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  • 1
    Electronic Resource
    Electronic Resource
    A Phase I and pharmacokinetics study of 2-chlorodeoxyadenosine in patients with solid tumors (1995)
    Springer
    Cancer chemotherapy and pharmacology 35 (1995), S. 397-402 
    Details
    ISSN: 1432-0843
    Keywords: Key words 2-chlorodeoxyadenosine ; Phase I ; Pharmacokinetics ; Solid tumors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Preclinical studies of 2-chlorodeoxyadenosine (2-CdA) against solid tumors in the human tumor cloning assay and evidence that 2-CdA is active against slow-growing or resting tumor cells have stimulated interest in the clinical activity of this agent against solid tumors. This study sought to estimate the maximum tolerated dose, dose-limiting toxicity, and plasma and urine pharmacokinetics accompanying the intravenous administration of 2-CdA by 120-h continuous infusion in patients with solid tumors. Treated patients were also assessed for other toxicities of therapy and for antitumor response. A total of 23 patients received 35 courses of treatment given at doses of 3.5, 5.3, 6.5 and 8.1 mg/m2 per day by continuous intravenous infusion for 5 days and repeated every 28 days. Blood and urine specimens were collected before, during, and after drug infusion. The dose-limiting toxicity at 8.1 mg/m2 per day manifested as granulocytopenia in 2 of 5 patients (3 of 7 courses of treatment) and as thrombocytopenia in 3 of 5 patients (3 of 7 courses of treatment). At the dose levels of 6.5 and 8.1 mg/m2 per day, recovery from thrombocytopenia was often delayed. Severe lymphocytopenia (〈1,000/μl) was observed at all dose levels of 2-CdA. Dose-related anemia and leukopenia were observed and were infrequently severe. Nonhematological toxicities were confined to mild-to-moderate nausea, vomiting, fatigue, and anorexia. Fever of 37°–40°C was induced during drug infusion in 19 patients. No antitumor response was observed. Average plasma concentrations at steady-state (Cpss) ranged from 3 ng/ml at the initial dose level to 13 ng/ml at the dose level of 8.1 mg/m2 per day. Both the Cpss and the area under the plasma concentration-time curve (AUC) were proportional to the dose. A relationship was observed between the percentage of change in absolute neutrophil count and the AUC. Renal excretion accounted for only 18% of the elimination of 2-CdA over the 5-day infusion period. The maximum tolerated dose for 2-CdA given by 5-day continuous infusion was 8.1 mg/m2 per day in this study. The recommended dose on this schedule for phase II studies is 6.5 mg/m2 per day. Granulocytopenia and thrombocytopenia were dose-limiting. No antitumor activity was observed during this study. On the basis of the plasma concentrations of 2-CdA observed, it is unlikely that this schedule of drug administration will permit achievement of the concentrations consistent with antitumor activity observed in preclinical studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050253
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  • 2
    Electronic Resource
    Electronic Resource
    Activity of the multitargeted antifolate LY231514 in the human tumor cloning assay (1999)
    Springer
    Cancer chemotherapy and pharmacology 44 (1999), S. 105-110 
    Details
    ISSN: 1432-0843
    Keywords: Key words Human tumor cloning assay ; LY231514 ; Multitargeted antifolate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: This study was performed to evaluate the activity of the multitargeted antifolate (MTA or LY231514) against a broad range of human tumors taken directly from patients. Materials and methods: Human tumor colony-forming units were treated with MTA at concentrations of 0.1, 1.0, and 10 μg/ml in 1-h exposure studies. The responses of a limited number of specimens were also evaluated concurrently in 1-h exposures to cisplatin, fluorouracil, irinotecan, and/or paclitaxel. Results: Of 358 specimens plated in the 1-h exposure studies, 148 (41%) were evaluable. Overall, responses were observed in 3% of specimens (4/144) at 0.1 μg/ml, 11% (17/148) at 1.0 μg/ml, and 23% (33/141) at 10 μg/ml. In this range of concentrations achievable clinically, there was a significant concentration-response relationship. At 10 μg/ml in the 1-h exposure studies, the response rate in colorectal cancer specimens was 32% (9/28), and the response rate in non-small-cell lung cancer was 25% (6/24). Responses were also observed in several chemoresistant tumors, including renal cell carcinoma, hepatocellular carcinoma, mesothelioma, and pancreatic carcinoma. The activity of MTA was not completely cross-resistant with that of cisplatin, fluorouracil, irinotecan, and paclitaxel. Conclusions: MTA demonstrated in vitro activity against a spectrum of tumors, including several tumors generally considered chemoresistant.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050953
