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Some fundamental considerations of the applications of pharmacokinetics to cancer chemotherapy. 药代动力学在肿瘤化疗中的应用的一些基本考虑。
Cancer chemotherapy reports Pub Date : 1975-07-01
K B Bischoff
{"title":"Some fundamental considerations of the applications of pharmacokinetics to cancer chemotherapy.","authors":"K B Bischoff","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The purpose of this paper is to document the procedures needed to construct pharmacokinetic models based on physiologic, physicochemical, and pharmacologic principles. Extensive descriptions of the basic ideas are provided, along with the corresponding equations. The notions of scaling between various animal species will be described and examples will be given. The important factors determining the choice and number of compartments are based on the properties of the drug and the desired purposes of the pharmacokinetic model. The important concept of flow-limiting conditions with regard to local uptake will be described. The quantitative description of plasma and tissue binding is discussed, along with the notion of effective protein concentrations for the latter. Using these basic ideas, the fundamental mass balances describing the flow, diffusion, and reactions of the drug are presented. An example of the prediction of the pharmacokinetics of a strongly bound drug is used as an illustration of the methods, and this example also indicates the types of useful simplifications that can be made. The special, but important, case of linear binding is next derived, and an example involving the drug methotrexate will illustrate the principles involved. Finally, cytosine arabinoside will be used to indicate methods that can be used for rapidly metabolized drugs. Since existing examples are primarily utilized, this paper brings together a comprehensive collection of the several sets of physiologic data and modeling techniques that have been used for the past several years. It is hoped that this documentation will provide a useful basis for the those wishing to use this approach to pharmacokinetics.</p>","PeriodicalId":9510,"journal":{"name":"Cancer chemotherapy reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1975-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12352639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Daunorubicin (NSC-82151), vincristine (NSC-67574), cytosine arabinoside (NSC-63878), and prednisone (NSC-10023) combination therapy for advanced adult acute leukemia. 柔红霉素(NSC-82151)、长春新碱(NSC-67574)、阿糖胞嘧啶(NSC-63878)和强的松(NSC-10023)联合治疗晚期成人急性白血病。
Cancer chemotherapy reports Pub Date : 1975-07-01
C P Burns
{"title":"Daunorubicin (NSC-82151), vincristine (NSC-67574), cytosine arabinoside (NSC-63878), and prednisone (NSC-10023) combination therapy for advanced adult acute leukemia.","authors":"C P Burns","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":9510,"journal":{"name":"Cancer chemotherapy reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1975-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12280183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Disposition of cytosine arabinoside (NSC-63878) and its metabolites: a pharmacokinetic simulation. 阿拉伯糖胞嘧啶(NSC-63878)及其代谢物的处置:药代动力学模拟。
Cancer chemotherapy reports Pub Date : 1975-07-01
P F Morrison, T L Lincoln, J Aroesty
{"title":"Disposition of cytosine arabinoside (NSC-63878) and its metabolites: a pharmacokinetic simulation.","authors":"P F Morrison,&nbsp;T L Lincoln,&nbsp;J Aroesty","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>A computer-based model of the pharmacokinetics of cytosine arabinoside (ara-C) and its active metabolite, ara-CTP, has been developed. This model, which is an intracellular extension of the Bischoff-Dedrick model of multi-organ pharmcokinetics gives predictions which are in agreement with the recent measurements of Chou et al on tissue concentrations of ara-CTP and Borsa et al on blood levels of ara-C. It is shown that the ara-CTP halving time in tissue is much greater than the ara-C halving time in blood because of low tissue levels of phosphatase. For a single dose at the LD10 level in mice, significant splenic DNA inhibition is calculated to occur for 26 hours, while the ara-C levels are negligible in 6 hours. The calculated duration of cytostatic effect at lower dosages (2.5 mg/kg) is 10 or 12 hours, while ara-C blood levels are negligible within 3 hours. Implications for cell kinetics and scheduling studies are also briefly described.