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Phase I trial of dihydrolenperone in lung cancer patients: A novel compound within vitro activity against lung cancer (1993)

Johnson, Bruce E. ; Parker, Robert ; Tsai, C. M. ; [et al.]

Springer

Investigational new drugs 11 (1993), S. 29-37

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ISSN: 1573-0646

Keywords: dihydrolenperone ; drug evaluation ; drug screening assays ; antitumor ; carcinoma ; non-small cell lung carcinoma ; oat cell

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Summary Antitumor activity of the butyrophenone dihydrolenperone in non-small cell lung cancer was initially suggested byin vitro screening against tumor cells derived from fresh surgical samples using the human tumor colony-forming assay. We have completed a directed phase I trial in patients with lung cancer. Thirty-two patients with lung cancer have completed 25 courses of therapy at doses of 10 to 60 mg/square meter orally on a twice daily schedule. Twenty-three men and 9 women with a median age of 55 (range 24–69) were entered. Twenty-four were performance status 0 or 1 and 8 were 2. The maximum tolerated dose was 50 mg/square meter orally twice daily and the dose limiting toxicity was somnolence. Of the 32 patients, 18 developed symptomatic hypotension (grade 1 or 2). There was no significant hematologic, renal, or hepatic toxicity.In vitro drug testing using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (thiazolyl blue)] assay confirmed 50% inhibition of non-small cell and small cell lung cancer cell line growth at 70–450 micromolar concentrations. Plasma dihydrolenperone levels were at least 75-fold less than levels at whichin vitro activity was observed. We conclude: 1) the maximum tolerated dose in our study is 50 mg/square meter orally twice daily, 2) the dose-limiting side effect of dihydrolenperone is somnolence, and 3) the concentrations of dihydrolenperone observed in plasma are significantly lower than those associated within vitro activity.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00873907

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Transferrin dependence of Ga(NO3)3 inhibition of growth in human-derived small cell lung cancer cells (1996)

Weiner, Ronald E. ; Avis, Ingallil ; Neumann, Ronald D. ; [et al.]

New York, N.Y. : Wiley-Blackwell

Journal of Cellular Biochemistry 63 (1996), S. 276-287

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ISSN: 0730-2312

Keywords: Ga nitrate ; transferrin ; transferrin receptors ; small cell lung cancer ; Life Sciences ; Molecular Cell Biology

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Biology , Chemistry and Pharmacology , Medicine

Notes: The effect of a combination of anti-transferrin receptor (TFR) antibody, 42/6, and Ga(No3)3 on cell growth was examined in small cell lung cancer (SCLC) cell lines: classic, NCl-H209, NCl-H345, NCl-H510; and variant, NCl-H82 and NCl-N417. The role of TFR and transferrin(TF) in Ga(No3)3 cellular uptake was also tested. Exogenous TF did not enhance the cytotoxicity of Ga. At 〉 3 μg/mL, Ga(No3)3 inhibited growth in all cell lines in TF-supplemented or deficient media. At 〈 3 μg/mL, Ga stimulated growth for all cells but this effect was eliminated by TF or 42/6. Classic SCLC lines required 3-4-fold less exogenous gallium than variant lines to reduce cell number by 50%. The mean Ga uptake (ng/106 cells) in H345 and H209 cell lines was 4-5-fold compared to H82 and N417 uptake (P 〈 0.001). 42/6 reduced exogenous TF-stimulated growth. Antibody plus Ga(No3)3 caused a slight further cell number decline in all cell lines in TF-supplemented or deficient media. These results suggest that the addition of 42/6 antibody treatment would not increase the effectiveness of Ga(No3)3 in patients. Both exogenous and endogenous TF and TFR play an important role in Ga uptake in these cells. © 1996 Wiley-Liss, Inc.

Additional Material: 5 Ill.