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  • 1
    Digitale Medien
    Digitale Medien
    Treatment of human prostate tumors PC-3 and TSU-PR1 with standard and investigational agents in SCID mice (1997)
    Springer
    Investigational new drugs 15 (1997), S. 99-108 
    Details
    ISSN: 1573-0646
    Schlagwort(e): prostate tumors ; PC-3 ; TSU-PR1 ; preclinical ; chemotherapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Abstract Both the PC-3 and the TSU-PR1 prostate tumor models were found to be satisfactory for chemotherapeutic investigations in ICR-SCID mice. The 30 to 60 mg fragments implanted took in all mice (as judged by 100% takes in the controls of all experiments as well as the passage mice). The tumor volume doubling time was 4.0 days for PC-3 and 2.5 days for TSU-Pr1. Nine agents were evaluated IV against early stage subcutaneous PC-3 tumors, with Nano-piposulfan being the only agent highly active (4.9 log kill). Three other agents were moderately active: Taxol (1.5 log kill), Cryptophycin-8 (1.6 log kill), Vinblastine (1.0 log kill). Five agents were inactive: VP-16, Adriamycin, CisDDPt, 5-FUra, and Cyclophosphamide. Ten agents were evaluated IV against early stage subcutaneous TSU-Pr1 tumors. Three agent were highly active, producing 〉 6 log kill and cures: Taxol (5/5 cures), Cryptophycin-8 (5/5 cures), Vinblastine (2/4 cures). Two other agents were moderately active: Nano-piposulfan (1.2 log kill), and Cyclophosphamide (1.1 log kill). Five agents were inactive: VP-16, Adriamycin, CisDDPt, 5-FUra, and BCNU. In part, activity was determined by the ability of the SCID mice to tolerate meaningful dosages of the agents. Agents producing granulocyte toxicity (e.g., Adriamycin) were poorly tolerated and appeared less active than expected. Vinblastine, producing little or no granulocyte toxicity was very well tolerated and appeared to be more active than expected.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1023/A:1005856605726
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  • 2
    Digitale Medien
    Digitale Medien
    Discovery of cryptophycin-1 and BCN-183577: Examples of strategies and problems in the detection of antitumor activity in mice (1997)
    Springer
    Investigational new drugs 15 (1997), S. 207-218 
    Details
    ISSN: 1573-0646
    Schlagwort(e): cryptophycin-1 ; discovery strategies ; preclinical
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Abstract Historically, many new anticancer agents were first detected in a prescreen; usually consisting of a molecular/biochemical target or a cellular cytotoxicity assay. The agent then progressed to in vivo evaluation against transplanted human or mouse tumors. If the investigator had a large drug supply and ample resources, multiple tests were possible, with variations in tumor models, tumor and drug routes, dose-decrements, dose-schedules, number of groups, etc. However, in most large programs involving several hundred in vivo tests yearly, resource limitations and drug supply limitations have usually dictated a single trial. Under such restrictive conditions, we have implemented a flexible in vivo testing protocol. With this strategy, the tumor model is dictated by in vitro cellular sensitivity; drug route by water solubility (with water soluble agents injected intravenously); dosage decrement by drug supply, dose-schedule by toxicities encountered, etc. In this flexible design, many treatment parameters can be changed during the course of treatment (e.g., dose and schedule). The discovery of two active agents are presented (Cryptophycin-1, and Thioxanthone BCN 183577). Both were discovered by the intravenous route of administration. Both would have been missed if they were tested intraperitoneally, the usual drug route used in discovery protocols. It is also likely that they would have been missed with an easy to execute fixed protocol design, even if injected IV.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1023/A:1005875015011
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  • 3
    Digitale Medien
    Digitale Medien
    Activity of flavone acetic acid (NSC-347512) against solid tumors of mice (1986)
    Springer
    Investigational new drugs 4 (1986), S. 207-220 
    Details
    ISSN: 1573-0646
    Schlagwort(e): flavone acetic acid ; solid tumor active