</p>","PeriodicalId":9510,"journal":{"name":"Cancer chemotherapy reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1975-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"11388305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Microbiologic assay for cytosine arabinoside (NSC-63878): the use of a mutant of streptococcus faecium var. durans resistant to methotrexate (NSC-740) and 6-mercaptopurine (NSC-755). 阿拉伯糖胞嘧啶(NSC-63878)的微生物测定:使用对甲氨蝶呤(NSC-740)和6-巯基嘌呤(NSC-755)耐药的粪链球菌变种durans。
Cancer chemotherapy reports Pub Date : 1975-05-01
B M Mehta, M B Meyers, D J Hutchison
{"title":"Microbiologic assay for cytosine arabinoside (NSC-63878): the use of a mutant of streptococcus faecium var. durans resistant to methotrexate (NSC-740) and 6-mercaptopurine (NSC-755).","authors":"B M Mehta,&nbsp;M B Meyers,&nbsp;D J Hutchison","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Cytosine arabinoside has been shown to be effective in the treatment of acute leukemias and lymphomas, especially in combination with other established anticancer agents such as methotrexate, 6-mercaptopurine, and 6-thioguanine. A microbiologic assay capable of detecting cytosine arabinoside in the presence of such anticancer agents in body fluids has been developed using a strain of Streptococcus faecium var. durans resistant to methotrexate and 6-mercaptopurine; the assay can also be used to determine cytosine arabinoside concentrations in the presence of l-thioguanine. In view of the present trend toward drug combinations, including those using tetrahydrouridine, in the chemotherapy for human neoplasms, the proposed assay method will be valuable in cytosine arabinoside distribution studies.</p>","PeriodicalId":9510,"journal":{"name":"Cancer chemotherapy reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1975-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12379481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Preclinical studies with triazinate (NSC-139105), an antifolate drug, in beagle dogs and rhesus monkeys. 抗叶酸药物三嗪酸酯(NSC-139105)在比格犬和恒河猴中的临床前研究。
Cancer chemotherapy reports Pub Date : 1975-05-01
E J Gralla, G L Coleman, W Osbaldiston, W L Sawicki, R M Jonas, J R Bertino
{"title":"Preclinical studies with triazinate (NSC-139105), an antifolate drug, in beagle dogs and rhesus monkeys.","authors":"E J Gralla,&nbsp;G L Coleman,&nbsp;W Osbaldiston,&nbsp;W L Sawicki,&nbsp;R M Jonas,&nbsp;J R Bertino","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The effects of the intravenous administration of triazinate by single and multiple injections were studied in beagle dogs and rhesus monkeys. In dogs, dose levels ranging from 0.3125 to 40 mg/kg were given either as single doses daily for 5 days, or once weekly for 6 weeks. The 5-day regimen was also studied in monkeys with dose levels from 2.5 to 40 mg/kg/day. Prominent drug-related and drug-dependent effects which appeared in both species were piloerection, muscular weakness, and respiratory difficulty which occurred during and immediately after the administration of dose levels of 10 mg/kg or greater. Gastrointestinal toxicity was severe in dogs but mild in monkeys. Lymphoid tissue toxicity was manifested by a circulating lymphopenia and localized cellular depletion in the germinal centers of lymphoid tissues. In dogs, signs of bone marrow toxicity consisted of a circulating neutropenia and, at necropsy, a reduction in the number of erythroid and myeloid elements plus megaloblastosis. Only the latter change was observed in monkeys. This difference in the hematopoietic toxicity between the beagle dog and the rhesus monkey was corroborated by the findings from in vitro studies with bone marrow. DNA synthesis in beagle bone marrow cells was depressed significantly by triazinate as compared with cells from rhesus marrow. A direct renal toxic effect was observed in monkeys given high doses of triazinate (20 and 40 mg/kg/day or 240-280 mg/m/day) for 5 days.</p>","PeriodicalId":9510,"journal":{"name":"Cancer chemotherapy reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1975-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12000202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Action of Cis-dichlorodiammineplatinum(II) (NSC-119875) at ehe cellular level. 顺式二氯二胺铂(II)在细胞水平上的作用。
