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  • 1
    Electronic Resource
    Electronic Resource
    cis-Bis(pyridine)platinum(II) organoamides with unexpected growth inhibition properties and antitumor activity (1992)
    s.l. : American Chemical Society
    Journal of medicinal chemistry 35 (1992), S. 3349-3353 
    Details
    ISSN: 1520-4804
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/jm00096a007
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  • 2
    Electronic Resource
    Electronic Resource
    Preparation, characterization, cytotoxicity, and mutagenicity of a pair of enantiomeric platinum(II) complexes with the potential to bind enantioselectively to DNA (1993)
    s.l. : American Chemical Society
    Journal of medicinal chemistry 36 (1993), S. 3663-3668 
    Details
    ISSN: 1520-4804
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/jm00075a022
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  • 3
    Electronic Resource
    Electronic Resource
    A phase I and pharmacokinetic study of 12-h infusion of flavone acetic acid (1992)
    Springer
    Cancer chemotherapy and pharmacology 29 (1992), S. 354-360 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary This phase I study investigated flavone acetic acid (FAA) given as a 12-h intravenous infusion every 3 weeks in the absence of urinary alkalinisation. Cohorts of three patients were treated at doses of 7, 10 and 13 g/m2. One subject had colon cancer; 5, renal cancer; and 3, lung cancer. The Eastern Cooperative Oncology Group (ECOG) performance status was 0 in four patients, 1 in two subjects and 2 in three cases. The maximum tolerated dose was 13 g/m2. The dose-limiting toxicities were WHO grade 3 hypotension and grade 3 diarrhoea. Other toxicities included lethargy and dizziness, nausea, temperature fluctuation, myalgia and dry mouth, but no significant myelosuppression was encountered. One patient receiving 10 g/m2 for renal cancer showed a partial response that lasted for 3 months and included the resolution of pulmonary and cutaneous metastases. The pharmacokinetics showed large interpatient variability. At 12–16 h post-infusion, the plasma elimination profile entered a plateau phase, with frequent increases in concentration suggesting enterohepatic recycling. Neither peak FAA levels nor AUC values were dose-dependent at the doses studied. Peak plasma levels were 101–402 μg/ml and AUC (0–48 h) values were 75–470 mg ml−1 min. Plasma protein binding varied with total concentration. Two metabolites were detected in the plasma, and both also underwent apparent enterohepatic recycling. Repeat dosing resulted in decreases of up to 48% in peak levels and AUC values for FAA in three of six patients. Of the total FAA dose, 39%–77% was excreted in the urine as FAA or metabolites within 2 days. The dose recommended for further phase II studies is 10 g/m2.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686003
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  • 4
    Electronic Resource
    Electronic Resource
    A phase I and pharmacokinetics study of prolonged ambulatory-infusion carboplatin (1995)
    Springer
    Cancer chemotherapy and pharmacology 37 (1995), S. 79-85 
    Details
    ISSN: 1432-0843
    Keywords: Key words Phase I ; Pharmacokinetics ; Carboplatin ; Ambulatory infusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  A total of 18 patients received 6-week ambulatory infusions of carboplatin in groups at dose levels of 14, 28, 35 and 42 mg/m2 per day. The dose-limiting toxicity was myelosuppression. At 42 mg/m2, three of four patients had WHO grade 4 and one of four had grade 3 neutropenia, whereas two patients had grade 3 thrombocytopenia. At 35 mg/m2, two of five patients had grade 3 neutropenia, whereas one had grade 4 and two had grade 3 thrombocytopenia. Non-hematological toxicities were predominantly gastrointestinal, with 3 of 18 patients experiencing grade 3 emesis. Total and ultrafiltrable platinum (UFPt) were assayed by flameless atomic absorption spectrometry in weekly and post-infusion plasma and urine samples. In plasma, levels of total platinum increased throughout the infusion, and the protein binding slowly increased from 60% platinum bound at week 1 to 90% bound by week 4. Although the UFPt level