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Abstract Flavone acetic acid (FAA) is a new antitumor agent that has recently entered Phase I clinical trials. In preclinical studies, we have found that FAA was broadly active against a variety of transplantable solid tumors of mice (colon #51, #07, #10, #26; pancreatic ductal adenocarcinomas #02 and #03; mammary adenocarcinoma #16/C/Adr; M5076 reticulum cell sarcoma and Glasgow's osteosarcoma). FAA was curative for colon adenocarcinoma # 10 and pancreatic ductal adenocarcinoma # 03. Thus, for the first time an agent has been identified with very broad, perhaps nearly universal solid tumor activity. FAA was also found to be orally active and stable in solution at 37 °C for 48 h. FAA was selectively cytotoxic in vitro for solid tumors over leukemias L1210 and P388 (in a soft-agar colony formation assay), thus correlating cellular selectivity in vitro with in vivo antitumor activity. The finding that FAA was active in vitro, established that the agent did not need metabolism (activation) outside the tumor cell. The main drawback of FAA was an unusual ‘threshold’ behavior in which only a narrow range of doses were active and splitting the dose markedly decreased activity.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00179586
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  • 4
    Digitale Medien
    Digitale Medien
    Chemotherapy of the squamous cell lung cancer LC-12 with 5-fluorouracil, cisplatin, carboplatin or iproplatin combinations (1988)
    Springer
    Investigational new drugs 6 (1988), S. 259-264 
    Details
    ISSN: 1573-0646
    Schlagwort(e): squamous cell ; murine lung cancer ; 5-fluorouracil ; cisplatin ; carboplatin ; iproplatin
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The combination of Cis-dichlorodiammineplatinum (II) (CisDDPt) + 5-Fluorouracil (5-FU) was compared with two CisDDPt analogues + 5-FU [Iproplatin (CHIP) + 5-FU and Carboplatin (CBDCA) + 5-FU] for relative efficacy against advanced stage squamous cell lung tumors (LC-12) in Balb/c mice. At equitoxic dosages, the numbers of regressions and cures were similar for the three combinations (5-FU/CISDDPt 2/10 PR's, 2/10 CR's, 2/10 cures; 5-FU/CBDCA 1/10 PR's, 5/10 CR's, 3/10 cures; 5-FU/CHIP 1/10 PR's, 3/10 CR's, 3/10 cures). The tumor growth delay among the mice not cured was slightly superior in the 5-FU/ CisDDPt regimen. All the agents were active singly against this tumor model. Based on these results, the substitution of CBDCA or CHIP for CisDDPt in a FU regimen did not offer a cytotoxic advantage. Because of different dose limiting toxicities for the platinum compounds the possibility exists that these analogues could be used in drug combinations in substitution for CisDDPt.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00173643
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  • 5
    Digitale Medien
    Digitale Medien
    5-Fluorouracil containing combinations in murine tumor systems (1989)
    Springer
    Investigational new drugs 7 (1989), S. 37-49 
    Details
    ISSN: 1573-0646
    Schlagwort(e): 5-fluorouracil ; murine tumor systems
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary 5-FUra is a familiar member of a variety of clinically useful regimens. Examples include: Cytoxan-Adriamycin-5-FUra (CAP); Methotrexate-Prednisone-Vincristine-Cytoxan-5-FUra (the Cooper regimen); and CisDDPt-5-FUra. In addition to its clinical utility, over 20 different 5-FUra-combinations have been reported to be therapeutically synergistic in experimental systems (Table 1). In this report, we will attempt to evaluate the reasons behind the widespread utility of this agent in combination therapy and suggest future directions for research efforts.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00178190
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  • 6
    Digitale Medien
    Digitale Medien
    Activity of batracylin (NSC-320846) against solid tumors of mice (1989)
    Springer
    Investigational new drugs 7 (1989), S. 295-306 
    Details
    ISSN: 1573-0646
    Schlagwort(e): batracylin ; ellipticine
