RESUMEN
A phase I study with TUT-7, a new anthracycline antitumor antibiotic, was conducted in 35 malignant tumor patients at 11 institutions nationwide. The study was initiated with a single dose at 100 mg/body which was equivalent to 2n, then the dose as escalated up to 700 mg/body in accordance with the modified Fibonacci's scheme. The dose limiting factor (DLF) was considered to be leukopenia, and maximum tolerated dose (MTD) was 700 mg/ body. The consecutive days dosing study subsequently conducted started with 25 mg/body/day, and the dose level was escalated up to 150 mg /body/day. TUT-7 was orally administered for seven (7) to fourteen (14) consecutive days in principle. It was considered that DLF was leukopenia and MTD was 100 mg/body/day for consecutive days dosing. The study indicated that serum drug concentrations reached their plateaus on the 5th day after initiation of TUT-7 treatment and the accumulation of this compound was low. With these findings, a regimen with a dose of 100 mg/body/day orally administered for 14 consecutive days was recommended for early phase II studies.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Menogaril/administración & dosificación , Neoplasias/tratamiento farmacológico , Administración Oral , Anciano , Antibióticos Antineoplásicos/sangre , Antibióticos Antineoplásicos/farmacocinética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Esquema de Medicación , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Menogaril/sangre , Menogaril/farmacocinética , Persona de Mediana Edad , Neoplasias/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismoRESUMEN
We have conducted Phase I study of a novel oral antitumor agent of fluorinated pyrimidines, S-1, in which tegafur (FT) is combined with two classes of modulator, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio of FT:CDHP:Oxo = 1:0.4:1 as a multi-center study with 16 institutions nationwide. Two administration methods, once and twice daily administrations, were evaluated. As a result, MAD was determined as 150 mg/body/day approximately 200 mg/body/day and 75 mg/body x2/day approximately 100 mg/body x2/day, respectively. DLF was myelosuppression, mainly consisting of leukopenia in the two administrations. Most adverse reactions observed, including myelosuppression, disappeared by discontinuation of administration, and recovery was in about 2 weeks. Adverse reactions other than myelosuppression which induced the discontinuation were rash and vomiting. Other adverse reactions observed were anorexia, malaise, diarrhea and stomatitis. Diarrhea and stomatitis were mild (Grade 1), except those observed at a dose of 200 mg/body/day, and did not induce discontinuation of administration. Based on these findings and pharmacokinetic evaluation, the recommended dose and administration for Early Phase II studies were determined as twice daily administration of 75 mg/body for 28 consecutive days with 14 days rest (1 course).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Administración Oral , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Esquema de Medicación , Combinación de Medicamentos , Femenino , Fluorouracilo/sangre , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Ácido Oxónico/administración & dosificación , Ácido Oxónico/farmacocinética , Piridinas/administración & dosificación , Piridinas/farmacocinética , Tegafur/administración & dosificación , Tegafur/farmacocinéticaRESUMEN
Retinal degeneration induced by a single intraperitoneal injection of N-methyl-N-nitrosourea (MNU) in male and female albino (GRS/A and DDD/1) and colored (C57BL) mice at 7 weeks of age was examined morphologically 1, 3, 7, 14 and 21 days after the treatment. A dose of 60 mg/kg body weight evoked progressive retinal degeneration in all mice. All albino and colored mice had a comparable progression of photoreceptor cell degeneration by an apoptotic mechanism, as confirmed by morphological and TUNEL methods. Apoptosis had already taken place 1 day after the treatment and was completed by Day 7. This process resulted in a thin remnant of retina with complete loss of photoreceptor cells-21 days after the treatment. During the course of apoptosis, the pigment epithelial cells were maintained in a continuous layer in all strains of mice. In colored mice, several layers of the swollen pigment-enriched cells were seen between the inner nuclear layer and the pigment epithelial layer 14 and 21 days after the treatment. In summary, the destruction of photoreceptor cells by the apoptotic process was the mechanism by which retinal degeneration was induced by MNU.
