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  • 1
    Electronic Resource
    Electronic Resource
    The pharmacokinetics and toxicity of the anthrapyrazole anti-cancer drug CI-941 in the mouse: a guide for rational dose escalation in patients (1989)
    Springer
    Cancer chemotherapy and pharmacology 23 (1989), S. 8-14 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary CI-941 is a new synthetic DNA-binding agent selected for phase I clinical evaluation. The drug has broad-spectrum antitumour activity against a number of murine tumours and, in contrast to doxorubicin, is unlikely to induce cardiotoxicity by a free-radical-mediated mechanism. In this study the toxicity and pharmacokinetics of CI-941 were studied in the mouse to enable the implementation of a pharmacokinetically guided dose-escalation strategy in patients. Following a single i.v. bolus injection in mice, CI-941 induced dose-dependent leukopenia. The white blood cell counts were suppressed on day 3 by 18%, 50% and 65% of control, at doses of 10, 15 and 20 mg/kg CI-941, respectively. Other toxicities such as weight loss, alopecia, diarrhoea and convulsions were observed at doses 〉20 mg/kg. Lethality studies in female Balb-c mice resulted in an LD10 value of 20 mg/kg (95% confidence limits; range, 19–21 mg/kg) and an LD50 value of 22 mg/kg (95% confidence limits; range, 21–23 mg/kg). The pharmacokinetics of CI-941 were studied at four dose levels from 1/10 of the LD10 to the LD10 (20 mg/kg). The drug was rapidly cleared from the plasma (250–400 ml/min per kg) at a rate approaching the cardiac output of mice, displaying triphasic plasma pharmacokinetics. The area under the plasma CI-941 concentration vs time curve (AUC) was linear with respect to the dose, up to and including 15 mg/kg (AUC=110 μM x min at 15 mg/kg), but became non-linear at 20 mg/kg (AUC=277 μM x min). Despite 80%–84% plasma protein binding, CI-941 was rapidly and extensively distributed into tissues, especially the kidney. Following i.v. bolus injections at doses of 1.5 and 15 mg/kg, elimination of the parent compound by urinary excretion accounted for 12%–18% of the delivered dose. A phase-I starting dose (based on that equivalent to 1/10 of the LD10 in the mouse) of 5 mg/m2 CI-941 is recommended for single administration schedules. In addition, a pharmacokinetically guided dose-escalation strategy, based on achieving a target AUC of 110 μM x min, is proposed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00258450
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  • 2
    Electronic Resource
    Electronic Resource
    Modulation of induced resistance to adriamycin in two human breast cancer cell lines with tamoxifen or perhexiline maleate (1988)
    Springer
    Cancer chemotherapy and pharmacology 22 (1988), S. 147-152 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The clinical utility of adriamycin in the treatment of patients with metastatic breast cancer is oftenlimited by the development of drug resistance. It has been recognized that in addition to the development of primary resistance against adriamycin, malignant cells can simultaneously develop cross-resistance to other agents. An adriamycin-resistant human breast cancer cell line (MCF 7Ad) was developed by exposing the parent line (MCF 7) to gradually increasing concentrations of adriamycin while the cells were being grown in monolayer. Using these lines in a clonogenic assay, the relative drug sensitivities to adriamycin, vinblastine, melphalan, 5-fluorouracil and methotrexate were studied. MCF 7Ad was 12.5-fold more resistant to adriamycin than MCF 7 and 500-fold cross-resistant to vinblastine. There was no cross-resistance to melphalan, 5-fluorouracil or methotrexate. The resistance of MCF 7Ad was decreased by simultaneous exposure to tamoxifen (by a factor of 3.33) or perhexiline maleate (by a factor of 7.50). This decreased resistance was evidenced by a shift to the left of the sensitivity curves. However, there was no consistent change in the sensitivity curves of MCF 7. At the selected concentration of tamoxifen and perhexiline maleate, the cloning efficiency of MCF 7 and MCF 7Ad was 80%–90% of control values in medium without tamoxifen, perhexiline maleate or cytotoxic drugs. The resistance of MCF 7Ad to adriamycin was associated with a lower accumulation of [14C]adriamycin than exhibited by the sensitive MCF 7 line. There was no consistent change in [14C]adriamycin accumulation in MCF 7 or MCF 7Ad when tamoxifen was added, but when perhexiline maleate was added the [14C] accumulation increased. These results suggest that the tamoxifen-induced change in MCF 7Ad adriamycin resistance was not due to an increase in the amount of cell-associated adriamycin, but rather to some other mechanism that increased the cytotoxicity of the adriamycin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00257313
