Evaluation of arylmethylaminopropanediols by a novel in vitro pharmacodynamic assay: correlation with antitumor activity in vivo.
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.
Adams
D J
DJ
Division of Cell Biology, Burroughs Wellcome, Research Triangle Park, North Carolina 27709.
Watkins
P J
PJ
Knick
V C
VC
Tuttle
R L
RL
Bair
K W
KW
D000818:Animals; D000873:Anthracenes / Q000493:pharmacokinetics / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002227:Carbazoles / Q000493:pharmacokinetics / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D002911:Chrysenes / Q000493:pharmacokinetics / Q000494:pharmacology; D005449:Fluorenes / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000378:metabolism*; D008744:Methylamines / Q000493:pharmacokinetics / Q000494:pharmacology; D011409:Propylene Glycols / Q000493:pharmacokinetics* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000873:Anthracenes; D002227:Carbazoles; D002911:Chrysenes; D005449:Fluorenes; D008744:Methylamines; D011409:Propylene Glycols; C007738:fluoranthene