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3.
Obstet Gynecol ; 118(5): 1169-1173, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22015888

RESUMO

A little more than half a century ago, young women were frequently dying of reproductive sequelae such as ectopic pregnancies and gestational trophoblastic disease. Mortality from these conditions was as high as 90% in the case of metastatic choriocarcinoma. If lives could be saved, it was in the operating theater and often at the expense of future reproductive potential. By the 1940s, however, targeted chemotherapy was starting to be explored, and the development of methotrexate for the treatment of childhood leukemia in 1949 eventually resulted in an unexpected, but nevertheless long and happy association with the field of gynecology. Here we trace the origins of methotrexate and how it came to be an effective medical treatment for two life-threatening gynecologic conditions. It illustrates how the contributions of many clinicians and scientists from many disciplines, over the greater part of a century, come together to improve the care of a single patient today.


Assuntos
Antimetabólitos Antineoplásicos/história , Neoplasias dos Genitais Femininos/história , Ginecologia/história , Metotrexato/história , Gravidez Ectópica/história , Antimetabólitos Antineoplásicos/uso terapêutico , Feminino , Neoplasias dos Genitais Femininos/tratamento farmacológico , História do Século XX , Humanos , Metotrexato/uso terapêutico , Gravidez , Gravidez Ectópica/tratamento farmacológico
4.
Jpn J Clin Oncol ; 39(1): 2-15, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19052037

RESUMO

Dushinsky et al. left a great gift to human beings with the discovery of 5-fluorouracil (5-FU). Approximately 50 years have elapsed from that discovery to the development of S-1 (TS-1). The concept of developing an anticancer agent that simultaneously possesses both efficacy-enhancing and adverse reaction-reducing effects could be achieved only with a three-component combination drug. S-1 is an oral anticancer agent containing two biochemical modulators for 5-FU and tegafur (FT), a metabolically activated prodrug of 5-FU. The first modulator, 5-chloro-2,4-dihydroxypyridine (CDHP), enhances the pharmacological actions of 5-FU by potently inhibiting its degradation. The second modulator, potassium oxonate (Oxo), localizing in mucosal cells of the gastrointestinal (GI) tract after oral administration, reduces the incidence of GI toxicities by suppressing the activation of 5-FU in the GI tract. Thus, S-1 combines FT, CDHP and Oxo at a molar ratio of 1:0.4:1. In 1999-2007, S-1 was approved for the treatment of the following seven cancers: gastric, head and neck, colorectal, non-small cell lung, breast, pancreatic and biliary tract cancers. 'S-1 and low-dose cisplatin therapy' without provoking Grade 3 non-hematologic toxicities was proposed to enhance its clinical usefulness. Furthermore, 'alternate-day S-1 regimen' may improve the dosing schedule for 5-FU by utilizing its strongly time-dependent mode of action; the former is characterized by the low incidences of myelotoxicity and non-hematologic toxicities (e.g. < or =Grade 1 anorexia, fatigue, stomatitis, nausea, vomiting and taste alteration). These two approaches are considered to allow long-lasting therapy with S-1.


Assuntos
Antimetabólitos Antineoplásicos/história , Ácido Oxônico/história , Tegafur/história , Animais , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/farmacologia , Combinação de Medicamentos , Fluoruracila/história , História do Século XX , História do Século XXI , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/história , Ácido Oxônico/farmacocinética , Ácido Oxônico/farmacologia , Tegafur/farmacocinética , Tegafur/farmacologia
6.
Cancer ; 112(11): 2341-51, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18398832