Asunto(s)
Apoptosis/efectos de los fármacos , Metilnitrosourea/farmacología , Mutágenos/farmacología , Células Fotorreceptoras/efectos de los fármacos , Animales , Fragmentación del ADN , Nucleótidos de Desoxiuracil , Digoxigenina , Femenino , Inyecciones Intraperitoneales , Masculino , Ratones , Ratones Endogámicos C57BL , Necrosis , Degeneración Nerviosa/efectos de los fármacos , Degeneración Nerviosa/fisiología , Células Fotorreceptoras/citología , Células Fotorreceptoras/patología , Coloración y EtiquetadoRESUMEN
LY188011 (Gemcitabine hydrochloride) is a new derivative of deoxycytidine. Phase I study was carried out by a cooperative study group. LY188011 was administered weekly for 3 consecutive weeks starting with an initial dose of 60 mg/m2 (1n) and then increasing the dosage to 1,000 mg/m2 (16.7n). Dose limiting factor was found to be myelosuppression (decreases of WBC, neutrophils and platelet), and MTD was considered to be 1,000 mg/m2. The nadir of WBC and platelet were observed after about 1-3 weeks. It took 1-2 weeks for their recovery. Other adverse reactions included fever, fatigue, anorexia, nausea/vomiting, anemia and transient elevations of GOT and GPT. However, those adverse reactions were mild. T1/2 rho of plasma concentration was about 19 min and the C5min was dependent on the dose. Anti-cancer effects were observed in one gastric cancer and two colon cancer patients. It is recommended that the dosing schedule for an early phase II study is 800 mg/m2 weekly for 3 weeks with 1 week of rest as one cycle, in multiple cycles.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Desoxicitidina/análogos & derivados , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anorexia/inducido químicamente , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Médula Ósea/efectos de los fármacos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Esquema de Medicación , Fatiga/inducido químicamente , Femenino , Fiebre/inducido químicamente , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Vómitos/inducido químicamente , GemcitabinaRESUMEN
The histoculture drug-response assay (HDRA) was recently evaluated in a retrospective clinical trial and was found to correlate to drug sensitivity, resistance, and patient survival. To further investigate the potential of HDRA to contribute to patient survival, 215 patients with gastric cancer from 45 medical centers were tested with the HDRA in a blinded study after resection of the primary lesion. One hundred sixty-eight patients received at least 20 mg/m2 of mitomycin C and a minimum of 30 g UFT, a mixture of tegafur and uracil at a molar ratio of 1:4, thereby making them eligible for the study. Of these cases 128 were evaluable by the HDRA. The evaluable patient tumors were tested by the HDRA with the [3H]thymidine incorporation end point measured by microautoradiography to be drug "sensitive" or "resistant." The in vitro conditions for distinguishing sensitivity and resistance that matched the response rates for historical controls for gastric carcinoma were 90% inhibition rate and 0.12 microgram/ml for mitomycin C and 70% inhibition rate and 1 microgram/ml for 5-fluorouracil, respectively. Most importantly in the blinded study, the overall and disease-free survival rates of the HDRA-sensitive group were found to be significantly higher than those of the HDRA-resistant group tested under the above conditions. The data further indicate the importance of three-dimensional tumor culture for obtaining accurate clinical information. The results demonstrate that the HDRA response correlates to patient survival, which suggests the potential of the HDRA to contribute to patient survival in gastric cancer when used prospectively.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/mortalidad , Ensayo de Tumor de Célula Madre/métodos , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Resistencia a Antineoplásicos , Femenino , Fluorouracilo/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Mitomicina/administración & dosificación , Análisis Multivariante , Estudios Prospectivos , Tasa de Supervivencia , Tegafur/administración & dosificación , Uracilo/administración & dosificaciónRESUMEN
