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  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and toxicity of 120-hour continuous-infusion hydroxyurea in patients with advanced solid tumors (1996)
    Springer
    Cancer chemotherapy and pharmacology 39 (1996), S. 254-258 
    Details
    ISSN: 1432-0843
    Keywords: Key words Hydroxyurea ; Pharmacokinetics ; Toxicity ; Human ; Drug therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  A group of 18 patients with advanced cancer were entered on a phase I study of a 120-h continuous intravenous infusion of hydroxyurea. The dose of hydroxyurea was escalated in cohorts of patients from 1 to 2 to 3.2 g/m2 per day. The primary dose-limiting toxicity was neutropenia, often accompanied by leukopenia, thrombocytopenia and generalized skin rash. Prophylactic treatment of patients with dexamethasone and diphenhydramine hydrochloride prevented the skin rash, but not the hematopoietic toxicities. The pharmacokinetics of hydroxyurea were studied in all patients. The steady-state concentrations of hydroxyurea were linearly correlated with the dose (R 2 = 0.71, n = 18, P〈0.0001). The mean±SE concentrations were 93±16, 230±6 and 302±27 μM at 1, 2 and 3.2 g/m2 per day, respectively. The mean±SE renal and nonrenal clearances of hydroxyurea were 2.14±0.18 and 3.39±0.28 l/h per m2 (n = 16), neither of which correlated with the dose. The concentration of hydroxyurea in plasma decayed monoexponentially with a mean±SE half-life of 3.25±0.18 h (n = 17). The steady-state concentration of hydroxyurea was 〉200 μM in all nine patients treated at 2 g/m2 per day, a dose which was well tolerated for 5 days. We recommend this dose for phase II trials in combination with other antineoplastic agents.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050569
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  • 2
    Electronic Resource
    Electronic Resource
    High-dose toremifene as a cisplatin modulator in metastatic non-small cell lung cancer: targeted plasma levels are achievable clinically (1998)
    Springer
    Cancer chemotherapy and pharmacology 42 (1998), S. 504-508 
    Details
    ISSN: 1432-0843
    Keywords: Key words Lung cancer ; Toremifene ; Cisplatin ; Protein kinase C ; Phase II trial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: The triphenylethylenes tamoxifen and toremifene have been reported to enhance the cytotoxicity of cisplatin by inhibition of protein kinase C (PKC) signal transduction pathways. However, the concentrations of tamoxifen and toremifene required for chemosensitization in preclinical models are generally ≥5 μM, at least tenfold higher than plasma levels observed in patients receiving these agents as antiestrogenic therapy. As part of a translational phase II trial investigating the efficacy and potential molecular mechanism of high-dose toremifene as a cisplatin modulator in metastatic non-small-cell lung cancer, plasma concentrations of toremifene and its active metabolite N-desmethyltoremifene were measured to determine whether targeted levels could be achieved clinically. Methods: Treatment consisted of toremifene, 600 mg orally on days 1–7, and cisplatin, 50 mg/m2 intravenously on days 4 and 11, repeated every 28 days. Toremifene and N-desmethyltoremifene were measured by reverse-phase HPLC assay on days 4 and 11 prior to cisplatin infusion. Results: In the initial 14 patients, the mean total plasma concentrations of toremifene plus its N-desmethyl metabolite on days 4 and 11 were 14.04 (±8.6) μM and 9.8 (±4.4) μM, respectively. Variability in concentrations achieved did not correlate with renal or hepatic function, gender, or body surface area. Levels of N-desmethyltoremifene were higher on day 11 relative to toremifene concentrations. Conclusions: We conclude that plasma levels achieved compare favorably with the levels required for cisplatin chemosensitization and PKC modulation in vitro. Targeted toremifene levels can be achieved clinically with 600 mg orally daily in combination with cisplatin and are well tolerated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050852
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  • 3
    Electronic Resource
    Electronic Resource
    Phase I study of mitomycin C and menadione in advanced solid tumors (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 293-298 
    Details
    ISSN: 1432-0843
    Keywords: Key words. Mitomycin C ; Menadione ; Phase I studies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  A phase I study of mitomycin C with menadione (2-methyl-1,4-naphthoquinone, a vitamin K analogue which lowers intracellular pools of reduced glutathione) was designed as an approach to overcoming tumor cell resistance to alkylating agent chemotherapy. Patients with refractory solid tumors (n=51) were treated with a 48-h continuous intravenous infusion of menadione followed by a bolus intravenous dose of mitomycin C at the completion of the menadione infusion. Initial menadione doses of 8.0 and 4.0 g/m2 over 48 h were associated with hemolysis, so subsequent dose levels of menadione ranged from 1.0 to 3.0 g/m2 with mitomycin C from 5 to 20 mg/m2. All three patients treated with menadione at 8.0 g/m2 and the single patient treated at 4.0 g/m2 with mitomycin C at 5 mg/m2 developed clinically significant hemolysis despite the presence of red blood cell glucose-6-phosphate dehydrogenase. Subsequently, a revised escalation scheme for menadione