reached a steady state within 1 week, the concentration did not increase with the dose level, remaining at a mean value of 0.58±0.24 μM. Renal excretion of platinum accounted for 70±12% of the dose at steady state. There was a high inter-patient variability in both total body clearance of UFPt (range, 83–603 ml/min) and renal clearance (range, 67–390 ml/min). A terminal elemination half-life of 13–27 h was noted for post-infusion UFPt. Neutropenia was linearly related to the total daily carboplatin dose, but neither neutropenia nor thrombocytopenia could be related to steady-stateUFPt or the UFPt area under the concentration-time curve (AUC). The recommended dose for phase II studies is 28 mg/m2 per day.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050370
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  • 5
    Electronic Resource
    Electronic Resource
    A phase I and pharmacokinetics study of prolonged ambulatory-infusion carboplatin (1995)
    Springer
    Cancer chemotherapy and pharmacology 37 (1995), S. 79-85 
    Details
    ISSN: 1432-0843
    Keywords: Phase I ; Pharmacokinetics ; Carboplatin ; Ambulatory infusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A total of 18 patients received 6-week ambulatory infusions of carboplatin in groups at dose levels of 14, 28, 35 and 42 mg/m2 per day. The dose-limiting toxicity was myelosuppression. At 42 mg/m2, three of four patients had WHO grade 4 and one of four had grade 3 neutropenia, whereas two patients had grade 3 thrombocytopenia. At 35 mg/m2, two of five patients had grade 3 neutropenia, whereas one had grade 4 and two had grade 3 thrombocytopenia. Non-hematological toxicities were predominantly gastrointestinal, with 3 of 18 patients experiencing grade 3 emesis. Total and ultrafiltrable platinum (UFPt) were assayed by flameless atomic absorption spectrometry in weekly and post-infusion plasma and urine samples. In plasma, levels of total platinum increased throughout the infusion, and the protein binding slowly increased from 60% platinum bound at week 1 to 90% bound by week 4. Although the UFPt level reached a steady state within 1 week, the concentration did not increase with the dose level, remaining at a mean value of 0.58±0.24 μM. Renal excretion of platinum accounted for 70±12% of the dose at steady state. There was a high inter-patient variability in both total body clearance of UFPt (range, 83–603 ml/min) and renal clearance (range, 67–390 ml/min). A terminal elemination half-life of 13–27 h was noted for post-infusion UFPt. Neutropenia was linearly related to the total daily carboplatin dose, but neither neutropenia nor thrombocytopenia could be related to steady-state UFPt or the UFPt area under the concentration-time curve (AUC). The recommended dose for phase II studies is 28 mg/m2 per day.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685632
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  • 6
    Electronic Resource
    Electronic Resource
    A pharmacokinetic and phase II study of gallium nitrate in patients with non-small cell lung cancer (2000)
    Springer
    Cancer chemotherapy and pharmacology 45 (2000), S. 55-58 
    Details
    ISSN: 1432-0843
    Keywords: Key words Gallium nitrate ; Pharmacokinetics ; Ultrafilterable ; Non-small cell lung cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study investigated the pharmacokinetics and activity of gallium nitrate in non-small cell lung cancer when 700 mg/m2 was given as a 30-min infusion with prehydration every 2 weeks. Gallium was measured in plasma and urine using flameless atomic absorption spectrophotometry, and pharmacokinetics of total and ultrafilterable gallium were calculated. Twenty-five patients with non-small cell lung cancer received 1–12 (median 2) courses of gallium nitrate every 2 weeks. Of 21 patients evaluable for response, 1 partial response was recorded, 4 patients had stable disease, and 16 had progressed. The most serious toxicities were renal impairment and optic neuritis. Hypocalcaemia was recorded in 3 patients. The mean Cmax was 15.2 ± 3.1 μg/ml (range 9.5–21.2). Most gallium remained ultrafilterable for the first 10 h, after which plasma protein binding increased, and at 48 h only 11% was present as ultrafilterable gallium. The elimination profiles of both