Cancer chemotherapy reports Pub Date : 1975-05-01
B Drewinko, J A Gottlieb
{"title":"Action of Cis-dichlorodiammineplatinum(II) (NSC-119875) at ehe cellular level.","authors":"B Drewinko,&nbsp;J A Gottlieb","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Asynchronous human lymphoma cells treated for 1 hour with increasing concentrations of cis-dichlorodiammineplatinum(II) revealed a marked decrease in survival as estimated by the colony-forming technique. When the treatmentwas extended for 8 hours at a concentration of 5micrograms/ml, a killing effect (greater than 3 log decades) was observed which was similar to that obtained when 50micrograms/ml is incubated with the cells for 1 hour. This finding suggests that better antitumor effects with fewer toxic effects may be obtained clinically by prolonged infusion of low doses of cis-dichlorodiammineplatinum (II). Synchronized lymphoma cells showed no significant degree of cell-cycle-stage sensitivity to cis-dichlorodiammineplatinum (II). The drug kills cells with similar efficiency in all stages of the cell cycle. No killing effect was elicited after incubation of the cells with spironolactone, a compound said to protect the kidneys from the toxic effects of heavy metals. However, simultaneous incubation of spironolactone and cis-dichlorodiammineplatinum (II) did not prevent the lethal action of the second drug. If spironolactone is proven to be an inhibitor of cis-dichlorodiammineplatinum (II) nephrotoxicity, it will become a valuable addition to the treatment of human neoplasia with this platinum compound. Lymphoma cells given a \"priming\" dose of 10 micrograms/ml of cis-dichlorodiammineplatinum (II) failed to repair the induced damage. A second exposure to 10 micrograms/ml of the drug at various subsequent intervals elicited greater killing effect than that produced by 20 micrograms/ml given at one time. A clear synergistic effect was noted when cis-dichlorodiammineplatinum (II) was given simultaneously with camptothecin or BCNU. The molecular mechanism by which this effect is accomplished is not presently apparent.</p>","PeriodicalId":9510,"journal":{"name":"Cancer chemotherapy reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1975-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12379308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Clinical studies of Platinum Coordination compounds in the treatment of various malignant diseases. 铂配位化合物治疗各种恶性疾病的临床研究。
Cancer chemotherapy reports Pub Date : 1975-05-01
J M Hill, E Loeb, A MacLellan, N O Hill, A Khan, J J King
{"title":"Clinical studies of Platinum Coordination compounds in the treatment of various malignant diseases.","authors":"J M Hill,&nbsp;E Loeb,&nbsp;A MacLellan,&nbsp;N O Hill,&nbsp;A Khan,&nbsp;J J King","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Following the prior work of Rosenberg et al, Rosenberg and VanCamp, and Speer et al, we started clinical trials with cis-dichlorodiammineplatinum(II) in April 1971. Marked tumor regression was noted in several malignant diseases in these initial clinical studies which were reported at the Chemotherapy Congress in Prague, August 1971. At the present time over 178 patients have been treated wihhis durg for a variety of malignant conditions. Approximately half of these patients received the platinum compound alone and the other half received it in combination with four other chemotherapeutic agents...</p>","PeriodicalId":9510,"journal":{"name":"Cancer chemotherapy reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1975-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12379489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Remission maintenance of acute nonlymphoblastic leukemia with BCNU (NSC-409962) and cyclophosphamide (NSC-26271). BCNU (NSC-409962)和环磷酰胺(NSC-26271)治疗急性非淋巴细胞白血病的缓解维持。
Cancer chemotherapy reports Pub Date : 1975-05-01
J Manaster, D H Cowan, J E Curtis, R Hasselback, D E Bergsagel
