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Pyrimido‐pyrimidine modulation of EGF growth‐promoting activity and p21 ras expression in rat mammary adenocarcinoma cells
Author(s) -
Lichtner Rosemarie B.,
Gallick Gary E.,
Nicolson Garth L.
Publication year - 1988
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.1041370211
Subject(s) - epidermal growth factor , fetal bovine serum , cell culture , cell growth , mammary tumor , clone (java method) , cell , biology , growth inhibition , medicine , cancer research , microbiology and biotechnology , endocrinology , biochemistry , cancer , dna , genetics , breast cancer
RA 233, a pyrimido‐pyrimidine analogue developed originally as an antiplatelet agent, has reduced the incidence of tumor metastases in clinical trials. However, in animal tumor models antimetastatic therapy using RA 233 has been inconsistent. We therefore tested RA 233 for additional effects, such as its direct action on tumor cells. Using the rat 13726NF mammary adenocarcinoma tumor system, low, nontoxic concentrations of RA 233 had pleiotropic and differential effects on two 13762NF tumor cell clones. The growth of MTC cells (low spontaneous metastatic potential) was not affected by low concentrations of RA 233 (50 m̈M) or epidermal growth factor (EGF) (up to 10 ng/ml) for 3 days in 0.5–10% fetal bovine serum. In contrast, MTLn3 (high spontaneous metastatic potential) cell cultures maintained for 3 days in low (0.5–1%) serum in the presence of 1.25–10 ng/ml EGF doubled in cell numbers compared with control cultures, and addition of 50 m̈M RA 233 abrogated the growth‐stimulatory effect of EGF. The inhibitory effect of RA 233 on MTLn3 cells was dose dependent and not due to cell toxicity as determined by cell viability, cell growth, and colony formation properties after drug removal. In addition, incubation of MTLn3 cell with 50 m̈M RA 233 resulted in an increase of p21 ras protein expression, whereas there was no effect on the level of p21 ras in identically treated MTC cells or when either clone was treated with 10 ng/ml EGF. The results suggest that among the heterogeneous effects of RA 233 on tumor cells, modulation of growth factor responses and regulatory molecules may be important.