total and ultrafilterable gallium were biphasic, and the distribution phase consisted of ultrafilterable gallium, with a distribution half-life of 1.4 h. Total gallium plateaued at 1.9 μg/ml at between 8 and 12 h, and the estimated elimination half-life was 63 h. The elimination half-life of ultrafilterable gallium was 16.5 h. Inter- and intra-patient variability in pharmacokinetics was minimal. A mean of 50 ± 14% of the gallium dose was excreted in the urine within 48 h. A short infusion of gallium nitrate achieving high peak plasma concentrations results in little efficacy in non-small cell lung cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00006743
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  • 7
    Electronic Resource
    Electronic Resource
    Effect of toremifene on antipyrine elimination in the isolated perfused rat liver (1993)
    Springer
    Cancer chemotherapy and pharmacology 31 (1993), S. 319-323 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Toremifene is a triphenylethylene antioestrogen with significant antitumour activity. It is structurally very similar to tamoxifen. Both drugs undergo extensive hepatic metabolism and tamoxifen is known to inhibit hepatic mixed-function oxidases (MFO). Using the isolated perfused rat-liver model, we investigated the effect of toremifene on the elimination of antipyrine, a standard marker of MFO activity. Perfusate consisted of 20% red cells in a modified Krebs-Henseleit buffer, and 80 ml was recirculated at 14 ml/min for 3 h. High but clinically relevant steady-state toremifene levels of 3 and 10 μg/ml were achieved using bolus plus constant infusion into the reservoir. Elimination of 2.5 mg antipyrine was not inhibited by steady-state toremifene, but methanol (maximal perfusate concentration, 1.29%), the vehicle used for toremifene administration, caused a statistically significant increase in the antipyrine elimination half-life (mean, 1.4±0.2 h for controls vs 2.2±0.3 h for methanol;P〈0.05,n=4). Whereas the methanol had no apparent effect on liver viability as assessed by bile flow and perfusate back-pressure, toremifene at a steady-state concentration of 10 μg/ml caused a statistically significant decrease in bile flow (value at 180 min, 0,22±0.05 ml/h as compared with 0.52±0.06 ml/h in the methanol control;P〈0.05) and a statistically significant increase in perfusate back-pressure (value at 180 min, 17.5±1.8 cm vs 11.0±2.6 cm in the methanol control;P〈0.05). Therefore, toremifene used at high doses can impair liver function in the isolated perfused rat liver, but it does not have any effect on antipyrine elimination.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685678
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  • 8
    Electronic Resource
    Electronic Resource
    Radioenhancement by cisplatin with accelerated fractionated radiotherapy in a human tumour xenograft (1997)
    Springer
    Cancer chemotherapy and pharmacology 40 (1997), S. 534-539 
    Details
    ISSN: 1432-0843
    Keywords: Key words Cisplatin ; Radiation enhancement ; Tumour growth delay ; Xenograft ; Squamous carcinoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The aim of the present study was to investigate whether cisplatin would enhance the radioresponse of a human tumour xenograft when given in different schedules combined with accelerated fractionated radiation therapy. A human squamous carcinoma of the hypopharynx, FaDu, was grown in the thigh of athymic nude mice. Tumours were exposed to twice-daily 2-Gy fractions, applied 6 h apart over 2 weeks, 5 days a week, alone or combined with cisplatin given at maximally tolerated doses in three different schedules: (1) i.p. as a single bolus (SB) or (2) i.p. as a daily bolus at 30 min before the first daily radiation fraction or (3) s.c. as a continuous infusion through a mini-osmotic pump over 13 days, commencing 24 h prior to the first daily radiation fraction. The end point for the study was tumour growth delay (TGD), calculated as the difference between the delay in regrowth to 200% of the initial tumour size in treated versus control mice. SB cisplatin plus radiation showed only an additive effect on TGD, whereas daily-bolus and continuous-infusion cisplatin demonstrated a greater than additive effect when combined with accelerated fractionated radiation in this human tumour model. Cisplatin appears to be especially beneficial as a radiation enhancer when given throughout the course of radiation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050699