{"title":"Remission maintenance of acute nonlymphoblastic leukemia with BCNU (NSC-409962) and cyclophosphamide (NSC-26271).","authors":"J Manaster,&nbsp;D H Cowan,&nbsp;J E Curtis,&nbsp;R Hasselback,&nbsp;D E Bergsagel","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Thirteen of 29 patients with acute nonlymphoblastic leukemia achieved complete remission with cyclophosphamide, cytosine arabinoside, and vincristine, and remissions were maintained with a combination of BCNU and cyclophosphamide. The maintenance drugs (200 and 1000 mg/m respectively) were given at 8-week intervals intravenously. Only six of the 13 patients achieving a complete remission have relapsed. The projected median duration of complete remission is 65 weeks and of survival from diagnosis is 144 weeks. These remission and survival durations compare favorably with the results achieved using other forms of remission-maintenance therapy. The advantage of our form of maintenance therapy is that only overnight hospitalization is required at 8-week intervals.</p>","PeriodicalId":9510,"journal":{"name":"Cancer chemotherapy reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1975-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12241300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Phase II study of chromomycin A3 (NSC-58514) in advanced colorectal carcinoma. 色霉素A3 (NSC-58514)治疗晚期结直肠癌的II期研究。
Cancer chemotherapy reports Pub Date : 1975-05-01
C G Moertel, A J Schutt, R G Hahn, T A Marciniak, R J Reitemeier
{"title":"Phase II study of chromomycin A3 (NSC-58514) in advanced colorectal carcinoma.","authors":"C G Moertel,&nbsp;A J Schutt,&nbsp;R G Hahn,&nbsp;T A Marciniak,&nbsp;R J Reitemeier","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":9510,"journal":{"name":"Cancer chemotherapy reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1975-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12379482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Fate of streptozotocin (NSC-85998)in patients with advanced cancer. 链脲佐菌素(NSC-85998)在晚期癌症患者中的命运
Cancer chemotherapy reports Pub Date : 1975-05-01
A B Adolphe, E D Glasofer, W M Troetel, J Ziegenfuss, J E Stambaugh, A J Weiss, R W Manthei
{"title":"Fate of streptozotocin (NSC-85998)in patients with advanced cancer.","authors":"A B Adolphe,&nbsp;E D Glasofer,&nbsp;W M Troetel,&nbsp;J Ziegenfuss,&nbsp;J E Stambaugh,&nbsp;A J Weiss,&nbsp;R W Manthei","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>We have investigated the distribution, biotranformation, and excretion of streptozotocin and its 14C- and 3H-labeled metabolities in 15 patients with advanced cancer. Streptozotocin was detected in the plasma during the first 3 hours after administration while radioactive products were present for longer than 24 hours. No unchanged streptozotocin was detected in the cerebrospinal fluid (CSF); however, 14C-labeled metabolites were detected in the 2-hour CSF sample in a concentration equivalent to the 2-hour plasma level. H activity is the CSF was not detected at this time period. Radioactivity measured in biopsied tissues indicated that streptozotocin labeled with 14C and 3H or its metabolites penetrated tumor tissue. 14C tissue levels were found to approximate plasma levels; however, 3H levels were found to be greater than the corresponding plasma levels. Fifteen percent of the total dose of streptozotocin administered was recovered in the urine. 3H-labeled metabolites were recovered in excess of 60% in the urine, and approximately 30% of the 14C-labeled metabolites were recovered in the urine during a similar interval. Less than 1% of the administered 14C and 3H was recovered in the feces. 14C-labeled CO2 was also recovered, although quantitative recovery was not attained. At least three major metabolites of streptozotocin were detected in the urine by radiochromatography. Two metabolites contained only 3H and one metabolite contained both 14C and 3H in the same ratio as administered.</p>","PeriodicalId":9510,"journal":{"name":"Cancer chemotherapy reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1975-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"11348208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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