Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Ciclo Celular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Neoplasias/enzimologiaRESUMO
PURPOSE: To define the toxicity profile and the recommended phase II doses of 9-aminocamptothecin (9-AC) administered as a weekly 120-h infusion. METHODS: 9-AC was administered over 120 h weekly to 55 adult cancer patients with solid tumors over doses ranging from 0.41 to 0.77 mg/m2 per day in a phase I and pharmacologic study. 9-AC formulated in dimethylacetamide/polyethylene glycol (DMA) was administered on a 3 of 4-week schedule, and the newer colloidal dispersion (CD) formulation was given on a 2 of 3-week schedule. RESULTS: Overall, 193 courses of therapy were administered over 122 dose levels. On the 3 of 4-week schedule, 9-AC DMA infused at > or = 0.6 mg/m2 per day for 120 h weekly produced dose-limiting neutropenia, thrombocytopenia, and diarrhea, or resulted in 1-2-week treatment delays. Shortening treatments to 2 of 3 weeks resulted in dose-limiting neutropenia and fatigue at infusion rates > 0.72 mg/m2 per day. The ratio of 9-AC lactone to total (carboxylate + lactone) drug plasma concentrations at steady-state was 0.15 +/- 0.07. Clinical toxicities and drug pharmacokinetics were not substantially different between the DMA and CD formulations. One objective response was observed in a patient with bladder cancer and minor responses were observed in patients with lung and colon cancers. Plasma area under the concentration versus time curve for 9-AC lactone modestly correlated with the degree of thrombocytopenia (r=0.51) using a sigmoid Emax pharmacodynamic model. CONCLUSION: The recommended phase II dose for the 9-AC DMA formulation is 0.48 mg/m2 per h over 120 h for 3 of 4 weeks and for the 9-AC CD formulation is 0.6 mg/m2 per day over 120 h for 2 of 3 weeks. Both regimens were well tolerated and feasible to administer.
Assuntos
Antineoplásicos/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/administração & dosagem , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/farmacocinética , Área Sob a Curva , Camptotecina/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Testes Hematológicos , Humanos , Infusões Intravenosas , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Neoplasias/metabolismo , Contagem de PlaquetasRESUMO
BACKGROUND: To determine the cardiotoxicity of paclitaxel (T) plus doxorubicin (A) combination therapy in women with advanced breast cancer. To define a dose range of A for use in AT. PATIENTS AND METHODS: The effect of cumulative A dose on risk of congestive heart failure (CHF) and alterations of myocardial contractility (left ventricular ejection fraction [LVEF] decrease > or = 20% or to <50%) was estimated from pooled data from 10 trials of AT. RESULTS: Thirty-one of 657 patients (4.7%) developed CHF at a median of 6.6 months (range 0.3-24.6) after initiation of AT. CHF was stabilized in 29 patients at a median of 17.3 months after diagnosis (range 4.1-31.2 months). The risk of developing CHF was < or = 5% at a total A dose < or = 380 mg/m2. In patients who received a total A dose > 440 mg/m2, the incidence of CHF was >25% but similar to that of A monotherapy. The risk of CHF was similar in women receiving AT or A monotherapy at a dose < or = 380 mg/m2 (2%-3%). LVEF progressively decreased in patients who received AT, especially at a cumulative A dose > 380 mg/m2. LVEF decreases were more frequent in patients who later developed CHF, but the majority of CHF patients did not experience LVEF alterations prior to symptoms. LVEF recovered after discontinuation of A in 25 of 67 women who developed LVEF < 50%. CONCLUSION: The reported cardiac effects are consistent with anthracycline-related cardiotoxicity. AT is associated with a cardiac risk similar to that of A monotherapy up to a cumulative A dose of 340-380 mg/m2.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Insuficiência Cardíaca/induzido quimicamente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/fisiopatologia , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Estudos Retrospectivos , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