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Batracylin (NSC 320846) is a water insoluble, solid tumor active compound discovered by the Developmental Therapeutics Program of the National Cancer Institute (NCI). In vivo, the NCI found this compound to be highly active [median treated tumor mass/median control tumor mass (T/C) = 0 to 20%] both orally and intraperitoneally against colon 38. In a disk diffusion, soft agar colony formation assay (500 ug/disk), we found solid tumor selectively (compared to leukemia L1210) against colon adenocarcinoma 38 (0–170 zu∶L1210 leukemia; 〉 950 zu∶C8), colon adenocarcinoma 9 (0–170 zu∶L1210; 〉 950 zu∶C9), colon adenocarcinoma 7/A (0–170 zu∶L1210; 250–400 zu∶C7), and pancreas ductal carcinoma 03 (0–170 zu∶L1210;〉950 zu∶Panc 03 (200 zone units [zu] = 6.5 mm zone of inhibition of cultured tumor colonies from drug disk). In vivo we have tested batracylin against mammary adenocarcinoma 16/C, colon 9, colon 38, colon 51, Panc 03, and hepatoma 129. Upon oral administration, batracylin was effective against colon 9 (T/C = 2.4%) and marginally active against colon 38 (T/C = 39%). Batracylin was orally ineffective against Panc 03 (T/C 〉 100%), colon #51 (T/C = 77%) and hepatoma 129 (T/C 〉 100%). Upon subcutaneous administration, batracylin was effective against colon #9 (T/C = 0%), and Panc 03 (T/C = 15%) but ineffective against mammary 16/C (T/C 〉 100%). At efficacious doses, delayed neurotoxicity, hepatic toxicity and a significant host weight loss was noted (with slow recovery). Both our in vitro data and the NCI in vivo data confirm its scant activity against L1210 (%ILS = 8 to 16%). Although showing activity against selected murine solid tumors, it lacked curative potential with early stage disease [C38, C9, Panc 03] and has shown relative inactivity in vitro against human solid tumor cell lines (H-125, CX-1, HCT-8, HCT-116). Batracylin has entered large animal toxicology trials at the NCI, anticipating phase I clinical evaluation.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00173759
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  • 7
    Digitale Medien
    Digitale Medien
    Activity of datelliptium acetate (NSC 311152; SR 95156A) against solid tumors of mice (1990)
    Springer
    Investigational new drugs 8 (1990), S. 253-261 
    Details
    ISSN: 1573-0646
    Schlagwort(e): datelliptium acetate ; NSC 311152 ; ellipticine ; SR 95156A
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Datelliptium acetate (NSC 311152) is a water soluble analogue of ellipticine. It is a solid tumor selective compound. In vitro, in a disk diffusion, soft agar colony formation assay (25 ug/disk), the compound demonstrated solid tumor selectivity (compared to leukemia L1210) against colon adenocarcinoma 38 and pancreas ductal carcinoma 03. Upon intravenous administration, NSC 311152 was effective in vivo against a variety of murine solid tumors. Responses at maximum tolerated doses were: colon #07/A (T/C = 33%; 0.60 log cell kill), #38 ((T/C = 0%; 4.2 log cell kill), colon #51/A (T/C = 2%; 1.2 log cell kill), undifferentiated colon #26/A (T/C = 38%; 0.4 log kill), mammary #16/C (T/C = 10%; 1.7 log cell kill), and pancreatic ductal carcinoma #03 (T/C = 0%; 80% cures through day 38). It was ineffective against pancreas #02 (T/C = 45%), mammary 17/A (T/C = 53%), and 17/A/ADR (T/C = 52%). At efficacious doses acute neurotoxicity (i.e. stupor and lethargy) and weight loss were noted (with rapid recovery from both toxicities). There were no delayed toxicities. The agent was slightly necrotizing and produced pain on SC injections. In lieu of its preclinical efficacy and toxicity profiles, we recommend further clinical investigation of this agent.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00171834
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  • 8
    Digitale Medien
    Digitale Medien
    Comparative efficacy of DMP 840 against mouse and human solid tumor models (1995)
    Springer
    Investigational new drugs 13 (1995), S. 195-203 
    Details
    ISSN: 1573-0646
    Schlagwort(e): DMP 840 ; preclinical ; antitumor activity
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Background DMP 840 is a compound from a class of bis-naphthalimide antitumor agents that recently completed Phase I clinical trials at three North American centers and is currently undergoing Phase II testing. Preclinically, it was shown to have curative activity against a variety of human tumor xenograft models. Purpose To test DMP 840 bothin vitro andin vivo for antiproliferative activity against predominantly mouse tumor models. Methods A disk diffusion soft agar colony formation assay was used to determine thein vitro growth inhibitory activity against a selection of mouse and human tumor cell lines, and the comparable selective mouse solid tumors were used forin vivo testing. Result In vitro DMP 840 exhibited equal cytotoxicity for human tumors (including MX-1 directly cultured from nude mice), mouse tumors and normal cells.In vivo DMP 840 was only modestly active or inactive against the following mouse