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  • 1
    Electronic Resource
    Electronic Resource
    Therapeutic response and potential pitfalls in phase I clinical trials of anticancer agents conducted in Japan (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 451-454 
    Details
    ISSN: 1432-0843
    Keywords: Key words: Phase I clinical trial – Anticancer agent – Response rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. The published reports of phase I clinical trials of anticancer agents conducted in Japan from 1981 to 1991 were reviewed. A total of 56 clinical studies that evaluated 38 different agents were reviewed. An average of five agents were studied each year. A total of 2200 patients had been recruited into the 56 clinical trials conducted during this period. A total of 91 patients (4.1%) responded to the treatment, with 23 showing a complete response (1.1%) and 48, a partial response (2.2%). In all, 62% of the responses were observed when patients were treated with doses ranging from 76% to 125% of the recommended doses for phase II studies. The response rates obtained for hematological malignancies were higher than those reported for other malignancies. The past status of phase I clinical trials in Japan can be summarized as follows. (1) A median of seven institutes participated in a single trial. The number of institutes participating correlated with the number of patients enrolled. However, too many institutes participated in a single phase I clinical trial in some studies. (2) The median duration of study for the clinical trials was 14 months. The duration of study was too long in some studies, considering the small number of patients enrolled. In conclusion, the methodology of phase I clinical trials of anticancer agents conducted in Japan should be improved in an efficient and scientific manner, especially for the testing of imported agents.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685653
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  • 2
    Electronic Resource
    Electronic Resource
    The influence of relative body weight on toxicity of combination chemotherapy with cisplatin and etoposide (1998)
    Springer
    Cancer chemotherapy and pharmacology 42 (1998), S. 386-390 
    Details
    ISSN: 1432-0843
    Keywords: Key words Body mass index ; Interpatient variability ; Dose adjustment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: This study was conducted to determine whether there was any relationship between the adverse toxicity of combination chemotherapy and clinical values including age, sex, creatinine clearance (Ccr), body surface area and relative body weight. Methods: Cisplatin at a dose of 80 mg/m2 on day 1 and etoposide at a dose of 100 mg/m2 on days 1, 2 and 3 were given to 42 consecutive patients with solid tumors. All patients had normal major organ function and received uniform hydration therapy. Results: Body Mass Index as a measure of relative body weight was inversely correlated with the percentage decrease in white blood cells (P = 0.0681) and platelet count (P = 0.0115). Body surface area was also inversely correlated with leukopenia (P = 0.0171) and thrombocytopenia (P = 0.0058). In contrast, age, sex and Ccr had no significant relationship with adverse toxicity. Conclusions: It is concluded that dose adjustment of combination chemotherapy with cisplatin and etoposide according to age or ideal body weight is not appropriate and that a conventional dose modification method based solely on body surface area is probably not sufficient to reduce interpatient variability of cancer chemotherapy. A pharmacokinetic and pharmacodynamic study of combination chemotherapy is warranted to establish the ideal dose modification method.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050834
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  • 3
    Electronic Resource
    Electronic Resource
    Pharmacokinetic study of low- versus high-dose medroxyprogesterone acetate (MPA) in women (1998)
    Springer
    Cancer chemotherapy and pharmacology 42 (1998), S. 1-8 
    Details
    ISSN: 1432-0843