The rapamycin ester, CCI-779, potently inhibits cell growth in vitro, inhibits tumor growth in vivo, and is currently in Phase I clinical trials. To further understand the relationship between plasma systemic exposure and inhibition of the target Ser/Thr kinase, mTOR/FRAP, two assays have been developed. The first assay involves determination of the 4E suppressor protein (4E-BP1) bound to eukaryotic initiation factor 4E (eIF4E), and the second is direct Western analysis of phosphorylation of residue Thr(70) of 4E-BP1. Under normal growth conditions in vitro, rapamycin caused rapid association of 4E-BP1 with eIF4E within 1 h in Rh30 and GC(3) human tumor cells. Association was persistent up to 16 h. In mice, administration of rapamycin (5 or 20 mg/kg) caused rapid association of 4E-BP1 with eIF4E within 4 h in both human colon adenocarcinoma GC(3) and rhabdomyosarcoma Rh30 xenografts. Using phospho-specific antibody against Thr(70) of 4E-BP1, rapid and persistent dephosphorylation within 30 min of exposure to rapamycin was detected in Rh18 rhabdomyosarcoma cells. Evaluation of CCI-779 against Rh18 xenografts showed this tumor to be growth inhibited at daily dose levels of > or =8.7 mg/kg. Because immunoblotting may be more suitable for assaying tumor biopsy tissue, a "blinded" comparison between the effect of CCI-779 on Thr(70) phosphorylation and growth inhibition of human tumor xenografts was undertaken. Mice were treated daily for 5 days with CCI-779 (20 mg/kg/day) or with drug vehicle, and tumor diameters were measured. Tumors were excised 1 h after the final administration and frozen, and phospho Thr(70) was determined by Western blot analysis. The correlation coefficient for decreases in Thr(70) phosphorylation and growth inhibition was high (r(2), 0.99). The results indicate that an assay of decreases in phosphorylation of Thr(70) of 4E-BP1 may be a useful surrogate for determining the inhibition of mTOR activity in tumor specimens.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Sirolimo/farmacologia , Proteínas Adaptadoras de Transdução de Sinal , Adenocarcinoma/metabolismo , Animais , Western Blotting , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular , Divisão Celular , Fator de Iniciação 4E em Eucariotos , Fatores de Iniciação em Eucariotos , Humanos , Immunoblotting , Camundongos , Camundongos Endogâmicos CBA , Transplante de Neoplasias , Fatores de Iniciação de Peptídeos/metabolismo , Fosfoproteínas/metabolismo , Fosforilação , Ligação Proteica , Rabdomiossarcoma/metabolismo , Sirolimo/análogos & derivados , Fatores de Tempo , Células Tumorais CultivadasRESUMO
PURPOSE: To investigate mechanism-directed regimens in maximizing the efficacy of fluorouracil (5-FU) in advanced colorected cancer. PATIENTS AND METHODS: Based on promising phase II data, a randomized comparison of various methods for the biochemical modulation of 5-FU was undertaken in patients with advanced colorectal cancer. The control group received single-agent 5-FU as a 24-hour infusion weekly. Patients (N = 1,120) with no prior chemotherapy for metastatic disease were randomized to one of the following arms: arm A, 5-FU 2,600 mg/m2 by 24-hour infusion, weekly; arm B, N-phosphonoacetyl-l-aspartic acid 250 mg/m2 day l, 5-FU 2,600 mg/m2 by 24-hour infusion day 2, weekly; arm C, 5-FU 600 mg/m2 with oral leucovorin (LV) 125 mg/m2 hourly for the preceding 4 hours, weekly; arm D, 5-FU 600 mg/m2 with intravenous (IV) LV 600 mg/m2, weekly; arm E, 5-FU 750 mg/m2/d IV by continuous infusion for 5 days, then 750 mg/m2 weekly, and recombinant interferon alfa-2a 9 million units subcutaneously three times weekly. Median follow-up was 4.8 years. RESULTS: Of the 1,098 assessable patients, 57% had measurable disease. The toxicity of all the regimens was tolerable. Grade 4 or worse toxicity occurred in 11%, 11%, 30%, 24%, and 22% on each arm, respectively; diarrhea was the most common adverse effect. These toxicity patterns favored significantly (P <.001) the 24-hour infusion arms. Median survival (months) by arm was A, 14.8; B, 11.9; C, 13.5; D, 13.6; and E, 15.2. These survival durations did not differ significantly. CONCLUSION: We conclude that a weekly infusion regimen of 5-FU is significantly less toxic than and as effective as 5-FU bolus regimens modulated by either LV or interferon in patients with metastatic colorectal cancer.
