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Evaluation of arylmethylaminopropanediols by a novel in vitro pharmacodynamic assay: correlation with antitumor activity in vivo.

Publication ,  Journal Article
Adams, DJ; Watkins, PJ; Knick, VC; Tuttle, RL; Bair, KW
Published in: Cancer Res
June 15, 1990

The pharmacodynamics of a new series of antitumor DNA intercalators, known as arylmethylaminopropanediols (AMAPs), has been evaluated in vitro against adherent (MCF-7 human breast cancer) and nonadherent (P388 murine leukemia) cell lines. Previous work had shown that the in vitro antitumor activity of the model AMAP crisnatol was a function of exposure (Cn x T), rather than concentration alone. A unique exposure parameter, the minimum C x T, was proposed as an end point for antitumor activity in cell culture. Comparison of crisnatol to several established agents by the minimum C x T versus the standard concentration producing 10% survival indicated that these end points were not equivalent. The current work examined the validity of the pharmacodynamic approach using AMAP isomers from three different ring systems that were known to exhibit a spectrum of activity against the P388 tumor in vivo. The results indicated that antiproliferative, but not cytotoxic, activity of AMAPs in the pharmacodynamic assay correlated with their differential activity in vivo, expressed as percentage of increase in life span. In contrast, the concentration producing 10% survival either at 1 h or after continuous exposure did not show a similar correlation. The pharmacodynamic assay also revealed that certain AMAPs, while equipotent by concentration alone, required significantly less time and therefore less overall exposure for efficacy. Finally, the activity of AMAP isomers in P388 cells differed from that in MCF-7 cells, which may indicate AMAP selectivity for certain tumor types. Since AMAP action was a function of exposure, drug effects on cellular targets could likewise depend on exposure rather than concentration. These findings emphasize the importance of relating drug mechanisms to the pharmacodynamics of anticancer agents.

Duke Scholars

Published In

Cancer Res

ISSN

0008-5472

Publication Date

June 15, 1990

Volume

50

Issue

12

Start / End Page

3663 / 3669

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Propylene Glycols
  • Oncology & Carcinogenesis
  • Methylamines
  • Leukemia, Experimental
  • Leukemia P388
  • Humans
  • Fluorenes
  • Chrysenes
  • Chemistry
 

Citation

APA
Chicago
ICMJE
MLA
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Adams, D. J., Watkins, P. J., Knick, V. C., Tuttle, R. L., & Bair, K. W. (1990). Evaluation of arylmethylaminopropanediols by a novel in vitro pharmacodynamic assay: correlation with antitumor activity in vivo. Cancer Res, 50(12), 3663–3669.
Adams, D. J., P. J. Watkins, V. C. Knick, R. L. Tuttle, and K. W. Bair. “Evaluation of arylmethylaminopropanediols by a novel in vitro pharmacodynamic assay: correlation with antitumor activity in vivo.Cancer Res 50, no. 12 (June 15, 1990): 3663–69.
Adams DJ, Watkins PJ, Knick VC, Tuttle RL, Bair KW. Evaluation of arylmethylaminopropanediols by a novel in vitro pharmacodynamic assay: correlation with antitumor activity in vivo. Cancer Res. 1990 Jun 15;50(12):3663–9.
Adams DJ, Watkins PJ, Knick VC, Tuttle RL, Bair KW. Evaluation of arylmethylaminopropanediols by a novel in vitro pharmacodynamic assay: correlation with antitumor activity in vivo. Cancer Res. 1990 Jun 15;50(12):3663–3669.

Published In

Cancer Res

ISSN

0008-5472

Publication Date

June 15, 1990

Volume

50

Issue

12

Start / End Page

3663 / 3669

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Propylene Glycols
  • Oncology & Carcinogenesis
  • Methylamines
  • Leukemia, Experimental
  • Leukemia P388
  • Humans
  • Fluorenes
  • Chrysenes
  • Chemistry