Proline analogues such as cis-4-hydroxy-L-proline (CHP) and L-azetidine-2-carboxylic
acid (
A2C) were tested for their antitumor activity in tissue culture and in vivo. In culture, CHP specifically inhibited those
tumor cells that synthesized basement-membrane
collagen. CHP appeared to selectively inhibit
collagen biosynthesis with only a slight effect on
protein synthesis. Culturing cells on
type IV collagen matrix did not alter the antiproliferative effect of CHP. The inhibition of 450.1 mouse mammary
tumor cells was fully reversible when cultures were incubated for 6 or 12 hours with 25 micrograms CHP/ml but was irreversible after 24 hours of exposure. Of the
proline analogues tested against 450.1
tumor cells,
A2C and CHP were the most potent inhibitors of cell growth. These two compounds were therefore tested in vivo using 3 transplantable
tumors, all of which synthesized basement-membrane
collagen. CHP and
A2C were given twice daily to mice for 7 to 10 days at doses ranging from 50 mg/kg (body wt) to 600 mg/kg (body wt) per injection. Both CHP and
A2C were completely inactive against the 450.1 mammary
tumor and the EHS
sarcoma. Both compounds also caused considerable liver toxicity. Against CD8F1 mammary
tumors, treatment with maximum tolerated doses of CHP and
A2C resulted in a slight but insignificant inhibition of
tumor growth. While our studies confirmed previous findings that CHP specifically inhibited those
tumor cells that synthesized basement-membrane
collagen, CHP and
A2C did not appear to be efficacious
antitumor agents.