    Keywords: Key words Pharmacokinetics ; MPA ; Drug-to-drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The present study was conducted to compare the pharmacokinetics (PK) of low-dose versus high-dose medroxyprogesterone (MPA) as a once-daily oral administration. Of 32 patients, all women, enrolled in this PK study, 18 received 600 mg MPA daily and 14 received 1200 mg daily. Detailed PK data were obtained on day 1 and after more than 4 weeks of MPA treatment. In addition, multiple data for the minimum steady-state concentration (Css min) were analyzed. The MPA serum concentrations were measured by high-performance liquid chromatography. Wide interpatient variability was found in the PK parameters obtained both on day 1 and after more than 4 weeks. There were no clear relationships between the oral dose and the MPA peak concentration (Cmax), area under the time versus concentration curve (AUC), or mean Css min. Weight gains of 10% or more were demonstrated more frequently in the high-dose group (P〈0.01). Liver dysfunction (n=5) did not influence the PK of MPA. Five patients demonstrated extremely low AUC and Cmax (〈10 ng/ml) values on day 1. Phenobarbital, dexamethasone and betamethasone were being taken concomitantly with the MPA each by one patient. The serum MPA concentrations were markedly increased after the discontinuation of phenobarbital in that patient, suggesting a drug interaction. At present we cannot recommend the high dose of MPA, except in clinical studies, from a PK or a pharmacodynamic points of view.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050777
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  • 4
    Electronic Resource
    Electronic Resource
    In vitro colony inhibition of carboplatin against stomach and lung cancer cell lines in comparison with cisplatin (1987)
    Springer
    Cancer chemotherapy and pharmacology 19 (1987), S. 197-200 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effects of carboplatin and cisplatin on colony formation in stomach and lung cancer cell lines were examined and compared. The colony-inhibitory activity of carboplatin against stomach and lung cancer cell lines was similar to that of cisplatin when one-tenth of the peak plasma concentration of each drug was used (r=0.80). One of the four stomach cancer cell lines was sensitive to carboplatin although all the stomach cancer cell lines were resistant to cisplatin. Of the three small cell lung cancer cell lines tested, two were sensitive to both carboplatin and cisplatin; and only one cell line (N857) was resistant to cisplatin; all the non-small cell cancer cell lines tested were resistant to both drugs. On the basis of these preliminary results, we suggest that carboplatin has potential therapeutic activity against stomach cancer and should be evaluated carefully from this aspect.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00252972
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  • 5
    Electronic Resource
    Electronic Resource
    The different effects of recombinant human tumor necrosis factor on rat fibrosarcoma sublines (1987)
    Springer
    Cancer immunology immunotherapy 24 (1987), S. 185-189 
    Details
    ISSN: 1432-0851
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The antitumor effect of recombinant human tumor necrosis factor (rH-TNF) on two clones of rat fibrosarcoma with different metastatic potential to lymph nodes was examined. The colony formation of clone A, which has high metastatic potential, was completely inhibited by continuous exposure to rH-TNF at 50 U/ml. In contrast, colony formation of clone G, which has low metastatic potential, was not inhibited by high concentrations of rH-TNF (10,000 U/ml). The inhibitory effect of rH-TNF on colony formation by clone A was also observed with a 1-h exposure to rH-TNF. This effect was time and concentration dependent, as determined by the colony assay, 3H-thymidine uptake assay, and 51Cr-release assay. 3H-thymidine and 3H-uridine uptake per cell of clone A exposed to rH-TNF was not decreased. This suggests that the mechanisms of the antitumor effect of rH-TNF were not due to inhibition of DNA and RNA synthesis of tumor cells. In vivo growth and lymph node metastases of clone A inoculated i.p. to Donryu strain rats were completely suppressed by 14 consecutive i.p. injections of 105 or 106 U/kg per day of rH-TNF. On the other hand the growth of clone G was not influenced by rH-TNF administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00205627
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  • 6
    Electronic Resource
    Electronic Resource
    Comparative study of the antitumor effect of two types of murine recombinant interferons, (β) and (γ), against B16-F10 melanoma (1988)
    Springer
    Cancer immunology immunotherapy 26 (1988), S. 109-113 
    Details
    ISSN: 1432-0851