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  • 3
    Electronic Resource
    Electronic Resource
    A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation (1999)
    Springer
    Cancer chemotherapy and pharmacology 44 (1999), S. 372-380 
    Details
    ISSN: 1432-0843
    Keywords: Key words Multitargeted ; Antifolate ; MTA ; LY231514
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: To determine toxicities, maximally tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of MTA, a novel antifolate compound which inhibits the enzymes thymidylate synthase (TS), glycinamide ribonucleotide formyltransferase (GARFT), and dihydrofolate reductase (DHFR). Methods: Patients with advanced solid tumors were given MTA intravenously over 10 min every 21 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients. Results: A total of 37 patients (27 males, 10 females, median age 59 years, median performance status 90%) were treated with 132 courses at nine dose levels, ranging from 50 to 700 mg/m2. The MTD of MTA was 600 mg/m2, with neutropenia and thrombocytopenia, and cumulative fatigue as the dose-limiting toxicities. Hematologic toxicity correlated with renal function and mild reversible renal dysfunction was observed in multiple patients. Other nonhematologic toxicities observed included mild to moderate fatigue, anorexia, nausea, diarrhea, mucositis, rash, and reversible hepatic transaminase elevations. Three patients expired due to drug-related complications. Pharmacokinetic analysis during the first course of treatment at the 600 mg/m2 dose level demonstrated a mean harmonic half-life, maximum plasma concentration (Cpmax), clearance (CL), area under the curve (AUC), and apparent volume of distribution at steady state (Vdss) of 3.08 h, 137 μg/ml, 40.0 ml/min per m2, 266 μg · h/ml, and 7.0 l/m2, respectively. An average of 78% of the compound was excreted unchanged in the urine. Partial responses were achieved in two patients with advanced pancreatic cancer and in two patients with advanced colorectal cancer. Minor responses were obtained in six patients with advanced colorectal cancer. Conclusions: The MTD and dose for phase II clinical trials of MTA when administered intravenously over 10 min every 21 days was 600 mg/m2. MTA is a promising new anticancer agent.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050992
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  • 4
    Electronic Resource
    Electronic Resource
    Activity of human leukocyte interferon in a human tumor cloning system (1982)
    Springer
    Cancer chemotherapy and pharmacology 8 (1982), S. 99-103 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Clinical trials using interferon to treat human malignancies are currently hampered by limited supplies of the compound. We have utilized a human tumor cloning system as an assay for the antitumor effects of human leukocyte interferon. Interferon was tested against 62 patients' tumors growing in this soft agar system. A dose-dependent cytotoxic effect of interferon was noted against only five of the patients' tumors. A≥70% decrease in tumor colony-forming units (TCFUs) was noted with one lymphosarcoma cell leukemia, one small cell lung cancer, one adenocarcinoma of the lung, one breast cancer, and a pancreatic cancer. One patient had his tumor cultured in vitro and had a clinical trial with interferon. This patient whose tumor demonstrated in vitro sensitivity had a clinical antitumor effect with interferon therapy. The in vitro results in this study suggest that the human leukocyte interferon currently available has a low level of activity in a human tumor cloning system. Additional testing is needed to determine whether the cloning system can identify the patient(s) who might have an antitumor effect from the interferon.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00292879
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  • 5
    Electronic Resource
    Electronic Resource
    Human tumor cloning: Feasibility and clinical correlations (1981)
    Springer