The effectiveness of the direct application of crystalline N-methyl-N-nitrosourea (MNU) onto the mammary gland was compared with the systemic intraperitoneal (i.p.) administration method for the induction of mammary carcinomas in female Sprague-Dawley (S-D) rats. The effectiveness was also tested in genetically resistant female Copenhagen (Cop) rats. The 10 mg crystalline MNU was dusted directly onto the right-inguinal mammary gland, or 50 mg/kg body weight MNU solution was given i.p. at 50 days of age. Animals were palpated for tumor detection twice weekly and killed when the tumor reached 1-2 cm in diameter or were necropsied 30 weeks after carcinogen treatment. In S-D rats, all of the 78 tumors produced by dusting were adenocarcinomas. By contrast, 40 tumors produced i.p. were adenocarcinomas, 1 was fibroadenoma, and 5 were lactating adenomas. The cumulative incidence of mammary carcinoma was high in the dusting and the i.p. groups (12/12; 100% and 11/13; 84%, respectively). However, the dusting groups showed a high number of carcinoma per rats (6.5 vs. 3.6; P < 0.01) and short cancer latency (13.8 weeks v.s. 28.1 weeks; P < 0.001) than the i.p. groups. In Cop rats, although low (4/11; 36%), adenocarcinomas were developed by the dusting method. In both strains, adenocarcinomas displayed various degrees of differentiation but no evidence was found for metastasis. For MNU-administration, the direct dusting technique is an effective method and offers added advantages of ease for the induction of mammary carcinomas in rats.
Asunto(s)
Adenocarcinoma/inducido químicamente , Neoplasias Mamarias Experimentales/inducido químicamente , Metilnitrosourea/administración & dosificación , Adenocarcinoma/patología , Animales , Cristalización , Femenino , Inmunohistoquímica , Inyecciones Intraperitoneales , Neoplasias Mamarias Experimentales/patología , Metilnitrosourea/toxicidad , Ratas , Ratas Sprague-DawleyRESUMEN
Formalin fixed autopsy tissue containing lipids were cut into 1-5 mm thick blocks, washed well, then postfixed in 2% OsO4 in 0.03 M veronal acetate buffer for 30, 60, 90, 120, or 180 min with or without ultrasonic treatment. Tissues exposed to ultrasound for 90 min showed superior penetration of OsO4 and well preserved histological architecture. Tissues also were immersed for 1 hr in veronal acetate buffer (pH 7.4) containing 0.5% imidazole or triazole and compared with untreated controls. Paraffin sections, 4 microns thick, were examined under a light microscope with an image analyzer. Both intensity and percentage area of osmium blackening were significantly higher in samples immersed in imidazole or triazole than in untreated controls. No difference was observed between imidazole- and triazole-immersed samples. The OsO4 method, modified by ultrasound treatment and imidazole- or triazole-immersion, can be applied to routine formalin fixed autopsy materials for improved lipid visualization.
Asunto(s)
Histocitoquímica/métodos , Imidazoles , Lípidos/análisis , Tetróxido de Osmio , Triazoles , Hígado Graso/metabolismo , Humanos , Hígado/química , Proteolípidos/análisis , Coloración y Etiquetado , Fijación del Tejido , UltrasonidoRESUMEN
An early phase II study of MST-16 for breast cancer was conducted with the participation of 9 hospitals. MST-16 was administered at three doses; 1) 1,600 mg/body for 5 consecutive days repeating every 4 weeks, 2) 1,200 mg/body for 10-14 consecutive days every 5 weeks, and 3) 1,200 mg/body daily for at least 4 weeks. A total of 28 patients were entered, and 27 cases were eligible. Twenty-five cases were evaluated for efficacy and 27 cases for safety. One patient achieved complete response, 2 patients attained partial response, and the response rate thus obtained was 12.0%. Major side effects observed were myelosuppression represented by leukopenia (69.2%) followed by gastrointestinal disorders. These symptoms, however, were reversible by the cessation of administration.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Piperazinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Esquema de Medicación , Femenino , Humanos , Leucopenia/inducido químicamente , Persona de Mediana Edad , Piperazinas/administración & dosificación , Piperazinas/efectos adversosRESUMEN