Assuntos
Antineoplásicos/administração & dosagem , Ácido Aspártico/análogos & derivados , Ácido Aspártico/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/administração & dosagem , Interferon-alfa/administração & dosagem , Leucovorina/administração & dosagem , Ácido Fosfonoacéticos/análogos & derivados , Ácido Fosfonoacéticos/administração & dosagem , Administração Oral , Idoso , Neoplasias Colorretais/mortalidade , Feminino , Fluoruracila/efeitos adversos , Humanos , Infusões Intravenosas , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas RecombinantesRESUMO
PURPOSE: To define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of the novel protein kinase inhibitor, UCN-01 (7-hydroxystaurosporine), administered as a 72-hour continuous intravenous infusion (CIV). PATIENTS AND METHODS: Forty-seven patients with refractory neoplasms received UCN-01 during this phase I trial. Total, free plasma, and salivary concentrations were determined; the latter were used to address the influence of plasma protein binding on peripheral tissue distribution. The phosphorylation state of the protein kinase C (PKC) substrate alpha-adducin and the abrogation of DNA damage checkpoint also were assessed. RESULTS: The recommended phase II dose of UCN-01 as a 72-hour CIV is 42.5 mg/m(2)/d for 3 days. Avid plasma protein binding of UCN-01, as measured during the trial, dictated a change in dose escalation and administration schedules. Therefore, nine patients received drug on the initial 2-week schedule, and 38 received drug on the recommended 4-week schedule. DLTs at 53 mg/m(2)/d for 3 days included hyperglycemia with resultant metabolic acidosis, pulmonary dysfunction, nausea, vomiting, and hypotension. Pharmacokinetic determinations at the recommended dose of 42.5 mg/m(2)/d for 3 days included mean total plasma concentration of 36.4 microM (terminal elimination half-life range, 447 to 1176 hours), steady-state volume of distribution of 9.3 to 14.2 L, and clearances of 0.005 to 0.033 L/h. The mean total salivary concentration was 111 nmol/L of UCN-01. One partial response was observed in a patient with melanoma, and one protracted period ( > 2.5 years) of disease stability was observed in a patient with alk-positive anaplastic large-cell lymphoma. Preliminary evidence suggests UCN-01 modulation of both PKC substrate phosphorylation and the DNA damage-related G(2) checkpoint. CONCLUSION: UCN-01 can be administered safely as an initial 72-hour CIV with subsequent monthly doses administered as 36-hour infusions.
