Suppression of rat mammary cancer development by N-(4-hydroxy-phenyDretinamide (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.

Inhibition of trans-Retinoic Acid-Resistant Human Breast Cancer Cell Growth by Retinoid X Receptor-Selective Retinoids

“…Retinoids, alone or in combination with an antiestrogen or interferons, inhibit the in vitro growth of human breast cancer cells (12-14, 29, 34, 51, 60-62). The natural retinoid derivative retinyl methyl ether (18) and the synthetic retinoids N-(4-hydroxyphenyl) retinamide (4-HPR) (44,45) and LGD1069 (17) effectively inhibited the development of carcinogen-induced mammary cancers in animals. Unfortunately, clinical trials on patients with advanced breast cancer showed no significant activity for retinoids (2,3,42).…”

Potent Cytotoxic Effects of Novel Retinamide Derivatives in Ovarian Cancer Cells

“…[13][14][15][16] It is currently in clinical trials for the treatment of several cancers. [17][18][19][20][21] However, the low plasma levels of 4-HPR available in patients have limited clinical trials, and led to a search for derivatives with better efficacy.…”

“…10) It has been reported that 4-HPR is cytotoxic against a wide variety of cancer cell lines, including ovarian cancer cells in vitro, 11,12) and is effective in reducing the sizes of breast, prostate, and ovarian cancer tumors in animal models. [13][14][15][16] Currently, 4-HPR is in clinical trials for the treatment of ovarian, breast, bladder, prostate, and lung cancers. [17][18][19][20][21] However, the plasma levels in patients receiving 200 mg of 4-HPR daily are under 1 mM, which is far less than the effective concentration (usually 10 mM) required to induce apoptosis in vitro.…”

Risks and Benefits of Retinoids in the Chemoprevention of Cancer

“…[57] It also inhibited the appearance of subsequent mammary tumours following removal of the first palpable tumour in carcinogentreated rats. [58] Fenretinide inhibition of carcinogenesis was enhanced by oophorectomy in rats with nitrosomethylurea-induced mammary cancers.l 59 ] When fenretinide was administered in the diet of rats whose first tumours were surgically removed, the animals had fewer recurrences and delayed latency compared with the control group. When the first tumour was not removed, fenretinide induced a regression of the lumps to a non-palpable stage.l 60 ] Fenretinide has been shown to work synergistically with the antiestrogen drug tamoxifen in inhibiting the induction of mammary tumours in carcinogen-treated rats.…”