A multi-institutional collaborative late phase II study of irinotecan hydrochloride (CPT-11) was performed on patients with advanced gastric cancer. CPT-11 was administered as a 100 mg/m2 weekly intravenous infusion or as 150 mg/m2 fortnightly. Of 81 registered patients, 77 cases were eligible and 60 cases were evaluable for response. The overall response rate for evaluable cases was 23.3% (14/60), and the response rate was 16.1% (9/45) for the patients who had received prior chemotherapy. The primary tumor showed a 4.5% response, while metastatic lesions in the lymph-nodes, lungs, and liver showed response rates of 36.4%, 33.3%, and 17.4%, respectively. The major toxicities (> or = Grade 3) were leukopenia (41.2%), anemia (28.9%), diarrhea (22.4%) and anorexia (19.7%). These toxicities were generally reversible. CPT-11 showed activity against advanced gastric cancer, suggesting that further clinical studies of CPT-11 combined with other active chemotherapy agents are warranted.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos Fitogénicos/uso terapéutico , Camptotecina/análogos & derivados , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adulto , Anciano , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/uso terapéutico , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Irinotecán , Leucopenia/inducido químicamente , Neoplasias Hepáticas/secundario , Metástasis Linfática , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/patologíaRESUMEN
A late phase II study of CPT-11 was conducted to evaluate the antitumor effect and toxicity of CPT-11 in patients with advanced pancreatic cancer as a cooperative study of 19 institutions. From February 1990 to June 1992, 61 patients with advanced pancreatic cancer were enrolled in this study. Fifty-seven patients were evaluable for toxicity and 35 for response. CPT-11 was administered as a 100 mg/m2 weekly intravenous infusion (regimen A) or as a 150 mg/m2 every two weeks (regimen B). The response rate was 11.4% (4/35). The primary tumor showed a 10.3% (3/29) response and the liver metastases showed a 10.5% (2/19) response. The major toxicities were myelosuppression and gastrointestinal symptoms. The incidences (> or = Grade 2) of leukopenia, anemia, anorexia, nausea/vomiting, alopecia and diarrhea were 61.4% (35/57), 56.1% (32/57), 70.2% (40/57), 56.1% (32/57), 40.4% (23/57) and 36.8% (21/57), respectively. The incidence of diarrhea was higher with regimen A than with regimen B, but the antitumor activity was no different between the two regimens. These results suggested that CPT-11 has some antitumor activity against advanced pancreatic cancer.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Camptotecina/análogos & derivados , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Alopecia/inducido químicamente , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/uso terapéutico , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Irinotecán , Leucopenia/inducido químicamente , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/patologíaRESUMEN
An early phase II study of irinotecan (CPT-11) in patients with advanced or recurrent breast cancer was undertaken by a cooperative study group of 15 institutes in Japan. CPT-11 was administered by intravenous drip-infusion. The administration schedules were 100 mg/m2 weekly (regimen A), 150 mg/m2 biweekly (regimen B), and 200 mg/m2 every 3-4 weeks (regimen C). There were 4 partial responses (PRs), 12 cases with no changes (1 minor response) and 9 cases of progressive diseases with a response rate of 16% (4/25). One out of 7 patients on regimen A and 3 patients out of 15 patients on regimen C achieved PR with a response rate of 14% and 20%, respectively. In three out of 4 PRs, prior chemotherapy, endocrinotherapy or radiotherapy had failed. Major adverse reactions were leukopenia 28/33 (85%), neutropenia 19/25 (76%), anemia 15/33 (46%), nausea/vomiting 28/33 (85%), anorexia 25/33 (76%), diarrhea 22/33 (67%) and alopecia 20/33 (61%). The incidence of leukopenia and thrombocytopenia seemed to be higher in regimen C than regimen A, and diarrhea was also more severe in regimen C than regimen A. The recovery of leukopenia was delayed in some patients on regimen C. The results suggested that CPT-11 was effective against advanced or recurrent breast cancer. The recommended administration schedule for a late phase II study was thought to be 100 mg/m2 weekly, considering efficacy and safety.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Camptotecina/análogos & derivados , Adulto , Anciano , Anorexia/inducido químicamente , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/uso terapéutico , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Irinotecán , Leucopenia/inducido químicamente , Persona de Mediana Edad , Náusea/inducido químicamente , Neutropenia/inducido químicamenteRESUMEN