Assuntos
Alcaloides/efeitos adversos , Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Adulto , Idoso , Alcaloides/administração & dosagem , Alcaloides/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Dano ao DNA , Relação Dose-Resposta a Droga , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Hiperglicemia/induzido quimicamente , Hipotensão/induzido quimicamente , Infusões Intravenosas , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/patologia , Neoplasias Cutâneas/tratamento farmacológico , Estaurosporina/análogos & derivados , Vômito/induzido quimicamenteRESUMO
Preclinical data suggest that some new anticancer agents directed at novel targets demonstrate tumor growth inhibition but not tumor shrinkage. Such cytostatic agents may offer clinical benefits for patients in the absence of tumor shrinkage. In addition, lower doses of some of these agents may be just as effective as higher doses, implying that toxicity may not be an ideal end point for dose finding. Because of these factors, the sequence and design of traditional phase I, II, and III trials used for cytotoxic agents (which typically shrink tumors and in a dose-dependent manner) may not be appropriate for cytostatic agents. This article discusses options for modifying trial designs to accommodate cytostatic agents. Examples are given where these options have been tried or are currently being tried. Recommendations given for choosing among the trial designs depend on what is known preclinically about the agents (eg, does one have a validated and reproducible biologic end point that can be used to guide a dose escalation?), what is known about the patient population being studied (eg, does one have a well-documented historical progression-free survival rate at 1 year for comparison with the experience of the new agent?), and the numbers of agents and patients available for participation in trials. Planned and ongoing trials will test the utility of some of these new approaches.
Assuntos
Antineoplásicos , Avaliação de Medicamentos/métodos , Projetos de Pesquisa , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Humanos , Tamanho da AmostraRESUMO
PURPOSE: We conducted a phase I and pharmacologic study of a weekly 96-hour infusion of irinotecan to determine the maximum-tolerated dose, define the toxicity profile, and characterize the clinical pharmacology of irinotecan and its metabolites. PATIENTS AND METHODS: In 26 adult patients with solid tumors, the duration and dose rate of infusion were escalated in new patients until toxicity was observed. RESULTS: In 11 patients who were treated with irinotecan at 12.5 mg/m(2)/d for 4 days weekly for 2 of 3 weeks, dose-limiting grade 3 diarrhea occurred in three patients and grade 3 thrombocytopenia occurred in two patients. The recommended phase II dose is 10 mg/m(2)/d for 4 days given weekly for 2 of 3 weeks. At this dose, the steady-state plasma concentration (Css) of total SN-38 (the active metabolite of irinotecan) was 6.42 +/- 1.10 nmol/L, and the Css of total irinotecan was 28.60 +/- 17.78 nmol/L. No patient experienced grade 3 or 4 neutropenia during any cycle. All other toxicities were mild to moderate. The systemic exposure to SN-38 relative to irinotecan was greater than anticipated, with a molar ratio of the area under the concentration curve (AUC) of SN-38 to irinotecan of 0.24 +/- 0.08. One objective response lasting 12 months in duration was observed in a patient with metastatic colon cancer. CONCLUSION: The recommended phase II dose of irinotecan of 10 mg/m(2)/d for 4 days weekly for 2 of 3 weeks was extremely well tolerated. Further efficacy testing of this pharmacologic strategy of administering intermittent low doses of irinotecan is warranted.
Assuntos
Camptotecina/análogos & derivados , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/sangue , Camptotecina/farmacocinética , Camptotecina/farmacologia , Esquema de Medicação , Feminino , Seguimentos , Doenças Hematológicas/induzido quimicamente , Humanos , Infusões Intravenosas , Irinotecano , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/sangue , Vômito/induzido quimicamenteRESUMO