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A comparative study of the antitumor effect of murine recombinant interferon(β) 〈Mu-rIFN(β)〉 and murine recombinant interferon(γ) 〈Mu-rIFN(γ)〉 on B16-F10 melanoma was conducted. Administration of Mu-rIFN(γ) i.p. into C57BL/6 mice on days 1 to 7 produced a higher suppressive effect than Mu-rIFN(β) both on the growth of s.c. implanted tumor and on the formation of artificial pulmonary metastasis. Pharmacokinetic study of Mu-rIFN(γ) demonstrated that high plasma levels were retained for a long time. In clonogenic assay, Mu-rIFN(γ) at 1000 units/ml showed about 80% inhibition of colonies of B16-F10 melanoma. However, Mu-rIFN(β) hardly inhibited the colonies, even at 1000 units/ml. Augmentation of natural killer (NK) cytotoxicity was much greater with Mu-rIFN(β) than Mu-rIFN(γ), whereas Mu-rIFN(γ) enhanced the cytotoxicity of peritoneal macrophages more strongly than Mu-rIFN(β). Injection of Mu-rIFN(γ) i.p. 1 day before tumor challenge also inhibited the formation of pulmonary metastasis of B16-F10 melanoma. However, pretreatment of mice with carrageenan significantly suppressed the inhibitory effect of Mu-rIFN(γ). From these results, it is suggested that the inhibitory effect of Mu-rIFN(γ) on the tumor growth and metastases of B16-F10 melanoma is mediated partly by direct antitumor effect and partly by the activation of macrophages, and that the augmentation of NK activity contributes mainly to the antitumor effect of Mu-rIFN(β).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00205602
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  • 7
    Electronic Resource
    Electronic Resource
    Prediction of the antitumor activity of new platinum analogs based on their ex vivo pharmacodynamics as determined by bioassay (1991)
    Springer
    Cancer chemotherapy and pharmacology 27 (1991), S. 263-270 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We report the predictive model for the clinical response of new platinum analogs against lung cancer by a bioassay using human lung-cancer cell lines including small-cell (SCLC) and non-small-cell lung cancer (NSCLC). Exponentially growing cells of six different SCLC and sic NSCLC lines were exposed to different concentrations of the three platinum compounds, cisplatin, carboplatin, and 254-S in a double-agar colony-forming cell assay. The concentrations inhibiting 50% of colony formation (IC50 value) for cisplatin, carboplatin and 254-S in SCLC cell lines were significantly lower than those in NSCLC cell lines. A total of 15 patients entered the pharmacological study. In all, 80 mg/m2 cisplatin, 450 mg/m2 carboplatin, and 100 mg/m2 254-S were each given to five patients by intravenous drip infusion. Bioassay as well as chemical assay was achieved by clonogenic techniques using NCI-H-69 (SCLC cell line) and PC-9 (NSCLC cell line) as target cells. Biological comparison of antitumor activity was performed on the basis of the antitumor activity of patients' plasma using the antitumor index (ATI), which was defined as the area under the percentage of colony suppression versus time curve obtained by bioassay and calculated by the trapezoidal rule. When NCI-H-69 and PC-9 were used as target cells for bioassay, colony-inhibitory activity was revealed by the ATIs. The ATIs obtained by bioassay showed better correlation than the AUCs obtained by chemical assay with the clinical response for cisplatin and carboplatin against SCLC and NSCLC, according to the following equation: [Reported Response (%)]=11.5668+0.0014×[ATI] (r=0.97). The response rates for 254-S against SCLC and NSCLC were predicted by this formula to be 40%–65% and 14%–16%, respectively. 254-S is prospectively suspected of having the same, if not more, activity then carboplatin against SCLC and of having almost the same activity as cisplatin against NSCLC.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685110
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  • 8
    Electronic Resource
    Electronic Resource
    A prognostic-factor risk index in advanced non-small-cell lung cancer treated with cisplatin-containing combination chemotherapy (1992)
    Springer
    Cancer chemotherapy and pharmacology 30 (1992), S. 1-6 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Prognostic factors for response and survival were retrospectively evaluated in 192 previously untreated patients with advanced non-small-cell lung cancer (NSCLC) who had received either vindesine plus cisplatin or mitomycin plus vindesine plus cisplatin as initial treatment. Univariate analysis demonstrated that squamous-cell histology, early stage, and a small number of metastatic sites were favorable prognostic factors for response to chemotherapy. Multivariate analysis using Cox's proportional hazard model indicated that the number of metastatic sites was the only significant pretreatment factor for response (P=0.0005). Multivariate regression analysis revealed that the number of metastatic sites (P=0.0002), sex (P=0.0009), serum albumen levels (P=0.0018), performance status (P=0.0026) and lactic dehydrogenase values (P=0.0026) contributed independently to survival. On the basis of these five prognostic factors, a prognostic index for survival was used to define three prognostic groupings (good, intermediate, and poor) for survival (median survival, 16.5 vs 9.4 vs 4.6 months;P=0.0001). This particular regression model should aid in the design and analysis of new treatment strategies and may be useful for indirect comparisons of different studies carried out in similar patient populations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686477