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  • 3
    Electronic Resource
    Electronic Resource
    A strategy for the development of two clinically active cisplatin analogs: CBDCA and CHIP (1990)
    Springer
    Cancer chemotherapy and pharmacology 25 (1990), S. 395-404 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The antitumor agent cisplatin has a broad antitumor spectrum and has been incorporated into regimens that are curative for some malignant diseases. However, one of the major limitations to its clinical usefulness is the incidence of severe toxicities involving several major organ systems. Therefore, much enthusiasm has been generated for the development of cisplatin analogs that demonstrate an improved therapeutic index in some preclinical models. The two most promising analogs are CBDCA (carboplatin) and CHIP (iproplatin). The preclinical and early clinical trial results have demonstrated that these two compounds show activity in cisplatin-responsive tumors. The preclinical background providing the rationale for the clinical development of these two analogs is described. We suggest a means of screening for each analog's clinical antitumor activity and determining the analogs' utility against specific malignant diseases compared with that of the parent compound or standard treatment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686049
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  • 4
    Electronic Resource
    Electronic Resource
    Preclinical pharmacokinetic, antitumor and toxicity studies with CL-994 (N-acetyldinaline) (1997)
    Springer
    Investigational new drugs 15 (1997), S. 187-194 
    Details
    ISSN: 1573-0646
    Keywords: CI-994 studies in mice
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract CI-994, a substituted benzamide derivative, is a compound that showed solid tumor selectivity for a variety of solid tumor models compared to L1210 leukemia. Due to its lack of aqueous solubility, it requires oral administration. Female B6D2F1 mice were treated with CI-994 once daily by oral administration of 50 mg/kg for 14 days. Following treatment mice were evaluated for pharmacodynamic effects as well as the pharmacokinetic behavior of CI-994 and the de-acetylated derivative dinaline. Mice samples (plasma, urine, feces) were analyzed using solid phase extraction, reverse phase HPLC and ultraviolet detection. The plasma distribution and elimination half-lives for CI-994 were 51 minutes and 9.4 hours, respectively, on D-1; 31 minutes and 3.4 hours, respectively on D-14. The apparent plasma distribution and elimination half-lives for dinaline were 27 minutes and 2.4 hours, respectively, on D-1; 40 minutes and 7.3 hours, respectively on D-14. The CI-994 AUC on D-1 and D-14 were 2879 and 2407 µ × minutes, respectively; while the dinaline AUC on D-1 and D-14 were 87 and 92 µg/ml × minutes, respectively. Urinary excretion for CI-994 and dinaline was higher on D-14, while the fecal excretion was the same on both days. The Colon #38 tumor growth in treated mice was reduced to 22% of that observed in the controls by D-19. The levels of all blood cells were reduced in the treated mice when compared to controls and the total WBC was the most affected (median 38%). Recovery to pretreatment levels occurred quickly following treatment cessation. Phase I evaluation of chronic oral administration of CI-994 is currently ongoing.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005846026398
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  • 5
    Electronic Resource
    Electronic Resource
    Cryptophycin 1 cellular levels and effects in vitro using L1210 cells (1998)
    Springer
    Investigational new drugs 16 (1998), S. 199-204 
    Details
    ISSN: 1573-0646
    Keywords: cryptophycin 1 with L1210 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Cryptophycin 1 is a natural product that was initially isolated from blue-green algae which has shown potent broad spectrum antitumor activity in preclinical in vitro and in vivo models. The drug strongly binds to tubulin and disrupts microtubule assembly for more than 24 hours after its removal. We evaluated cell survival, intracellular levels and inhibition of macromolecular synthesis in L1210 cells following exposure to cryptophycin 1 in vitro. Cell survival was strongly inhibited following drug exposure for either 1 or 4 hours. Intracellular drug levels were minimally affected by temperature (4°C versus 37°C) or exposure times up to 1 hour. However, extracellular drug concentration in culture media and increasing cell numbers did affect the concentration of intracellular drug levels in a nearly proportional manner. The synthesis of DNA and RNA was inhibited less than 5%, while protein synthesis inhibition was near 30%. Thus, none of the macromolecules were inhibited enough to explain the inhibition of tumor cell growth.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006148127527
