In vitro evaluation of an estradiol-linked nitrosourea in mammary carcinomas of mouse, rat and man.
In vitro activity of 1-(2-chloroethyl)-1-nitrosocarbamoyl-L-alanine-estradiol-17-ester (CNC-ala-17-E2) at three concentrations in transplanted MXT mammary carcinoma in B6D2F1 mice and autochthonous methylnitrosourea (MNU)-induced mammary carcinoma in Sprague-Dawley rats, as well as in 30 human primary breast carcinomas using the bilayer soft agar assay is described. Eighty-five per cent of MXT tumors showed a more than 70% inhibition of colony formation following CNC-ala-17-E2. In the MNU-induced model this high degree of inhibition was not observed: only 5% of individual tumors showed an inhibition up to 70%, but a superiority of the hormone-linked agent over the unlinked single agents was nevertheless discernible. In contrast, in human breast carcinomas a response at this sensitivity level could not be assessed. Thus, in the MXT mammary carcinoma the in vitro results paralleled previous findings in vivo, whereas in the MNU-induced autochthonous tumor model this close in vivo-in vitro correlation was not observed. The discrepancy between in vivo and in vitro results found in the autochthonous rat model indicates that hormone-linked nitrosoureas should not necessarily be abandoned for the treatment of human breast carcinoma on the basis of negative in vitro results alone.
Petru
E
E
Institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg, F.R.G.
Berger
M R
MR
Zeller
W J
WJ
Kaufmann
M
M
D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004958:Estradiol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005038:Ethylnitrosourea / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D008770:Methylnitrosourea; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D009588:Nitrogen Mustard Compounds / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; C017139:1-(2-chloroethyl)-1-nitrosourea; D004958:Estradiol; D008770:Methylnitrosourea; C056364:1-(2-chloroethyl)-1-nitrosocarbamoylalanine estradiol-17-ester; D005038:Ethylnitrosourea