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  • 1
    Electronic Resource
    Electronic Resource
    Preclinical antitumor activity of CI-994 (1996)
    Springer
    Investigational new drugs 14 (1996), S. 349-356 
    Details
    ISSN: 1573-0646
    Keywords: acetyldinaline ; CI-994 ; preclinical antitumor activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00180810
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  • 2
    Electronic Resource
    Electronic Resource
    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
    Keywords: preclinical ; antitumor ; XK469 analog
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006174622061
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  • 3
    Electronic Resource
    Electronic Resource
    Preclinical efficacy of thioxanthone SR271425 against transplanted solid tumors of mouse and human origin (1999)
    Springer
    Investigational new drugs 17 (1999), S. 17-27 
    Details
    ISSN: 1573-0646
    Keywords: Thioxanthone ; SR 271425 ; antitumor ; preclinical
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract A highly active and broadly active thioxanthone has been identified: N-[[1-[[2-(Diethylamino)ethyl]amino]-7-methoxy-9-oxo-9H-thioxanthen-4-yl] methylformamide (SR271425, BCN326862, WIN71425). In preclinical testing against a variety of subcutaneously growing solid tumors, the following %T/C and Log10 tumor cell kill (LK) values were obtained: Panc-03 T/C = 0, 5/5 cures; Colon-38 (adv. stage) T/C = 0, 3/5 cures, 4.9 LK; Mam-16/C T/C = 0, 3.5 LK; Mam-17/0 T/C = 0, 2.8 LK; Colon-26 T/C = 0, 1/5 cures, 3.2 LK; Colon-51 T/C= 0, 2.7 LK; Panc-02 T/C = 0, 3.1 LK; B16 Melanoma T/C = 13%, 4.0 LK; Squamous Lung-LC12 (adv. stage) T/C = 14%, 4.9 LK; BG-1 human ovarian T/C = 16%, 1.3 LK; WSU-Br1 human breast T/C = 25%, 0.8 LK. The agent was modestly active against doxorubicin (Adr)-resistant solid tumors: Mam-17/Adr T/C =23%, 0.8 LK; and Mam-16/C/Adr T/C = 25%, 1.0 LK, but retained substantial activity against a taxol-resistant tumor: Mam-16/C/taxol T/C = 3%, 2.4 LK. SR271425 was highly active against IV implanted leukemias, L1210 6.3 LK and AML1498 5.3 LK. The agent was equally active both by the IV and oral routes of administration, although requiring approximately 30% higher dose by the oral route. Based on its preclinical antitumor profile, it may be appropriate to evaluate SR271425 in clinical trials.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006267517726
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  • 4
    Electronic Resource
    Electronic Resource
    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
    Keywords: DMP 840 ; preclinical ; antitumor activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00873800
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  • 5
    Electronic Resource
    Electronic Resource
    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
    Keywords: cryptophycin-1 ; discovery strategies ; preclinical
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005875015011
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  • 6
    Electronic Resource
    Electronic Resource
    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
    Keywords: squamous cell ; murine lung cancer ; 5-fluorouracil ; cisplatin ; carboplatin ; iproplatin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00173643
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  • 7
    Electronic Resource
    Electronic Resource
    5-Fluorouracil containing combinations in murine tumor systems (1989)
    Springer
    Investigational new drugs 7 (1989), S. 37-49 
    Details
    ISSN: 1573-0646
    Keywords: 5-fluorouracil ; murine tumor systems
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00178190
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  • 8
    Electronic Resource
    Electronic Resource
    Activity of batracylin (NSC-320846) against solid tumors of mice (1989)
    Springer
    Investigational new drugs 7 (1989), S. 295-306 
    Details
    ISSN: 1573-0646
    Keywords: batracylin ; ellipticine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00173759
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  • 9
    Electronic Resource
    Electronic Resource
    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
    Keywords: prostate tumors ; PC-3 ; TSU-PR1 ; preclinical ; chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005856605726
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  • 10
    Electronic Resource
    Electronic Resource
    Preclinical antitumor activity of XK469 (NSC 656889) (1998)
    Springer
    Investigational new drugs 16 (1998), S. 287-296 
    Details
    ISSN: 1573-0646
    Keywords: quinoxaline ; XB947 ; myelotoxicity ; human xenograft and mouse activity ; Assure® ; XK469, NSC 697887* ; NSC 698215* ; NSC 698216* ; preclinical development
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract XK469 (NSC 656889) is a water-soluble member of the novel quinoxaline family of antitumor agents. In vitro, XK469 demonstrated selective cytotoxicity for several murine solid tumors including colorectal and mammary adenocarcinoma cell lines, when compared to both leukemia and normal epithelial cells. In vivo, XK469 was active against 7/7 murine tumors tested, including pancreatic ductal carcinomas #02 and #03, colon adenocarcinomas #38 and #51/A, mammary adenocarcinoma #16/C and the Adriamycin resistant mammary adenocarcinomas #16/C/ADR and #17/ADR. XK469 was efficacious both intravenously and orally. Regardless of dosing schedule, conventional mice tolerated higher total doses than SCID or nu/nu mice did. Despite these reduced doses, XK469 was active against xenografts of 4/6 human tumor lines including mammary adenocarcinoma MX-1, the small cell lung cancer DMS 273, the prostate model LNCaP and the CNS tumor SF295. The lower doses in the xenograft studies were below curative levels. The dose-limiting toxicity appeared to be myelosuppression with rapid host recovery (5–8 days), and in vitro assays of XK469 toxicity to murine bone marrow neutrophil progenitors CFU-GM (colony forming unit-granulocyte/macrophage) demonstrated concentration-dependent toxicity from 0.5–30 μg/mL. The difference in drug tolerance between BDF1 and SCID mice was detected in vitro as a 3-fold difference in the IC90 for CFU-GM, despite similar IC50 values. Comparative in vitro hematotoxicology studies revealed that human bone marrow CFU-GM tolerated XK469 as well as their SCID counterparts (IC90 values 5.7 vs. 7.4 μg/mL). Based on comparison with previously tested anti-cancer agents, these data suggest that humans will be able to tolerate XK469 doses that are efficacious against human tumor xenografts.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006206814025
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