tumors: Mam 16/C, T/C=30% (T/C=Percent Tumor Growth Inhibition); Mam 16/C/ADR, T/C=33%; Colon 38, T/C=9%; Panc 03, T/C=53%; Colon 51/A, T/C=28%; Pane 02, T/C= 52%; P388/0, 36% ILS (Percent Increased Life Span) and P388/ADR, 14% ILS. Furthermore, the antitumor activity was only observed at the highest non-toxic dose and was associated with a large body weight loss. In contrast, the agent was highly active against the human breast tumor MX-1 implanted subcutaneously in either athymic nude or SCID mice (Nudes: T/C=0%; 1/5 cures; SCIDS: T/C=0%; 5/5 cures). Conclusions Although there was no selective cytotoxicity in our clonogenic assay for human versus mouse tumor cell lines, selective activityin vivo for human xenograft tumors was noted. Overall, this compound is rather unique in its differential degree ofin vivo activity for human versus mouse tumors.Implications: Phase II trials, which are ongoing, will help determine if the preclinicalin vivo selective activity of DMP 840 translates to clinical activity in man.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00873800
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  • 9
    Digitale Medien
    Digitale Medien
    Preclinical antitumor activity of CI-994 (1996)
    Springer
    Investigational new drugs 14 (1996), S. 349-356 
    Details
    ISSN: 1573-0646
    Schlagwort(e): acetyldinaline ; CI-994 ; preclinical antitumor activity
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary CI-994 [aka: acetyldinaline; PD 123654; 4-acetylamino-N-(2′aminophenyl)-benzamide] (Figure 1) is a novel antitumor agent with a unique mechanism of action. It is the acetylated metabolite of dinaline, a compound previously identified as having cytotoxic and cytostatic activity against several murine and human xenograft tumor models. CI-994 had activity against 8/8 solid tumors tested (log cell kills at the highest non-toxic dose): pancreatic ductal adenocarcinoma #02 (4.7); pancreatic adenocarcinoma#03 (3.0; 1/6 cures); colon adenocarcinoma #38 (1.6); colon adenocarcinoma #51/A (1.1); mammary adenocarcinoma #25 (1.7); mammary adenocarcinoma #17/ADR (0.5); Dunning osteogenic sarcoma (4.0); and the human prostate carcinoma LNCaP (1.2). CI-994 had the same spectrum of activity in vivo as dinaline. It also behaved similarly in schedule comparison/toxicity trials. Prolonged administration with lower drug doses was more effective than short-term therapy at higher individual doses. If doses were kept between 40 and 60 mg/kg/injection, prolonged administration (〉 50 days) was tolerated with no gross toxicity. Doses ≥90 mg/kg/injection caused lethality after 4–5 days of administration. The maximum tolerated total dose was also increased with smaller individual doses administered for prolonged intervals. Clinical Phase I trials are ongoing with this agent.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00180810
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  • 10
    Digitale Medien
    Digitale Medien
    Preclinical antitumor efficacy of analogs of XK469: sodium-(2-[4-(7-chloro-2-quinoxalinyloxy)phenoxy]propionate (1998)
    Springer
    Investigational new drugs 16 (1998), S. 129-139 
    Details
    ISSN: 1573-0646
    Schlagwort(e): preclinical ; antitumor ; XK469 analog
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Abstract A series of quinoxaline analogs of the herbicide Assure® was found to have selective cytotoxicity for solid tumors of mice in a disk-diffusion-soft-agar-colony-formation-assay compared to L1210 leukemia. Four agents without selective cytotoxicity and 14 agents with selective cytotoxicity were evaluated in vivo for activity against a solid tumor. The four agents without selective cytotoxicity in the disk-assay were inactive in vivo (T/C 〉 42%). Thirteen of the fourteen agents with selectivity in the disk-assay were active in vivo (T/C 〈 42%). Five of the agents had curative activity. These five agents had a halogen (F, Cl, Br) in the 7-position (whereas Assure® had a Cl in the 6 position). All agents with curative activity were either a carboxylic acid, or a derivative thereof, whereas Assure® is the ethyl ester of the carboxylic acid. All other structural features were identical between Assure® and the curative agents. Assure® had no selective cytotoxicity for solid tumors in the disk-assay, and was devoid of antitumor activity. The analog XK469 is in clinical development.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1023/A:1006174622061
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