The antiproliferative properties of lycopene, the major tomato carotenoid, were compared with those of alpha- and beta-carotene. Lycopene, delivered in cell culture medium from stock solutions in tetrahydrofuran, strongly inhibited proliferation of endometrial (Ishikawa), mammary (MCF-7), and lung (NCI-H226) human cancer cells with half-maximal inhibitory concentration of 1-2 microM; alpha- and beta-carotene were far less effective inhibitors. For example, in Ishikawa cells, a 4-fold higher concentration of alpha-carotene or a 10-fold higher concentration of beta-carotene was needed for the same order of growth suppression. The inhibitory effect of lycopene was detected after 24 hours of incubation, and it was maintained for at least three days. In contrast to cancer cells, human fibroblasts were less sensitive to lycopene, and the cells gradually escaped growth inhibition over time. In addition to its inhibitory effect on basal endometrial cancer cell proliferation, lycopene also suppressed insulin-like growth factor-I-stimulated growth. Insulin-like growth factors are major autocrine/paracrine regulators of mammary and endometrial cancer cell growth. Therefore, lycopene interference in this major autocrine/paracrine system may open new avenues for research on the role of lycopene in the regulation of endometrial cancer and other tumors.
Various studies support the view that analogs of luteinizing hormone-releasing hormone (LH- des-Gly10-[D-Ser(tBu)6]LH-RH ethylamide (buserelin) had no effect. The antagonists SB-29 and SB-30 also inhibited the rate of cell growth, as measured by cell number, while the LH-RH agonist buserelin had no significant effect. These results support the concept that these new LH-RH antagonists can directly inhibit the growth of human mammary tumors and thus might be suitable for the treatment of breast cancer.RHChronic administration of potent agonists of luteinizing hormone-releasing hormone (LH-RH) results in the inhibition of pituitary and gonadal function (1, 2) and creates a state of sex-steroid deficiency. Consequently, agonists of LH-RH can be used for the treatment of some hormone-dependent tumors, such as prostatic and breast cancer (1, 2). In view of many expected medical applications of LH-RH derivatives, more than 2000 analogs have been synthesized since the isolation and structural elucidation of LH-RH (3). Many agonistic analogs more potent than the parent hormone have been made (1, 2, 4). Several of these agonists are being used clinically (1, 2, 5). Potent inhibitory analogs of LH-RH, which block ovulation in laboratory animals, have also been synthesized (4). Several antagonists of LH-RH have been tested in men and women and shown to be active enough for practical use (4). LH-RH antagonists may offer certain advantages in the treatment of cancer as compared with the superagonists. While a repeated administration of LH-RH agonists is required to inhibit the pituitary and gonadal function and reduce the levels of sex steroids, the same effect may be obtained by a single administration of LH-RH antagonists (4). The inhibition of gonadotropin release by LH-RH antagonists starts immediately after its administration, while the agonists cause a transient stimulation of pituitary and gonadal function, which may result in a temporary clinical "flare-up" of the disease (5).LH-RH antagonists are frequently characterized by the nature of the residue at position 6. Some potent LH-RH antagonists contained D-arginine (hydrophilic basic substitution) at this position. However, this class of analogs produced transient edema of the face and extremities when administered subcutaneously to rats (6, 7). In preliminary human tolerance studies, side effects were also observed in some cases after administration of antagonists with basic D-amino acids at position 6. These reactions could be due to histamine liberation. These side effects delayed clinical use of LH-RH antagonists in humans.To MATERIALS AND METHODSPeptides. Buserelin was a gift from J. Sandow (Hoechst), ORG 30276 was obtained from L. Tax (Organon), the antagonists SB-29 and SB-30 were synthesized and purified in the Veterans Administration/Tulane University laboratory as reported (4). 1648The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U....
Several studies have supported the idea that LH-releasing hormone (LHRH) antagonists have a direct effect on mammary tumor cells. In this study, we have evaluated the potential role of the insulin-like growth factors (IGFs) on the growth of MCF-7 mammary tumor cells and the effect of LHRH analogs on IGF action. The mitogenic effects of IGF-I, IGF-II, and insulin were compared. IGF-I was found to be 3 times more potent than IGF-II and 30 times more potent than insulin, suggesting that the effects of these growth factors are mediated by the IGF-I receptor. IGFs released by MCF-7 cells were measured by specific RIA after acid extraction and chromatography, so as to avoid the interference of IGF-binding proteins. MCF-7 cells secreted IGF-II, but not IGF-I. Estradiol (10(-9) mol/L) stimulated IGF-II release; this release preceded the effect of estradiol on cell growth. The LHRH antagonist [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,D-Cit6,D-Ala10] LHR H (SB-75, CETRORELIX) inhibited basal, estrogen-induced, and IGF-induced growth. Moreover, this antagonist almost completely inhibited IGF-II release from MCF-7 cells. This effect preceded the inhibition of tumor cell growth. We conclude that a LHRH antagonist can inhibit the growth of breast tumors by interfering with the autocrine action of IGF-II and by directly inhibiting the growth stimulatory effect of IGFs.
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