , Bolsa de Fabricius/imunologia , Bolsa de Fabricius/metabolismo , Embrião de Galinha , Galinhas , DNA Circular/isolamento & purificação , Fígado/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Microscopia Eletrônica , Peso Molecular
12.
Arch Virol ; 54(3): 263-9, 1977.
Artigo em Inglês | MEDLINE | ID: mdl-196580

RESUMO

Human papilloma virus DNA has been examined for heterogeneity by electron microscopy, reassociation kinetics, and restriction endonuclease digestion. No heterogeneity in contour length was detected. The reassociation rate of papilloma DNA isolated from pooled warts was consistent with that expected for a homogeneous, unique DNA of molecular weight 5 X 10(6). Restriction endonuclease digestions of five papilloma DNA preparations isolated from pooled warts yielded predominantly fragments of the expected sizes, but significant quantities of fragments atypical in size were also commonly produced.


Assuntos
DNA Viral/análise , Papillomaviridae/análise , Verrugas/microbiologia , Sequência de Bases , Enzimas de Restrição do DNA/metabolismo , Humanos , Peso Molecular , Conformação de Ácido Nucleico
13.
NCI Monogr ; (5): 105-9, 1987.
Artigo em Inglês | MEDLINE | ID: mdl-2963228

RESUMO

Trimetrexate is a 2,4-diaminoquinazoline inhibitor of dihydrofolate reductase (DHFR) which is cytotoxic in vitro and in vivo to several tumors resistant to methotrexate. It is more lipophilic than the parent antifolate, and is not transported by the reduced folate carrier. These features promise activity greater than that of methotrexate in the clinic; its inability to undergo polyglutamylation may also enhance the therapeutic index. In preclinical models, the activity of trimetrexate was highly schedule dependent, being superior on repeated dose schedules. Phase I studies have demonstrated that myelosuppression is the major toxic effect of trimetrexate on all schedules tested in man. Phase II studies will evaluate a 5-day schedule initially; trials in multiple tumor types and examination of the role of schedule are already under way.


Assuntos
Antagonistas do Ácido Fólico , Neoplasias/tratamento farmacológico , Quinazolinas/uso terapêutico , Animais , Disponibilidade Biológica , Esquema de Medicação , Avaliação de Medicamentos , Humanos , Leucemia P388/tratamento farmacológico , Camundongos , Quinazolinas/farmacocinética , Relação Estrutura-Atividade , Trimetrexato
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