PURPOSE: A phase II study was conducted to evaluate the antitumor effect and toxicity of CPT-11 in patients with metastatic colorectal cancer. PATIENTS AND METHODS: From December 1989 to March 1991, 67 patients with metastatic colorectal cancer were enrolled in this study. Sixty-three patients were assessable for toxicity and response. Their median age was 57 years (range, 24 to 72). Forty-six patients (73%) had a good performance status of 0 or 1. Fifty-one patients (81%) had received prior chemotherapy. The major sites of metastasis were liver (63%) and lung (44%). CPT-11 was administered as a 100 mg/m2 weekly intravenous infusion, or as 150 mg/m2 every 2 weeks. The dose was reduced based on the grade of leukopenia and diarrhea, if necessary. RESULTS: A partial response was obtained in 17 of 63 assessable patients (27%; 95% confidence interval, 16% to 38%). The response rate in patients with prior radiotherapy or chemotherapy was 25% (13 of 52). Liver metastases showed a 15% (six of 40) response and lung metastases showed a 39% (11 of 28) response. The median duration of partial response was 127 days (range, 49 to 353) and the median overall duration of response was 208 days (range, 99 to 381). The major toxicities (> or = grade 3) were leukopenia (16%), diarrhea (13%), nausea and vomiting (13%), and alopecia (11%). Adverse effects were generally well tolerated and reversible. Treatment could be continued on an outpatient basis for patients without severe toxicity. Hemorrhagic cystitis was not encountered in this study. CONCLUSION: CPT-11 showed promising antitumor activity against metastatic colorectal cancer that was resistant to prior therapy. Further clinical trials of combination chemotherapy using CPT-11 are justified.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos Fitogénicos/efectos adversos , Camptotecina/efectos adversos , Camptotecina/uso terapéutico , Neoplasias Colorrectales/patología , Femenino , Humanos , Irinotecán , Leucopenia/inducido químicamente , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Metástasis Linfática , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Especificidad de Órganos , Vómitos/inducido químicamenteRESUMEN
TT-62 is a new derivative of FdUMP, which is the active metabolite of 5-FU. A phase I clinical study of TT-62 was conducted by a cooperative study. The same patients received single and 2-week oral administration of TT-62. Starting from 60 mg/m2 (1n), the dose was escalated to 420 mg/m2 (7n). In the single administration, the maximum tolerated dose (MTD) could not be determined. In the 2-week administration, MTD was 420 mg/m2, and the dose limiting factor was gastro-intestinal disturbances such as anorexia, nausea, vomiting and diarrhea. Increases in GOT.GPT and a decrease in hemoglobin content were observed. After administration was stopped all side effects disappeared. TT-62 was detected mainly in the plasma, while trace amounts of 5-FU and FUdR were also detected. TT-62 was excreted mostly in the urine, as alpha-fluoro-beta-alanine (FBAL). The cumulative urinary excretion of FBAL was about 80% of the total dose, and the oral absorption of TT-62 was thus thought to be good.
Asunto(s)
Antineoplásicos/administración & dosificación , Fluorodesoxiuridilato/análogos & derivados , Neoplasias/tratamiento farmacológico , Administración Oral , Adolescente , Adulto , Anciano , Anorexia/inducido químicamente , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Esquema de Medicación , Femenino , Fluorodesoxiuridilato/administración & dosificación , Fluorodesoxiuridilato/efectos adversos , Fluorodesoxiuridilato/farmacocinética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismoRESUMEN
To prevent extraction of lipids during a double staining procedure for electron microscopy, the tissue slices, double fixed with glutaraldehyde and osmium tetroxide to preserve microvesicular lipid droplets in the cytoplasm, were immersed for 2 hr in veronal buffer (pH 9.0) containing 0.5% p-phenylenediamine and 0.5% imidazole immediately after postfixation. The stained sections of the immersed tissue slice showed blackened, well circumscribed lipid droplets similar to those in corresponding unstained sections. Moreover, highly contrasting features of the cellular architecture could be visualized with the double stained, as well as routinely prepared sections.
