Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fenretinide [N-(4-hydroxyphenyl)retinamide, 4-HPR] is an effective agent for the inhibition of N-nitroso-N-methylurea-induced breast cancer in rats. This compound has been studied extensively and proved to be safer and less teratogenic than many other retinoids. A major characteristic of 4-HPR is its ability to concentrate in the granular and fat tissue of the breast instead of in the liver. Between January and June 1986, we carried out a phase I study on 101 patients divided into four randomized groups receiving placebo and 100, 200, and 300 mg/day of 4-HPR. Patients received the drug for 6 months without any major toxic effect. This finding was confirmed by another 6-month study in which patients received a common dose of 200 mg/day. In March 1987, a phase III study was started to evaluate the effectiveness of 4-HPR in preventing contralateral primary tumors in women who had already been treated for breast cancer. If 4-HPR succeeds in preventing second primaries in breast cancer patients, it may be useful for a wider group of subjects at high risk for breast cancer. This randomized study was designed with two arms: an intervention group versus a group receiving no treatment. Patients in the intervention group will be treated with 200 mg/day 4-HPR for 5 years. Patients in the control group will not be treated. A further 2 years of follow-up is planned for both groups. Currently, 2450 patients have been recruited. We expect a total accrual of 3500 patients by the end of 1992.
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PMID:Chemoprevention of breast cancer with retinoids. 153 5

The inhibitory effects of N-(4-hydroxyphenyl)retinamide (HPR) and its glucuronide derivative on the growth of MCF-7 human breast cancer cells in vitro were compared. The results indicate that the glucuronide had slightly greater potency and much less cytotoxicity than the free retinoid. At a concentration of 10(-6) M, HPR inhibited MCF-7 cell growth by approximately 25%, whereas an equimolar concentration of the glucuronide caused a 40% growth inhibition. Higher concentrations of HPR were highly cytotoxic. At a 10(-5) M concentration of the glucuronide, cell viability was 77%, and 65% of the cells were able to resume growth. On the other hand, at 10(-5) M HPR, cell viability dropped to 49%, and only 15% of the cells were capable of resuming growth. The lower cytotoxicity and higher potency of the retinoid glucuronide compared to the parent retinamide suggest that the conjugate may have a chemotherapeutic advantage over the parent compound. The apparent higher efficacy of HPR in combination with glucarate (GT) compared to the single agents could be due to increased net formation of HPR glucuronide conjugate following conversion of GT to the beta-glucuronidase inhibitor, D-glucaro-1,4-lactone. However, HPLC analysis of the cell metabolites did not show any detectable levels of the retinoid glucuronide upon treatment of MCF-7 cells with HPR and GT.
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PMID:Growth suppression of human breast carcinoma cells in culture by N-(4-hydroxyphenyl)retinamide and its glucuronide and through synergism with glucarate. 182 40

These studies describe the detection of a haptoglobin species, its characterization as the HPR gene product, and its association with both pregnancy and neoplasia. Previous work showed that the early recurrence of human breast cancer correlated with immunohistochemical staining with a commercial antiserum ostensibly directed against pregnancy-associated plasma protein A (PAPP-A). Use of this antiserum to guide purification of the putative antigen led to the present identification and purification of a strongly immunoreactive protein species distinct from PAPP-A that was present in the plasma of pregnant women at term. Unlike PAPP-A, a homotetramer of 200-kDa polypeptides, the immunoreactive protein consists of a light (alpha) chain (16.5 kDa) and a heavy (beta) chain (40 kDa); protein microsequencing of the beta chain showed it to be a member of the haptoglobin family. The alpha chain of this haptoglobin species differs from ordinary haptoglobin 1 and 2 alpha chains both structurally and immunologically and represents the product of the HPR gene, haptoglobin-related protein (Hpr), since (i) the apparent molecular mass is the same as that predicted for Hpr alpha chain, (ii) the peptide map differs from that of haptoglobin 1 in a manner predicted by the HPR nucleotide sequence, (iii) monospecific antibodies that react with epitopes shared by the unique alpha chain and a synthetic peptide derived from the HPR nucleotide sequence do not detect these epitopes in either haptoglobin 1 or 2, and (iv) sequences of alpha-chain peptides were consistent with this identification, excluding haptoglobin 1 but not haptoglobin 2. The immunohistochemical reactivity of antibodies raised to the synthetic Hpr peptide is similar to that of anti-PAPP-A. Moreover, staining of neoplastic breast tissue is abolished by preincubation with purified Hpr.
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PMID:Expression of haptoglobin-related protein and its potential role as a tumor antigen. 246 47