    Cancer chemotherapy and pharmacology 6 (1981), S. 265-271 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The human tumor cloning system is a soft agar technique which allows the growth of human tumors in vitro. We report here our experience with culturing 2,365 patients' tumors in the system. Overall 1,844 (78%) have formed colonies in vitro. However, only 51% have formed ≥30 colonies per 500,000 cells plated. Despite the limitations of inadequate growth for some tumors there are a number of clinical applications for the system, which are reported here. These include: (1) Use of the system to predict for sensitivity of an individual patient's tumor to a particular chemotherapeutic agent; (2) screening new anticancer agents to predict for in vivo activity; 3) monitoring patients' bone marrows for tumor involvement; and (4) use of the number of colonies which form in the assay as a prognostic factor for survival. All of these clinical applications are in their infancy of development and will require carefully designed prospective trials to determine the final place of the human tumor cloning system in the practice of clinical oncology.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00256979
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  • 6
    Electronic Resource
    Electronic Resource
    Application of a new preclinical drug screening system for cancer of the large bowel (1988)
    Springer
    Cancer chemotherapy and pharmacology 21 (1988), S. 31-34 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We report a prospective evaluation of three human, continuous colorectal cancer cell lines and a new semiautomated radiometric technique (Bactec system) as a primary screening procedure for cytotoxic compounds with activity against cancer of the large bowel. COLO 320DM, Ht-29, and the metastatic OM-1 colon cancer cell line that have previously been shown to yield clinically relevant information in terms of drug sensitivity patterns in humans were all tested against 11 new compounds currently being investigated in phase I or early phase II clinical trials. Our results suggest that trimetrexate, DUP-785, didemnin B, and flavone-8-acetic acid may be clinically effective for the treatment of colorectal cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00262734
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  • 7
    Electronic Resource
    Electronic Resource
    Adozelesin, a potent new alkylating agent: cell-killing kinetics and cell-cycle effects (1992)
    Springer
    Cancer chemotherapy and pharmacology 30 (1992), S. 348-354 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Adozelesin (U-73975) was highly cytotoxic to V79 cells in culture and was more cytotoxic than several clinically active antitumor drugs as determined in a human tumor-cloning assay. Phase-specificity studies showed that cells in the M + early G1 phase were most resistant to adozelesin and those in the late G1 + early S phase were most sensitive. Adozelesin transiently slowed cell progression through the S phase and then blocked cells in G2. Some cells escaped the G2 block and either divided or commenced a second round of DNA synthesis (without undergoing cytokinesis) to become tetraploid. Adozelesin inhibited DNA synthesis more than it did RNA or protein synthesis. However, the dose needed for inhibition of DNA synthesis was 10-fold that required for inhibition of L1210 cell growth. The observation that cell growth was inhibited at doses that did not cause significant inhibition of DNA synthesis and that cells were ultimately capable of completing two rounds of DNA synthesis in the presence of the drug suggests that adozelesin did not exert its cytotoxicity by significant inhibition of DNA synthesis. It is likely that adozelesin alkylates DNA at specific sites, which leads to transient inhibition of DNA synthesis and subsequent G2 blockade followed by a succession of events (polyploidy and unbalanced growth) that result in cell death.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689961
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  • 8
    Electronic Resource
    Electronic Resource
    Preclinical and phase I trials of topoisomerase I inhibitors (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. S41 
    Details
    ISSN: 1432-0843
    Keywords: CPT-11 ; Topotecan ; Intoplicine ; Topoisomerase I