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  • 9
    Electronic Resource
    Electronic Resource
    A phase I and pharmacokinetic study of paclitaxel and epirubicin in advanced cancer (1999)
    Springer
    Investigational new drugs 17 (1999), S. 73-80 
    Details
    ISSN: 1573-0646
    Keywords: taxanes ; anthracyclines ; pharmacology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The objectives of this phase I trial were to determine the maximally tolerated doses of the combination of epirubicin and paclitaxel with and without G-CSF (granulocyte colony stimulating factor) support and to investigate whether epirubicin pharmacokinetics are altered by paclitaxel. Patients with advanced cancer, performance status 0–2, and a normal left ventricular ejection fraction who had received up to 1 prior chemotherapy regimen were treated with epirubicin followed by a 3-hour infusion of paclitaxel repeated every 3 weeks. Dose levels studied were (paclitaxel/epirubicin) 155/75, 175/75, 175/90, 200/90 mg/m2 without G-CSF and 175/90 mg/m2 with G-CSF. Thirty-five patients were entered and all were assessable for toxicity. The dose-limiting dose level was 175 mg/m2 paclitaxel and 90 mg/m2 epirubicin with limiting toxicities of febrile neutropenia, diarrhea and esophagitis. The addition of G-CSF did not allow escalation of epirubicin. No significant cardiac toxicity was observed. Epirubicin pharmacokinetics were studied during the first 2 cycles in 6 patients, who were randomized to receive 1 cycle with no interval between the completion of the epirubicin and the commencement of the paclitaxel infusion and the other cycle with a 72-hour interval between the drugs. There was no substantial effect of paclitaxel on epirubicin or epirubicinol pharmacokinetics, although there was a marginal increase in glucoronidation. In conclusion, paclitaxel 175 mg/m2 and epirubicin 75 mg/m2 is recommended for phase II and III studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006219601797
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  • 10
    Electronic Resource
    Electronic Resource
    Activity and DNA binding of new organoamidoplatinum (II) complexes (1999)
    Springer
    Investigational new drugs 17 (1999), S. 1-15 
    Details
    ISSN: 1573-0646
    Keywords: cisplatin analogues ; in vitro transcription ; DNA interstrand crosslinks ; cell uptake ; anticancer activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Two series of organoamidoplatinum (II) complexes were synthesized [Class 1, Pt(NRCH2)2L2 and Class 2, Pt(NRCH2CH2NR2′)L(X)] and their antitumour activity examined by a range of in vitro, cellular and animal studies. All Class 1 compounds exhibited activity comparable to cisplatin in mouse leukemia L1210 cells, but were at least 8-fold more active against the cisplatin-resistant L1210/R line. The lead compound 1a (R=p−HC6F4) caused nearly complete tumour regression in the ADJ/PC6 mouse tumour model. Compound 1a exhibited similar DNA reactivity to cisplatin, resulting in virtually identical DNA sequence specificity as cisplatin, and had similar time and concentration dependency of interstrand crosslinks. Compared with cisplatin, 1a showed 3-fold greater cellular uptake into human ovarian carcinoma 2008 cells, and this was dramatically enhanced to 17-fold in the cisplatin-resistant 2008/R line. The activity of 1a, therefore, appears to be due at least in part to a greater cellular uptake into tumour cells, particularly cisplatin-resistant cells, and once in the cell it reacts with DNA in a similar manner to that of cisplatin. The enhanced uptake and enhanced cytotoxicity of Class 1 compounds, and 1a in particular, may be due to a greater hydrophobicity compared with cisplatin. The activity of the Class 2 compounds, especially in the cisplatin-resistant cell lines, is unusual because they have trans amine ligands, and further study of both classes of compounds is warranted.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006263917610
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