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  • 9
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of (glycolato-0,0′)-diammine platinum (II), a new platinum derivative, in comparison with cisplatin and carboplatin (1989)
    Springer
    Cancer chemotherapy and pharmacology 23 (1989), S. 243-246 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pharmacokinetics of (glycolato-0,0′)-diammine platinum (II) (254-S; NSC 375101D), one of the new platinum analogues, was examined in a phase I study of this drug and compared with that of cisplatin and carboplatin. All drugs were given in short-term (30-min) i.v. drip infusions; the doses of 254-S, cisplatin, and carboplatin were 100, 80, and 450 mg/m2, respectively. Platinum concentrations in whole plasma, plasma ultrafiltrate, and urine were determined by atomic absorption spectrometry. After the infusion, the plasma concentration of total platinum for the three agents decayed biphasically. Ultrafilterable platinum in plasma decreased in a biexponential mode after infusions of 254-S and carboplatin, whereas the free platinum of cisplatin showed a monoexponential disappearance. The peak plasma concentrations and AUC for free platinum were 5.31 μg/ml and 959 μg/min per ml for 254-S, 3.09 μg/ml and 208 μg/min per ml for cisplatin, and 19.90 μg/ml and 3446 μg/min per ml for carboplatin, respectively. The mean ratio of plasma ultrafilterable platinum to total platinum were calculated, and the results showed that the protein-binding abilities of 254-S and carboplatin were almost identical. More than 50% of the 254-S was excreted in the urine within the first 480 min after its administration. Thrombocytopenia was reported as a dose-limiting toxicity for both 254-S and carboplatin. This similarity in side effects may mainly be due to the comparable pharmacokinetic behavior of these two platinum compounds.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00451649
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  • 10
    Electronic Resource
    Electronic Resource
    Therapeutic response and potential pitfalls in phase I clinical trials of anticancer agents conducted in Japan (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 451-454 
    Details
    ISSN: 1432-0843
    Keywords: Phase I clinical trial ; Anticancer agent ; Response rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The published reports of phase I clinical trials of anticancer agents conducted in Japan from 1981 to 1991 were reviewed. A total of 56 clinical studies that evaluated 38 different agents were reviewed. An average of five agents were studied each year. A total of 2200 patients had been recruited into the 56 clinical trials conducted during this period. A total of 91 patients (4.1%) responded to the treatment, with 23 showing a complete response (1.1%) and 48, a partial response (2.2%). In all, 62% of the responses were observed when patients were treated with doses ranging from 76% to 125% of the recommended doses for phase II studies. The response rates obtained for hematological malignancies were higher than those reported for other malignancies. The past status of phase I clinical trials in Japan can be summarized as follows. (1) A median of seven institutes participated in a single trial. The number of institutes participating correlated with the number of patients enrolled. However, too many institutes participated in a single phase I clinical trial in some studies. (2) The median duration of study for the clinical trials was 14 months. The duration of study was too long in some studies, considering the small number of patients enrolled. In conclusion, the methodology of phase I clinical trials of anticancer agents conducted in Japan should be improved in an efficient and scientific manner, especially for the testing of imported agents.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685653
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    Paper (German National Licenses)
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