RESUMO

Decitabine (5-aza-2'-deoxycytidine) is a hypomethylating agent with a dual mechanism of action: reactivation of silenced genes and differentiation at low doses, and cytotoxicity at high doses. The original studies in the 1980s used decitabine as a classical anticancer drug, at its maximum clinically tolerated dose, 1500 to 2500 mg/m(2) per course. At these doses, decitabine was found to be active in leukemia, but was associated with delayed and prolonged myelosuppression. After a better understanding of epigenetics in cancer and the role of decitabine in epigenetic (hypomethylating) therapy was gained, it was reevaluated at approximately 1/20th of the previous doses (ie, at 'optimal biologic' doses that modulate hypomethylation). In these dose schedules of decitabine (100 to 150 mg/m(2) per course), the drug was found to be active with manageable side effects in patients with myelodysplastic syndromes (MDS) and other myeloid tumors. Optimizing dosing schedules of decitabine to maximize hypomethylation (low dose, high dose intensity, and multiple cycles) have further improved results, suggesting that decitabine is an active therapy that alters the natural course of MDS. Combination therapies that augment the epigenetic effect of decitabine will likely improve responses and extend its use for the treatment of other malignancies.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Azacitidina/análogos & derivados , Antimetabólitos Antineoplásicos/história , Antimetabólitos Antineoplásicos/farmacocinética , Azacitidina/história , Azacitidina/farmacocinética , Azacitidina/farmacologia , Ensaios Clínicos como Assunto , Decitabina , Avaliação Pré-Clínica de Medicamentos , História do Século XX , História do Século XXI , Humanos , Síndromes Mielodisplásicas/tratamento farmacológico
7.
Hematol Oncol Clin North Am ; 20(5): 1087-97, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16990109

RESUMO

Cladribine is effective therapy for HCL, and there are several ways to achieve the adequate concentrations of the active metabolites in relevant cells, without the need for long-term continuous infusions. This simplifies therapy, although careful control of patients is required during and after treatment in most instances because of the significant activity of the drug on leukemia cells of various types and also on lymphoid cells and normal stem cells.


Assuntos
Adenosina/análogos & derivados , Adenosina/farmacocinética , Antimetabólitos Antineoplásicos/farmacocinética , Leucemia de Células Pilosas/tratamento farmacológico , Adenosina/história , Adenosina/uso terapêutico , Adenosina Desaminase/metabolismo , Inibidores de Adenosina Desaminase , Antimetabólitos Antineoplásicos/história , Antimetabólitos Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Desoxicitidina Quinase/antagonistas & inibidores , Desoxicitidina Quinase/metabolismo , História do Século XX , História do Século XXI , Humanos , Leucemia de Células Pilosas/enzimologia , Leucemia de Células Pilosas/história , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo
9.
Gynecol Oncol ; 89(2): 193-8, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12765173

RESUMO

Dr. Roy Hertz is one of two scientists credited with discovering the first medical cure of a solid cancer. This paper presents a biographical history of Dr. Hertz and discusses his roles in the discovery of a cure for choriocarcinoma and as a pioneer for future research in cancer chemotherapy. This biography not only serves as a testament to the pioneering individuals in the field of chemotherapeutics but also represents the unique blend of medical, pharmacological, and physiological histories that led to the profound discovery. The timing and significance of the work of Drs. Hertz and Li cannot be overestimated. Their discovery was a spectacular success, demonstrating proof of the principle that chemotherapy can cure metastatic cancer and that an almost uniformly fatal cancer in young patients could be cured with a single chemotherapeutic agent, which stands as one of the greatest achievements in cancer research.


Assuntos
Antimetabólitos Antineoplásicos/história , Coriocarcinoma/história , Metotrexato/história , Antimetabólitos Antineoplásicos/uso terapêutico , Coriocarcinoma/tratamento farmacológico , Coriocarcinoma/secundário , História do Século XX , Humanos , Oncologia/história , Metotrexato/uso terapêutico , National Institutes of Health (U.S.)/história , Estados Unidos
10.
Curr Pharm Biotechnol ; 1(2): 137-64, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11467334