was used, and all patients tolerated menadione doses of 1–2.5 g/m2 over 48 h with mitomycin C doses up to 20 mg/m2. Since the 3.0 g/m2 dose of menadione was associated with mild hemolysis in three of four patients, the maximum tolerated dose of menadione was established at 2.5 g/m2. All of the mitomycin dose levels were tolerated without unexpected toxicities attributable to the combination. Prolonged infusions of menadione at doses which have been associated with lowering of intracellular glutathione pools in short-term exposure are limited by dose-dependent hemolysis, probably due to depletion of erythrocyte glutathione by menadione-related redox cycling. There was no detectable deleterious effect of pre-exposure to menadione on mitomycin C tolerance. We recommend a combination of menadione at 2.5 g/m2 as a continuous intravenous infusion and mitomycin C at 15 mg/m2 for further study in solid tumors for which treatment with single-agent mitomycin C is appropriate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689046
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  • 4
    Electronic Resource
    Electronic Resource
    Phase I study of mitomycin C and menadione in advanced solid tumors (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 293-298 
    Details
    ISSN: 1432-0843
    Keywords: Mitomycin C ; Menadione ; Phase I studies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A phase I study of mitomycin C with menadione (2-methyl-1,4-naphthoquinone, a vitamin K analogue which lowers intracellular pools of reduced glutathione) was designed as an approach to overcoming tumor cell resistance to alkylating agent chemotherapy. Patients with refractory solid tumors (n=51) were treated with a 48-h continuous intravenous infusion of menadione followed by a bolus intravenous dose of mitomycin C at the completion of the menadione infusion. Initial menadione doses of 8.0 and 4.0 g/m2 over 48 h were associated with hemolysis, so subsequent dose levels of menadione ranged from 1.0 to 3.0 g/m2 with mitomycin C from 5 to 20 mg/m2. All three patients treated with menadione at 8.0 g/m2 and the single patient treated at 4.0 g/m2 with mitomycin C at 5 mg/m2 developed clinically significant hemolysis despite the presence of red blood cell glucose-6-phosphate dehydrogenase. Subsequently, a revised escalation scheme for menadione was used, and all patients tolerated menadione doses of 1–2.5 g/m2 over 48 h with mitomycin C doses up to 20 mg/m2. Since the 3.0 g/m2 dose of menadione was associated with mild hemolysis in three of four patients, the maximum tolerated dose of menadione was established at 2.5 g/m2. All of the mitomycin dose levels were tolerated without unexpected toxicities attributable to the combination. Prolonged infusions of menadione at doses which have been associated with lowering of intracellular glutathione pools in short-term exposure are limited by dose-dependent hemolysis, probably due to depletion of erythrocyte glutathione by menadione-related redox cycling. There was no detectable deleterious effect of pre-exposure to menadione on mitomycin C tolerance. We recommend a combination of menadione at 2.5 g/m2 as a continuous intravenous infusion and mitomycin C at 15 mg/m2 for further study in solid tumors for which treatment with single-agent mitomycin C is appropriate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689046
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  • 5
    Electronic Resource
    Electronic Resource
    Effects of storage on the binding of carboplatin to plasma proteins (1995)
    Springer
    Cancer chemotherapy and pharmacology 35 (1995), S. 254-256 
    Details
    ISSN: 1432-0843
    Keywords: Carboplatin ; CBDCA ; Protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Plasma ultrafiltrates are routinely used in pharmacokinetic studies of carboplatin. Experiments were performed to detect and quantitate artifactual decreases in the platinum concentration of ultrafiltrates prepared from plasma samples stored at −20°C and −70°C. Carboplatin was added to anticoagulated, whole human blood to produce a 20 μg/ml concentration. Plasma produced from the blood was stored frozen at either −20°C or −70°C. Aliquots from each storage condition were thawed and ultrafiltered once a week for up to 100 days. Platinum concentrations in ultrafiltrates and plasma were determined by flameless atomic absorption spectrometry. There was no loss of ultrafilterable platinum in plasma samples stored at −70°C, whereas there was a steady decrease in free platinum concentration in ultrafiltrates prepared from plasma samples stored at −20°C. These results imply that pharmacokinetic studies of carboplatin should use ultrafiltrates prepared immediately or that plasma for such studies should be stored at −70°C. Storage of carboplatincontaining plasma at −20°C and subsequent ultrafiltration is not acceptable, because measurement of platinum in such ultrafiltrates will be artifactually low.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686557
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  • 6
    Electronic Resource
    Electronic Resource
    Mitomycin C and menadione for the treatment of advanced gastrointestinal cancers: a phase II trial (1995)
    Springer
    Journal of cancer research and clinical oncology 121 (1995), S. 103-106 
    Details
    ISSN: 1432-1335