Anticancer cytotoxic agents go through a process by which their antitumor activity-on the basis of the amount of tumor shrinkage they could generate-has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/diagnóstico , Avaliação de Resultados em Cuidados de Saúde/métodos , Biomarcadores Tumorais , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Endoscopia , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Radiografia , Estudos Retrospectivos , Resultado do Tratamento , UltrassonografiaRESUMO
The purpose of this study was to perform a Phase I trial of raltitrexed, a selective inhibitor of thymidylate synthase, and to determine the pharmacokinetic and toxicity profiles as a function of raltitrexed dose. Fifty patients with advanced solid tumors and good performance status were treated with raltitrexed as a 15-min i.v. infusion every 3 weeks, at doses escalating from 0.6 to 4.5 mg/m2. Asthenia, neutropenia, and hepatic toxicity were the most common dose-limiting toxicities in this largely pretreated patient population, but they occurred during the initial cycle in only one of nine patients treated with 4.0 mg/m2 and in two of nine patients treated with 4.5 mg/m2. Only 2 of 13 patients treated with 3.5 mg/m2 ultimately experienced unacceptable toxicity after three and seven cycles, compared with 42 and 56% of patients receiving 4.0 and 4.5 mg/m2 after medians of three and two cycles, respectively. The maximum raltitrexed plasma concentration and the area under the plasma concentration-time curve increased in proportion to dose. Raltitrexed clearance was independent of dose and was associated with the estimated creatinine clearance. Asthenia, neutropenia, and hepatic transaminitis were dose-related and tended to occur more frequently when patients received three or more cycles of therapy. A 3-week treatment interval was feasible in the majority of patients at all doses. Although 4.0 mg/m2 appeared to be a safe starting dose in this pretreated patient population, about half who received two or more courses ultimately experienced dose-limiting toxicity. A dose of 3.5 mg/m2 was well tolerated in most patients.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Quinazolinas/efeitos adversos , Quinazolinas/uso terapêutico , Tiofenos/efeitos adversos , Tiofenos/uso terapêutico , Adulto , Idoso , Antimetabólitos Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Inibidores Enzimáticos/farmacocinética , Feminino , Antagonistas do Ácido Fólico/efeitos adversos , Antagonistas do Ácido Fólico/farmacocinética , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Quinazolinas/farmacocinética , Tiofenos/farmacocinética , Timidilato Sintase/antagonistas & inibidoresRESUMO
Cyclin-dependent kinases (CDKs) have been recognized as key regulators of cell cycle progression. Alteration and deregulation of CDK activity are pathogenic hallmarks of neoplasia. Therefore, inhibitors or modulators would be of interest to explore as novel therapeutic agents in cancer, as well as other hyperproliferative disorders. Flavopiridol is a semisynthetic flavonoid that emerged from an empirical screening program as a potent antiproliferative agent that mechanistic studies demonstrated to directly inhibit CDKs 1, 2, and 4 as a competitive ATP site antagonist. Initial clinical trials have shown that concentrations that inhibit cell proliferation and CDK activity in vitro can be safely achieved in humans, and additional clinical trials will establish its clinical potential. To address the need for additional chemotypes that may serve as lead structures for drugs that would not have the toxicities associated with flavopiridol, compounds with a similar pattern of cell growth inhibitory activity in the National Cancer Institute's in vitro anticancer drug screen have been recognized by the computer-assisted pattern recognition algorithm COMPARE and then screened for anti-CDK activity in a biochemical screen. The benzodiazepine derivative NSC 664704 (7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one) was revealed by that approach as a moderately potent (IC50 0.4 microM) inhibitor of CDK2, which in initial experiments shows evidence of causing cell cycle redistribution in living cells. NSC 664704 is, therefore, a candidate for further structural optimization, guided in part by understanding of the ATP-binding site in CDK2. This approach represents one way of combining empirical screening information with structure-based design to derive novel candidate therapeutic agents directed against an important cellular target.