RESUMO

The role of oral chemotherapy has been getting expanded because of the potential advantage in patients' convenience and better quality of life as well as in cost-effectiveness as compared with intravenous chemotherapy. In this article, the history, mechanism of anti-tumor activity, and clinical use of oral chemotherapy using 5-fluorouracil (5-FU) derivative chemotherapeutic agents are reviewed. Pharmacological analysis has revealed that 5-FU, a basic chemotherapeutic agent widely used against a variety of malignant tumors, shows a time dependent anti-tumor activity, and that continuous maintenance of 5-FU concentration in blood is the optimal method in 5-FU administration. UFT, a combination drug of ftorafur (tetrahydrofuranyl-5-fluorouracil, tegafur, FT) and uracil, has been developed to have potent anti-tumor activity by maintaining higher 5-FU concentration in blood and tumor tissues for a long time. FT is a pro-drug that releases 5-FU continuously, and uracil is added to inhibit degradation of the released 5-FU. Clinically, oral administration of UFT has proved to be effective as an adjuvant therapy after surgery for some malignant tumors such as non-small cell lung cancer. Moreover, UFT has proved to be effective for inoperable advanced malignancies such as colorectal cancer, especially in combination with leucovorin or cisplatin. Recently, S-1, a more active oral 5-FU derivative chemotherapeutic agent has been developed in Japan. Several factors to affect anti-tumor effects and/or toxicities of 5-FU and the derivatives, such as thymidylate synthase activity, dehydropyrimidine dehydrogenase activity and p53 status, are also discussed in the article. In conclusion, oral administration of 5-FU derivatives such as UFT may have several clinical advantages over intravenous 5-FU administration.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Fluoruracila/análogos & derivados , Fluoruracila/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antimetabólitos Antineoplásicos/história , Antimetabólitos Antineoplásicos/farmacologia , Fluoruracila/história , Fluoruracila/farmacologia , História do Século XX , Humanos , Neoplasias/história
11.
Oncology (Williston Park) ; 12(10 Suppl 7): 19-22, 1998 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9830620

RESUMO

The cycle-specific schedule-dependent antimetabolite 5-fluorouracil (5-FU) has been in clinical use for 40 years and has evolved as an important agent in the treatment of a large spectrum of tumors, including all gastrointestinal cancers, breast cancer, head and neck cancer, and bladder cancer. Over these 4 decades, there has been an increased understanding of the optimal method and schedule of administration of 5-FU. Furthermore, the concept of pharmacomodulation and biochemical modulation of 5-FU to increase therapeutic efficacy has emerged as a new strategy in cancer chemotherapy. The specific mechanism by which 5-FU induces lethal injury may vary depending on the administration schedule or the type of biochemical modulation applied. The optimal infusion duration and dose intensity of 5-FU continues to be debated as does the question of the need for biochemical modulation when using infusional schedules. Infusional administration of 5-FU has become the gold standard in the treatment of head and neck cancer, esophageal cancer, gastric cancer (in Great Britain), and rectal and anal cancer. The recent availability of oral formulations for 5-FU in conjunction with the capability of manipulating the metabolism of 5-FU, particularly with dihydropyrimidine dehydrogenase (DPD) inhibitors, may provide a substantial incremental improvement in these therapies by eliminating the need for parenteral administration and the use of ambulatory infusion pumps.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Fluoruracila/administração & dosagem , Administração Oral , Antimetabólitos Antineoplásicos/história , Ensaios Clínicos Fase III como Assunto , Fluoruracila/história , História do Século XX , Humanos , Infusões Intravenosas , Injeções Intravenosas
12.
Chem Biol Interact ; 111-112: 239-54, 1998 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-9679558

RESUMO

L-S,R-buthionine sulfoximine (L-S,R BSO) is a potent specific inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting step in glutathione (GSH) biosynthesis. GSH is an important component of tumor drug resistance based on a strong association and recent transfection studies. Depletion of intracellular GSH by BSO significantly enhances the cytotoxicity of many cytotoxic agents, principally alkylating agents and platinating compounds but also irradiation and anthracyclines. Phase I clinical trials of BSO + melphalan (L-PAM)have been carried out and observed little toxicity with BSO alone and increased myelosuppression with BSO + L-PAM. Consistent and profound (< 10% of control) GSH depletion was observed in serial determinations of tumor GSH levels in patients receiving continuous infusion (CI) BSO. Evidence of clinical activity has been observed in patients with alkylating or platinating agent-refractory tumors. Phase II evaluation of CI BSO with L-PAM is in progress.