Asunto(s)
Imidazoles , Lípidos/análisis , Fenilendiaminas , Coloración y Etiquetado/métodos , Corteza Suprarrenal/citología , Animales , Femenino , Masculino , Microscopía Electrónica/métodos , Microtomía , RatasRESUMEN
We conducted a phase I study of CI-898 (trimetrexate), a new diaminoquinazoline antifolate in 22 patients with solid cancer in a multicenter collaborative study. The dosage schedule was single-dose intravenous administration (single treatment), followed by one or two courses of 5-day intravenous administration (5-day treatment) at 3-week intervals. Starting at 2 mg/m2 (1 n), the dose was increased up to 15 mg/m2 (7.5 n) for single treatment and 12 mg/m2 (6 n) for 5-day treatment. Evaluable cases numbered 18 for single treatment and 17 for 5-day treatment. In single treatment, the highest dose of 15 mg/m2 caused no serious side effect and did not reach the maximum tolerated dose (MTD). In 5-day treatment, leukocytopenia and thrombocytopenia were found dose dependently, the dose-limiting factor was bone marrow depression, and MTD was 10 mg/m2/day. The leukocyte and platelet counts reached the nadir in 1-3 weeks after initiation of 5-day treatment. The recovery from the nadir required about one week. Subjective side effects included mucitis (mouth, anus), malaise and gastro-intestinal symptoms (nausea, anorexia, diarrhea). None of alopecia, cardiotoxicity and nephrotoxicity were found. In the present phase I study, a tendency of tumor reduction was found in one case each of breast cancer (adenoma) and lung cancer (squamous cell carcinoma). The plasma concentration of the unchanged compound after single treatment showed a biphasic elimination pattern (t1/2 alpha 0.8-1.4 hr, t1/2 beta 9.4-13.0hr). The urinary excretion of the unchanged compound was 14.7-23.5% of the administered dose. In 5-day treatment, no accumulation was found. From the results of the present study, the recommended dosage of CI-898 in the early phase II study was considered to be 8 mg/m2/day intravenously for 5 days (every 3-4 weeks).
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Quinazolinas/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias del Sistema Digestivo/tratamiento farmacológico , Esquema de Medicación , Evaluación de Medicamentos , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Neoplasias/patología , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , TrimetrexatoRESUMEN
A phase I study of YM-881 (zinostatin stimalamer), neocarzinostatin combined with butylesterified styrene maleate, suspended in iodized poppy oil ethyl ester, was conducted in patients with hepatocellular carcinoma by giving single intra-arterial infusions via catheters inserted by Seldinger's method. Four dose levels, 2, 4, 6, and 8 mg, were tested. Major adverse reactions were fever, anorexia, nausea, vomiting, and abnormal hepatic function. Both the incidence and severity of adverse reactions tended to increase with the 8 mg dose. Tumor regression of 50% or more occurred in one receiving 2 mg and one receiving 4 mg. The results of the study suggest that doses of 6 mg or less may be appropriate for the phase II studies.
Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Anhídridos Maleicos/uso terapéutico , Poliestirenos/uso terapéutico , Cinostatina/análogos & derivados , Adulto , Anciano , Anorexia/inducido químicamente , Esquema de Medicación , Evaluación de Medicamentos , Femenino , Fiebre/inducido químicamente , Arteria Hepática , Humanos , Infusiones Intraarteriales , Masculino , Anhídridos Maleicos/administración & dosificación , Anhídridos Maleicos/efectos adversos , Persona de Mediana Edad , Náusea/inducido químicamente , Poliestirenos/administración & dosificación , Poliestirenos/efectos adversos , Cinostatina/administración & dosificación , Cinostatina/efectos adversos , Cinostatina/uso terapéuticoRESUMEN
A phase II study of YM 881 (zinostatin stimalamer) to determine the response and safety was conducted in patients with hepatocellular carcinoma by injecting a suspension of the drug into the hepatic artery. Repeated doses of 4 to 6 mg of the drug were given every 4 weeks so that the tumor tissues were filled with the suspension. Of the 195 registered patients, 15 were ineligible for the study, 8 dropped out, and data were missing for 5. A total of 167 patients completed the study. Response was assessed in the 167 patients who completed the study. CR was found in one, PR in 59, MR in 25, NC in 67, and PD in 15, with a response rate of 35.9. The safety of the drug was assessed in 177, excluding ineligible patients and 3 who dropped out because of the concurrent use of other drugs. Adverse reactions were found in 93.2% of the patients, and abnormal values in clinical laboratory tests in 60.5%. Major unwanted symptoms included fever, nausea, vomiting, and anorexia. Major abnormal changes in laboratory tests were elevated total bilirubin and LDH and abnormal hepatic function. About half the patients had malaise and pain related to the intra-arterial infusion therapy. The one year survival rate was 56.9%, and the duration of survival of 50% of the patients was 407 days.
Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Anhídridos Maleicos/uso terapéutico , Poliestirenos/uso terapéutico , Cinostatina/análogos & derivados , Adulto , Anciano , Anorexia/inducido químicamente , Carcinoma Hepatocelular/mortalidad , Esquema de Medicación , Evaluación de Medicamentos , Femenino , Fiebre/inducido químicamente , Arteria Hepática , Humanos , Infusiones Intraarteriales , Neoplasias Hepáticas/mortalidad , Masculino , Anhídridos Maleicos/administración & dosificación , Anhídridos Maleicos/efectos adversos , Persona de Mediana Edad , Náusea/inducido químicamente , Poliestirenos/administración & dosificación , Poliestirenos/efectos adversos , Tasa de Supervivencia , Cinostatina/administración & dosificación , Cinostatina/efectos adversos , Cinostatina/uso terapéutico , alfa-Fetoproteínas/metabolismoRESUMEN
A phase I clinical study by intravenous injection of zinostatin stimalamer (YM 881), a protein anti-cancer drug, was conducted in 50 patients with malignant tumors. The initial dose was 0.5 mg/m2 (n) in the single dose test, and 0.2 mg/m2/day in the repeated dose test for 5 successive days. Doses were increased up to 12n according to the modified Fibonacci's method in both the single and repeated dose tests. The dose limiting factor was thrombopenia in both the single and repeated dose tests. The maximum tolerated dose was 6.0 mg/m2 (12n) in the single dose test, and the subtoxic dose was 2.4 mg/m2/day in the five day repeated dose study. These results indicate that dose of 1.0 to 1.4 mg/m2/day (5 n to 7 n) are appropriate for the phase II repeated dose study.
Asunto(s)
Anhídridos Maleicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Poliestirenos/uso terapéutico , Cinostatina/análogos & derivados , Adulto , Anciano , Esquema de Medicación , Evaluación de Medicamentos , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Anhídridos Maleicos/administración & dosificación , Anhídridos Maleicos/efectos adversos , Persona de Mediana Edad , Poliestirenos/administración & dosificación , Poliestirenos/efectos adversos , Trombocitopenia/inducido químicamente , Cinostatina/administración & dosificación , Cinostatina/efectos adversos , Cinostatina/uso terapéuticoRESUMEN
An early phase II multicentered study of YM 881 (zinostatin stimalamer) was conducted in 36 patients to investigate response and the safety of the drug in malignant tumors. The response could be evaluated in 18 patients, one with brain tumor, 2 with lung cancer, one with breast cancer, one with liver cancer, one with pancreatic cancer, 6 with gastric cancer, and 6 with colon cancer. PR was found in the patient with brain tumor. Major subjective unwanted effects were gastrointestinal symptoms. Objective evidence of hematological changes (thrombocytopenia, decreased hematocrit, and lymphocytopenia) was also obtained.