The early discrimination of clinically aggressive breast cancer from indolent disease would be clinically useful. Some human breast cancers express haptoglobin-related protein (Hpr), the HPR gene product, or a substance that shares epitopes with it. We retrospectively examined the association between the expression of Hpr and the recurrence of cancer in 70 patients with early breast cancer (Stage I or II) treated by mastectomy from 1977 through 1985, using immunohistochemical analysis of routinely processed paraffin-embedded tissue and evaluating it without knowledge of the patients' status. The expression of Hpr epitopes was associated with earlier recurrence according to life-table analysis (P less than 0.0002). Progesterone-receptor status (determined in 64 patients), tumor size, clinical stage, axillary-lymphnode status, mitotic index, and tumor necrosis also predicted recurrence, but multivariate analysis showed that Hpr-epitope expression was an independent prognostic factor. Since both Hpr status and progesterone-receptor status were independent predictors of recurrence, they could be combined to stratify the cases further: breast cancer was found to have recurred in 11 of 12 patients (92 percent) who were positive for Hpr and negative for progesterone receptors, in 5 of 11 (45 percent) who were positive for Hpr and positive for progesterone receptors, and in 9 of 41 (22 percent) who were negative for Hpr, in whom progesterone-receptor status had little effect. We conclude that Hpr-epitope expression is a clinically important predictor of the recurrence of cancer in patients with early breast cancer, especially in combination with progesterone-receptor status.
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PMID:Haptoglobin-related protein (Hpr) epitopes in breast cancer as a predictor of recurrence of the disease. 247 78

Fenretinide, N-(4-hydroxyphenyl)retinamide (HPR), is a synthetic retinoid which has been proven effective in inducing cell differentiation and in inhibiting carcinogen induced mammary tumors in rodents. Because of its efficacy and low toxicity in animals, HPR has been proposed for chemopreventive evaluation in humans. Thus, a randomized trial has been conducted to select a dose which can be administered over a lengthy period of time and with acceptable toxicity. The retinoid was administered orally to patients already operated on for breast cancer in daily doses of 100, 200 and 300 mg for 6 months and subsequently at 200 mg for another 6 months. No acute toxicity was found. Dermatological toxicity was minimal and no liver function abnormalities were observed. Nausea and headaches were infrequent and always mild. Menstrual irregularities were recorded with similar frequency in the treatment and placebo groups and appeared to be more age related than drug dependent. After 6 months of treatment one of 25 patients taking 300 mg HPR daily experienced impaired night vision, confirmed by the electroretinogram, and resolved by interruption of treatment. Because the 300 mg daily dose is possibly associated with impaired dark adaptation, the recommended dose for chemoprevention trials of HPR is 200 mg per day.
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PMID:Tolerability of the synthetic retinoid Fenretinide (HPR). 252 70

