Suppression of rat mammary cancer development by N-(4-hydroxyphenyl)retinamide (4-HPR) following surgical removal of first palpable tumor

Abstract

A study was conducted to determine whether N-(4-hydroxyphenyl)retinamide (4-HPR) affects the development of new mammary tumors subsequent to the surgical removal of the first palpable tumor. Sprague-Dawley female rats were injected i.v. with 35 mg N-methyl-N-nitrosourea (MNU) per killogram body weight at 50 days of age. The first palpable tumor was removed when 0.3-0.5 cm in diameter, and the animals placed on diets containing either 1, 2 or 3 mmol 4-HPR/kg diet. Placebo diet without 4-HPR served as control. Some animals were killed at the time of surgical removal of the first tumor and whole mounts of the mammary glands were prepared. Moreover, five animals per group were bled at 1, 3 and 6 months after commencing the 4-HPR diet and the levels of 4-HPR and N-(4-methoxyphenyl)retinamide (4-MPR) were determined. 4-HPR decreased tumor multiplicity in a dose-related manner, but cancer formation was only inhibited at the 2 and 3 mmol levels of 4-HPR. Whole mounts of mammary glands of rats treated with MNU demonstrated the presence of nonpalpable microscopic tumors in addition to the palpable tumor which was excised. Plasma levels of 4-HPR and 4-MPR increased with increasing dietary dose levels, but a linear relationship was not evident. However, the increase in plasma 4-HPR was directly correlated with an increased survival of the tumor-bearing animals. The results indicate that 4-HPR effectively inhibits the appearance of subsequent mammary tumors following excision of the first palpable tumor, and thus may be suitable for use as a chemopreventive agent in patients at increased risk for breast disease.