Assuntos
Butionina Sulfoximina/história , Animais , Antimetabólitos Antineoplásicos/história , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Butionina Sulfoximina/uso terapêutico , Resistência a Medicamentos , Inibidores Enzimáticos/história , Inibidores Enzimáticos/uso terapêutico , Feminino , Glutamato-Cisteína Ligase/antagonistas & inibidores , História do Século XX , Humanos , Masculino , Melfalan/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo
13.
Semin Oncol ; 24(5 Suppl 18): S18-3-S18-7, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9420015

RESUMO

Since the clinical introduction of 5-fluorouracil (5-FU) in 1958, improvements in the treatment of advanced colorectal cancer have been modest. However, improvements in response rates have been demonstrated when 5-FU is administered in conjunction with leucovorin, and when methotrexate or trimetrexate is administered preceding 5-FU, indicating that higher response rates could be achieved by biomodulating the activity of 5-FU. Thus, significant emphasis has been placed on designing more effective 5-FU-based combination regimens. Novel agents, including the thymidylate synthase inhibitor raltritrexed and the topoisomerase I inhibitor irinotecan, also have demonstrated activity in colorectal cancer. Other new approaches include the administration of oral 5-FU prodrugs. The development of novel agents, new therapeutic approaches, and the refinement of existing agents and regimens in the clinic will likely improve response rates and, ultimately, patient survival. The history, current treatment options, and future opportunities for advances in chemotherapy for the treatment of colorectal cancer are discussed.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/uso terapêutico , Pró-Fármacos/uso terapêutico , Animais , Antimetabólitos Antineoplásicos/história , Antimetabólitos Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Floxuridina/história , Floxuridina/farmacologia , Floxuridina/uso terapêutico , Fluoruracila/história , Fluoruracila/farmacologia , História do Século XX , Humanos , Pró-Fármacos/história , Pró-Fármacos/farmacologia , Uridina/análogos & derivados , Uridina/história , Uridina/farmacologia , Uridina/uso terapêutico
14.
Pediatr. día ; 10(1): 53-5, mar.-abr. 1994.
Artigo em Espanhol | LILACS, MINSALCHILE | ID: lil-135487

RESUMO

Serendipia: palabra derivada de serendipity en inglés original, acuñada por el investigador Horace Walpole en 1574, y que provenía a su vez de un antiguo cuento de Ceilán, Los tres príncipes de Serendip, de los que se decía estaban siempre haciendo descubrimientos, por accidente y sagacidad, de cosas que no se habían planteado. Actualmente, este término define a los descubrimientos accidentales de la ciencia


Assuntos
Humanos , Antibióticos Antineoplásicos/história , Antimetabólitos Antineoplásicos/história , Leucemia/história , Leucemia/tratamento farmacológico , Linfoma/história , Linfoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico
15.
Adv Exp Med Biol ; 339: 277-87; discussion 289-90, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8178723

RESUMO

The antifolate thymidylate synthase inhibitors represent an exciting area in new drug development and show that with an understanding of the structural basis for toxicity, new drugs can be synthesised which have a more manageable spectrum of side effects whilst retaining activity. ICI D1694 does not show the nephrotoxicity which affected the development of CB 3717. Myelosuppression and gut toxicity are seen and are more typical of the toxicities one associates with this class of agent. Changes in hepatic enzymes have been seen with both drugs, and are also seen with other anti-folates including MTX, but these changes settle with repeat dosing and with cessation of treatment. We await the results of the planned phase II trials of ICI D1694 with great interest.


Assuntos
Antimetabólitos Antineoplásicos/história , Ácido Fólico/análogos & derivados , Quinazolinas/história , Tiofenos/história , Timidilato Sintase/antagonistas & inibidores , Animais , Ensaios Clínicos Fase I como Assunto , Ácido Fólico/história , História do Século XX , Estrutura Molecular , Reino Unido
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