Assuntos
Antineoplásicos/uso terapêutico , Quinases Ciclina-Dependentes/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Ensaios Clínicos como Assunto , Quinases Ciclina-Dependentes/antagonistas & inibidores , Humanos , Técnicas In VitroRESUMO
A Phase I and pharmacological study of paclitaxel administered as an outpatient, 3-h i.v. infusion just before a 5-day regimen of daily cisplatinum (CP) and a continuous infusion of 5-fluorouracil (5-FU) was performed in patients with advanced solid tumors. A secondary objective was to determine the objective response rate to this regimen. Forty-two patients were enrolled and were evaluable for toxicities. Eighteen patients were previously untreated, whereas the rest had received prior treatment with radiation (J. H. Schiller et al., J. Clin. Oncol., 12: 241-248, 1994), chemotherapy (M. J. Kennedy et al., Clin. Cancer Res., 4: 349-356, 1998), or both modalities (J. H. Schiller et al., J. Clin. Oncol., 12: 241-248, 1994). The paclitaxel dose was escalated from 100-135-170-200-225 to 250 mg/m2, whereas i.v. 5-FU and CP doses were fixed at 1.0 g/m2/day continuous infusion and 20 mg/m2/day, respectively, daily for 5 days. Granulocyte colony-stimulating factor (G-CSF; 5 microg/kg/day) was administered s.c. from day 6, routinely after 250 mg/m2 dose of paclitaxel or after a lower dose of paclitaxel if ANC <500/microl or febrile neutropenia was observed. Patients were treated every 28 days. Plasma and urine samples were collected to determine the pharmacokinetics of paclitaxel. In previously untreated patients, the maximally tolerated dose of paclitaxel in the drug regimen was determined to be 170 mg/m2 without and 250 mg/m2 with G-CSF support. At the higher dose level, mucositis and thrombocytopenia were dose-limiting. In previously treated patients, these toxicities were observed at all dose levels of paclitaxel > or =135 mg/m2. With increasing doses of paclitaxel, a disproportionate increase in the peak concentrations, as well as the area under plasma concentration time-curve, was seen. This nonlinearity was due to saturable total body clearance and volume of distribution of paclitaxel (P < 0.001). The apparent plasma elimination half-life was unaffected by the dose of paclitaxel. CP and 5-FU had no apparent effect on the metabolism of paclitaxel. Among 32 patients evaluable for response, 22 demonstrated an objective response, including five complete remissions. Therefore, a regimen of 3-h infusion of 250 mg/m2 paclitaxel before CP and FU is tolerable with G-CSF (as above) support in previously untreated patients. The regimen also seems to be highly active against breast and esophageal cancers.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Fluoruracila/uso terapêutico , Neoplasias/tratamento farmacológico , Paclitaxel/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Seguimentos , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Pessoa de Meia-Idade , Neoplasias/metabolismo , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinética , Seleção de Pacientes , Resultado do TratamentoAssuntos
Antineoplásicos/farmacologia , Camptotecina/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores da Topoisomerase I , Animais , Antivirais/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , DNA Topoisomerases Tipo I/química , DNA Topoisomerases Tipo I/fisiologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Irinotecano , Radiossensibilizantes/farmacologia , Topotecan/farmacologiaRESUMO
The camptothecins are a new class of antitumor agents that target topoisomerase I. Irinotecan and topotecan are the most widely used camptothecin analogs in clinical practice, with documented clinical activity in colorectal and ovarian cancer. Ongoing clinical trials with these agents are further characterizing their spectra of clinical activity and determining their optimal schedule of administration in combination with other anticancer agents. Newer camptothecin analogs in clinical development, such as 9-aminocamptothecin, 9-nitrocamptothecin, GI1147211, and DX-8951f, are also being studied to determine if they have improved toxicity and efficacy profiles compared with existing analogs. The successful development of the camptothecins as antitumor agents demonstrates the importance of topoisomerase 1 as a target for cancer chemotherapy.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , DNA Topoisomerases Tipo I/fisiologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Inibidores da Topoisomerase I , Topotecan/farmacologia , Topotecan/uso terapêutico , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , IrinotecanoRESUMO
PURPOSE: We conducted a phase I trial of the cyclin-dependent kinase inhibitor, flavopiridol (National Service Center [NSC] 649890), to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacology of flavopiridol given as a 72-hour infusion every 2 weeks. PATIENTS AND METHODS: Seventy-six patients with refractory malignancies with prior disease progression were treated with flavopiridol, with first-cycle pharmacokinetic sampling. RESULTS: Forty-nine patients defined our first MTD, 50 mg/m2/d x 3 with dose-limiting toxicity (DLT) of secretory diarrhea at 62.5 mg/kg/d x 3. Subsequent patients received antidiarrheal prophylaxis (ADP) to define a second MTD, 78 mg/m2/d x 3 with DLT of hypotension at 98 mg/m2/d x 3. Other toxicities included a proinflammatory syndrome with alterations in acute-phase reactants, particularly at doses >50 mg/ m2/d x 3, which in some patients prevented chronic therapy every 2 weeks. In some patients, ADP was not successful, requiring dose-deescalation. Although approximately 70% of patients displayed predictable flavopiridol pharmacology, we observed unexpected interpatient variability and postinfusion peaks in approximately 30% of cases. At the two MTDs, we achieved a mean plasma flavopiridol concentration of 271 nM (50 mg/m2/d x 3) and 344 nM (78 mg/m2/d x 3), respectively. One partial response in a patient with renal cancer and minor responses (n=3) in patients with non-Hodgkin's lymphoma, colon, and renal cancer occurred. CONCLUSION: The MTD of infusional flavopiridol is 50 mg/m2/d x 3 with dose-limiting secretory diarrhea at 62.5 mg/m2/d x 3. With ADP, 78 mg/m2/d x 3 was the MTD, with dose-limiting hypotension at 98 mg/m2/d x 3. Based on chronic tolerability, 50 mg/m2/d x 3 is the recommended phase II dose without ADP. Antitumor effect was observed in certain patients with renal, prostate, and colon cancer, and non-Hodgkin's lymphoma. Concentrations of flavopiridol (200 to 400 nM) needed for cyclin-dependent kinase inhibition in preclinical models were achieved safely.
Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Flavonoides/uso terapêutico , Neoplasias/tratamento farmacológico , Piperidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Quinases Ciclina-Dependentes/antagonistas & inibidores , Diarreia/induzido quimicamente , Relação Dose-Resposta a Droga , Esquema de Medicação , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Flavonoides/efeitos adversos , Flavonoides/farmacocinética , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Piperidinas/farmacocinéticaRESUMO
UCN-01 (7-hydroxystaurosporine; NSC 638850) is a protein kinase antagonist selected for clinical trial based in part on evidence of efficacy in a preclinical renal carcinoma xenograft model. Schedule studies and in vitro studies suggested that a 72-h continuous infusion would be appropriate. In rats and dogs, maximum tolerated doses produced peak plasma concentrations of approximately 0.2-0.3 microM. However, concentrations 10-fold greater are well tolerated in humans, and the compound has a markedly prolonged T1/2. Specific binding to human alpha1-acidic glycoprotein has been demonstrated. These findings reinforce the need to consider actual clinical pharmacology data in "real time" with phase I studies.
Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Proteína Quinase C/antagonistas & inibidores , Adulto , Alcaloides/farmacocinética , Alcaloides/toxicidade , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Proteínas Sanguíneas/metabolismo , Cromatografia Líquida de Alta Pressão , Cães , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/toxicidade , Humanos , Infusões Intravenosas , Camundongos , Camundongos Nus , Ligação Proteica , Ratos , Estaurosporina/análogos & derivados , Transplante Heterólogo/imunologiaRESUMO
Colorectal cancer will be diagnosed in approximately 150,000 patients in the USA this year. Chemotherapy has recently been shown to improve survival when given as adjuvant therapy to surgery in patients with stage III colorectal cancer. Demonstration of this benefit required large, randomized controlled trials. Either 5-fluorouracil (5-FU) and leucovorin for 6 months or 5-FU and levamisole for 12 months are currently considered standard adjuvant treatment for stage III colorectal cancer. However, current adjuvant trials are comparing continuous infusion and intravenous bolus 5-FU regimens and oral uracil/Ftorafur with intravenous 5-FU and leucovorin, as well as studying the timing of chemotherapy in the adjuvant setting. Subsequent adjuvant trials will examine newer regimens with activity in advanced colorectal cancer, as well as the efficacy of monoclonal antibodies. Other trials will study which type of surgery is optimal and whether adjuvant therapy is helpful in stage II colon cancer. Trials in metastatic disease will focus on combinations of newer agents which may improve survival in this patient group. Studies in rectal cancer will focus on determining which agents are optimal in combination with radiation therapy in the adjuvant setting. Molecular characteristics of tumor cells are being defined, which may guide therapy in the future. Careful, logically designed clinical trials will hopefully provide more efficacious therapy for this common cancer.