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A total of three topoisomerase I inhibitors, including topotecan, CPT-11 (irinotecan), and intoplicine, have been studied in both preclinical and clinical/clinical pharmacology studies. In in vitro testing against human tumor colony-forming units, all three compounds were significantly more effective when tested as a continuous exposure as compared with a 1-h exposure. The dose-limiting toxicities were different for all three of the agents, with neutropenia and thrombocytopenia being dose-limiting for topotecan; diarrhea, for CPT-11; and hepatotoxicity, for intoplicine. In these phase I studies a number of marginal responses were noted with topotecan; partial and marginal responses, with CPT-11 (particularly in patients with colon cancer); and no response, with intoplicine. The detailed pharmacology of all three agents documented a very short half-life for topotecan, an intermediate half-life for CPT-11, and a prolonged half-life for intoplicine. Based on our experience to date, these compounds (particularly CPT-11) have promise as useful additions to our tremendous therapeutic armamentarium.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00684862
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  • 9
    Electronic Resource
    Electronic Resource
    Pharmacokinetic study of fludarabine phosphate (NSC 312887) (1986)
    Springer
    Cancer chemotherapy and pharmacology 17 (1986), S. 277-280 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Characterization of the pharmacokinetics of 2-FLAA has been completed in seven patients receiving 18 or 25 mg/m2 daily x5 of 2-FLAMP over 30 min. Assuming 2-FLAMP was instantaneously converted to 2-FLAA, the plasma levels of 2-FLAA declined in a biexponential fashion. Computer fitting of the plasma concentrationtime curves yielded an average distribution half-life (t1/2α) of 0.60 h and a terminal half-life (t1/2β) of 9.3 h. The estimated plasma clearance was 9.07±3.77 l/h per m2 and the steady state volume of distribution, 96.2±26.0 l/m2. There was a significant inverse correlation between the area under the curve (AUC) and absolute granulocyte count (r=-0.94, P〈0.02). A relationship between creatinine clearance and total body clearance was noted, but was not statistically significant (r=0.828; P〈0.1). Aproximately 24%±3% of 2-FLAA was excreted renally over the 5-day course of drug administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00256699
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  • 10
    Electronic Resource
    Electronic Resource
    A phase I and pharmacokinetic comparison of hepatic arterial and peripheral vein infusions of bisantrene for liver cancer (1985)
    Springer
    Cancer chemotherapy and pharmacology 15 (1985), S. 144-148 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Bisantrene (NSC-337766) was administered to five patients with cancer of the liver (one case of hepatocellular carcinoma, two of metastatic carcinoma of unknown primary, two of metastatic colorectal carcinoma). Under fluoroscopic guidance, percutaneous hepatic venous catheters were placed in five patients and percutaneous hepatic arterial catheters in four. A fifth patient's hepatic arterial catheter was implanted at laparotomy. Hepatic plasma flow was estimated by the Fick principle using peripheral vein indocyanine green infusion. On the first day of treatment, patients received a 2- or 4 h hepatic arterial infusion of bisantrene (130 mg/m2); peripheral venous, hepatic arterial, and hepatic venous timed blood samples were drawn during and for 18 h after drug infusion. On the second day of treatment, 2- or 4 h peripheral vein infusion of bisantrene (130 mg/m2) was followed by the same blood sampling schedule. Patients were followed weekly for toxicity. Four patients received only one course of treatment, while a fifth received two courses. All patients experienced leukopenia (median nadir 2400/mm3; range 1400–2700/mm3). Two patients developed fever after drug infusion. No antitumor responses were observed. Plasma bisantrene concentrations were measured by HPLC. Pharmacokinetic analyses are reported for four patients. The hepatic extraction ratio ranged from 15% to 49%, hepatic plasma clearances were 0.029–0.353 l/min/m2; peripheral vein areas under the concentration-time curve during hepatic arterial infusion ranged from 35% to 50% of peripheral vein areas under the curve during peripheral vein infusion. We conclude that hepatic arterial bisantrene infusion offers only modest pharmacokinetic advantage to the target organ or to the systemic circulation over peripheral vein infusion.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00257525
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