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  • 6
    Electronic Resource
    Electronic Resource
    Echinomycin: The first bifunctional intercalating agent in clinical trials (1985)
    Springer
    Investigational new drugs 3 (1985), S. 403-410 
    Details
    ISSN: 1573-0646
    Keywords: Echinomycin ; intercalator ; Quinomycin A
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Echinomycin is a quinoxaline antibiotic that was originally isolated from Streptomyces echinatus. Based on its antitumor activity against two i.p. implanted murine tumors, the B16 melanoma, and the P388 leukemia, it was brought into clinical trials by the National Cancer Institute. Recent studies on its cytotoxic action have related its antitumor activity with its ability to bifunctionally intercalate with double stranded DNA. Toxicologic studies were carried out in CDF1 mice and beagle dogs using intravenous injections. For the mice studies the dose ranges were 288–692 mcg/kg (864–2076 mcg/m2) by single bolus, and 112–254 mcg/kg/day (336–762 mcg/m2/day) for five consecutive days. In the dog, dose ranges studied were 8.9–89.4 mcg/kg (178–1788 mcg/m2) by single bolus, and 3.4–33.5 mcg/kg/day (68–670 mcg/m2/day) for five consecutive days. The major toxic effects were found in the gastrointestinal, hepatic, and lymphoreticular systems. These were reversible at all but the highest dose, in dogs that had been treated for five consecutive days. Phase I clinical trials using various intravenous schedules were sponsored by the National Cancer Institute. Nausea, vomiting, reversible liver enzyme abnormalities, and allergic reactions were the most common toxicities encountered. Based on results from these studies, the National Cancer Institute has recently begun phase II trials in a broad range of diseases. These trials will further characterize echinomycin's toxic effects and its antitumor activity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00170766
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  • 7
    Electronic Resource
    Electronic Resource
    Phase I trial of Adozelesin using the treatment schedule of daily × 5 every 3 weeks (1995)
    Springer
    Investigational new drugs 13 (1995), S. 321-326 
    Details
    ISSN: 1573-0646
    Keywords: daily × 5 Adozelesin Phase I
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary CC-1065 is a unique alkylating agent that preferentially binds in the minor groove of double-stranded DNA at adenine-thymine-rich sites. Although it has broad antitumor activity in preclinical models its development was discontinued because of deaths observed during preclinical toxicology studies. Adozelesin is a potent synthetic analog that was chosen for clinical development because it had a similar preclinical antitumor spectrum, but did not produce deaths similar to CC-1065 at therapeutic doses. Phase I evaluations using a variety of Adozelesin treatment schedules have been conducted. This report describes our experience using a multiple dose treatment schedule. Endpoints including antitumor response, maximum tolerated dose, dose limiting toxicity as well as other toxicities and the recommended Phase II starting dose were determined. Adozelesin was given as a 10 minute IV infusion for 5 consecutive days every 21 days or upon recovery from toxicity. The dose range evaluated was 6–30 mcg/m2/day. All patients had refractory solid tumors and had received prior cytotoxic treatment. Thirty-three patients (22 men: 11 women) were entered onto the study and 87 courses were initiated. Dose limiting toxicity was cumulative myelosuppression (leucopenia, thrombocytopenia). The maximum tolerated dose was 30 mcg/m2/day. The only other significant toxicity was an anaphylactoid syndrome that occurred in 2 patients. A partial response was observed in a patient with refractory soft tissue sarcoma. The recommended Phase II starting dose of Adozelesin using a 10 minute IV infusion for 5 consecutive days is 25 mcg/m2/day to be repeated every 4–6 weeks to allow recovery from myelotoxicity, based on our experience. Additional Phase I and II studies with Adozelesin are recommended.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00873138
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