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto/tendências , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/uso terapêutico , National Institutes of Health (U.S.) , Humanos , Estados UnidosRESUMO
The camptothecin topoisomerase I-targeting agents are new class of antitumor drugs with demonstrated clinical activity in human malignancies, such as colorectal cancer and ovarian cancer. Currently, irinotecan and topotecan are the most widely used camptothecin analogs in clinical use and clinical trials are ongoing to better characterize their spectra of clinical activity, to determine their optimal schedules of administration and to define their use in combination with other chemotherapeutic agents. Newer camptothecin analogs in clinical development, such as 9-aminocamptothecin, 9-nitrocamptothecin, GI147211 and DX-8951f, are also being studied to determine if they have improved toxicity and efficacy profiles compared with existing analogs. Other potential clinical applications include the use of camptothecin derivatives as radiation sensitizers or as antiviral agents. The successful development of the camptothecins as antitumor agents highlights the importance of topoisomerase I as a target for cancer chemotherapy.
Assuntos
Camptotecina/uso terapêutico , Inibidores da Topoisomerase I , Antineoplásicos/química , Antineoplásicos/farmacocinética , Camptotecina/análogos & derivados , Ensaios Clínicos Fase I como Assunto , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Estrutura MolecularRESUMO
The pharmacokinetics of UCN-01 after administration as a 72- or 3-h infusion to cancer patients in initial Phase I trials displayed distinctive features that could not have been predicted from preclinical data. The distribution volumes (0.0796-0.158 liters/kg) and the systemic clearance (0.0407-0.252 ml/h/kg) were extremely low, in contrast to large distribution volume and rapid systemic clearance in experimental animals. The elimination half-lives (253-1660 h) were unusually long. In vitro protein binding experiments demonstrated that UCN-01 was strongly bound to human alpha1-acid glycoprotein. The results suggest that unusual pharmacokinetics of UCN-01 in humans could be due, at least in part, to its specifically high binding to alpha1-acid glycoprotein.
Assuntos
Alcaloides/farmacocinética , Alcaloides/uso terapêutico , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Orosomucoide/metabolismo , Alcaloides/sangue , Animais , Antineoplásicos/sangue , Cães , Esquema de Medicação , Humanos , Infusões Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ligação Proteica , Ratos , Albumina Sérica/metabolismo , Estaurosporina/análogos & derivados , Especificidade por SubstratoRESUMO
9-Aminocamptothecin (9-AC) is a camptothecin derivative with broad antitumor activity in preclinical studies. Prior investigations suggested that prolonged maintenance of 9-AC lactone plasma concentrations above 10 nmol/l and frequent administration of the drug are important determinants of antitumor activity. Our phase II study, therefore, examined a 5-day continuous infusion of 9-AC weekly for 3 weeks in patients with advanced colorectal cancer. Eighteen patients previously untreated for metastatic disease received 480 microg/m2/day of 9-AC. No responses were observed in 17 evaluable patients. Severe toxicities included granulocytopenia, nausea, vomiting and diarrhea. The median absolute granulocyte count (AGC) nadir was 2,300/microl (range 0-9,000/microl) and occurred on day 10. Eight patients received an escalated dose of 600 microg/m2/day. The median AGC nadir at the escalated dose was 1,500/microl (range: 300-2,700/microl) and occurred on day 22. The median number of courses given was 2 (range: 1-8); and the median time to disease progression was 8 weeks (range: 1-40 weeks). 9-AC administered by this schedule lacked antitumor activity in patients with advanced colorectal carcinomas.