    Keywords: Mitomycin C ; Menadione Gastrointestinal cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A phase II trial of menadione (2.5 g/m2 as a continuous intravenous infusion over 48 h) followed by mitomycin C (10–20 mg/m2 i.v. bolus) administered every 4–6 weeks was performed in 43 patients with advanced gastrointestinal cancer. Menadione, a vitamin K analog that lowers intracellular pools of reduced glutathione, was combined with mitomycin C in an attempt to overcome thiol-mediated resistance to alkylating-agent chemotherapy. The median age of patients entered on this trial was 58 years; performance status ranged from 60%–100%. None of the 43 evaluable patients obtained an objective response to this combination regimen. Median survival was 6.6 months. Treatment with menadione and mitomycin C was reasonably well tolerated except for hematological toxicity. A total of 27% of treatment courses were complicated by grade 3 or 4 hematological toxicity including one episode of hemolytic anemia and one episode of hemolytic uremic syndrome. One patient developed irreversible interstitial pneumonitis, and 1 patient had an asymptomatic decrease in the left0ventricular ejection fraction. Despite preclinical evidence indicating that menadione pretreatment enhances the cytotoxicity of mitomycin C, our study documents the resistance of advanced gastrointestinal cancers, particularly colorectal cancer, to mitomycin C modulated by menadione.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01202221
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  • 7
    Electronic Resource
    Electronic Resource
    Mitomycin C and menadione for the treatment of lung cancer: a phase II trial (1995)
    Springer
    Investigational new drugs 13 (1995), S. 157-162 
    Details
    ISSN: 1573-0646
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A phase II trial of menadione [2.5 gm/m2 as a continuous intravenous (iv) infusion over 48 hours] followed by mitomycin C (10–20 mg/m2 iv bolus) administered every 4 to 6 weeks was performed in 23 patients with advanced lung cancer. Menadione, a vitamin K analog which lowers intracellular pools of reduced glutathione (GSH), was combined with mitomycin C in an attempt to overcome thiol-mediated resistance to alkylating agent chemotherapy. The median age of patients entered on this trial was 62 years; performance status ranged from 60–90%. Two of the 23 patients (9%; 95% confidence interval, 1% to 28%) had objective responses lasting 3.5 months and 13 months respectively, while 4 additional patients developed short unconfirmed responses (lacking follow-up response data to estimate response duration). Median survival for all patients was 5.5 months. Treatment with mitomycin C and menadione was well tolerated except for hematologic toxicity and cardiac events of unclear relationship to the study drugs. Thirty-one percent of treatment courses were complicated by grade 3 or 4 hematologic toxicity including one episode of hemolytic anemia. One patient developed interstitial pneumonitis. Two patients developed a decrease in left ventricular ejection fraction: one patient remained asymptomatic, but the other patient developed congestive heart failure. Although only 9% of patients had confirmed objective responses, 28% (5 of 18) of the patients with non-small cell lung cancer demonstrated biological activity (tumor regressions fulfilling the criteria for objective response on a single occasion but 3 patients lacking a follow-up measurement to document response duration) to this combination of mitomycin C and menadione. We conclude that further studies of chemomodulation in non-small cell lung cancer are appropriate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00872865
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  • 8
    Electronic Resource
    Electronic Resource
    Phase II trial of pyrazine diazohydroxide in androgen-independent prostate cancer (1998)
    Springer
    Investigational new drugs 16 (1998), S. 179-182 
    Details
    ISSN: 1573-0646
    Keywords: prostate cancer ; hormone refractory ; pyrazine diazohydroxide ; Phase II trial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract No effective therapy has been demonstrated for hormone refractory prostate cancer (HRPC). Pyrazine diazohydroxide (PZDH) is a novel antineoplastic agent with a broad range of activity in preclinical studies and a moderate toxicity profile in Phase I trials. We undertook a Phase II study of PZDH in HRPC utilizing decline in PSA as the primary end point. Fifteen patients were enrolled, median age of 70 (55–86), median pretherapy PSA 206 ng/ml (range 42–10,000). Four patients were African American. Sites of disease: bone only 7, soft tissue only 2, both 6. All were evaluable for toxicity and response. PZDH was administered at 250 mg/m2 IV every three weeks. The median number of cycles administered was two (range 1–6). Toxicity was mild, with only one patient manifesting serious (grade 3–4) toxicity. Unfortunately, activity was minimal with only a single patient demonstrating a 〉75% decline in PSA. As this patient's PSA began to rise almost immediately the response was considered transient and not felt to justify pursuing a second stage of the trial. Supporting this conclusion was the disappointing median survival of 220 days. In summary, we conclude that PZDH, while well tolerated at this dose and schedule has only minimal activity in HRPC.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006097109088
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