Fenretinide (HPR) is a synthetic retinoid which has been shown to cause a reduction in the incidence of carcinogen-induced epithelial tumors in experimental animals, and it has been chosen to be tested as a chemopreventive agent in humans. A study on plasma concentrations of HPR, of its metabolite N-(4-methoxyphenyl)retinamide (MPR), and on its effects on endogenous retinol was performed in groups of 14 to 18 breast cancer patients who received p.o. daily doses of placebo or 100, 200, and 300 mg of HPR for 6 mo and subsequently 200 mg for an additional 6 mo. After the first 5 mo of treatment, there was a linear relationship between doses of HPR administered and HPR, MPR, and retinol levels. HPR and MPR levels increased with the increase in dose, whereas retinol levels decreased, and the reduction was statistically significant compared with the placebo group after all the doses tested. Plasma retinol binding proteins (RBP) decreased proportionally to retinol (r = 0.96). The effect of HPR on retinol and RBP occurred early, since retinol and RBP levels had already been decreased, compared with the initial levels, by 38% and 26%, respectively, 24 h after a 200-mg HPR dose. After 12 mo of treatment, in patients treated with 200 mg daily, the dose chosen for a chemopreventive trial, HPR and retinol levels were similar to those found at 5 mo, suggesting no drug accumulation and no further retinol reduction, whereas MPR levels were higher. Following interruption of treatment, as HPR decreased, retinol increased with a linear relationship between log levels (r = 0.78); after about 50 days, HPR was present in trace amounts, and retinol levels were in the range of those of the placebo group. These data show that HPR treatment lowers retinol and RBP plasma concentrations. This effect is related to HPR levels and is reversible on cessation of HPR administration.
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PMID:Plasma retinol level reduction by the synthetic retinoid fenretinide: a one year follow-up study of breast cancer patients. 252 28

One hundred and one patients participating in a phase I study with the synthetic retinoid 4-HPR (4-hydroxyphenyl retinamide) were evaluated. The study was set up by Veronesi et al. during 1986 at the National Cancer Institute of Milan. The patients were randomized into 4 groups of therapy: 25 in the placebo group, 25 in the group receiving a daily dose of 100 mg of HPR, 26 in the group receiving 200 mg/day of HPR, and 25 in the group receiving 300 mg/day of HPR. All patients were previously treated at our Institute for breast cancer. None had received adjuvant therapy, chemotherapy or hormone therapy. After 4-5 months from the beginning of treatment, all patients received a series of tests to evaluate anxiety, depression and sexual life. Moreover, during one the follow-up checkups after 4-5 months, the patients filled-out a self-scoring mood questionnaire. The results did not show any particular differences between the groups, although we found that the administered drug and experimental setting do not interfere with the psychologic state of the participating patients.
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PMID:Psychologic aspects of patients participating in a phase I study with the synthetic retinoid 4-hydroxyphenyl retinamide. 296 38

Serum prolactin (HPr) has been measured in 459 patients 1 day before (HPr-1) and in 433 patients 10 days after (HPr-2) treatment. These came from an unselected sequence of 739 patients with operable breast cancer who had been referred to Guy's Hospital over a period of 5 yr. In addition HPr was measured in 100, or more, women at 3, 6 or 12 months after mastectomy. The median levels of either HPr-1 or HPr-2 were higher in pre-menopausal compared with postmenopausal patients (P = 0.03 and 0.06, respectively). Mastectomy was associated with increased serum HPr in both pre- and post-menopausal patients (P less than 0.001 in both cases). Average levels at 3 months, or after, were similar to those found before treatment. Nulliparous women had a higher median amount of HPr-1 than parous which was significant in premenopausal patients (P less than 0.008) whilst HPr-2 levels were not related to parity. Thus the rise in HPr associated with surgery was greater in parous than nulliparous women. Prolactin levels were not related to nodal status or tumour size. However, the amounts of HPR-2 were significantly greater in women with histological grade 3 tumours than those with grade 1 or 2. Standardising for either nodal status, tumour size or histological grade seven situations were found in which HPr-1 or HPr-2 levels were of prognostic significance. Although some of these significant associations could be fortuitous all shared a common feature that the least favourable prognosis was associated with the highest HPr levels.
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PMID:Serum prolactin levels in women with breast cancer and their relationship to survival. 373 52

Certain retinoids serve as effective chemopreventive agents against breast cancer. The effective retinoids are also antiproliferative agents for the mammary gland both in vivo and in vitro. N-(4-hydroxyphenyl)retinamide (HPR) can inhibit the occurrence of hyperplastic alveolar nodules in C3H mice in vivo and 7,12-dimethylbenz[a]anthracene-induced nodule-like alveolar lesions in vitro. Moreover, HPR can also inhibit the phorbol ester-induced promotion of hyperplastic alveolar nodule development in vitro. HPR is metabolized by the mammary gland in vitro and one of the metabolites competes for the cytosolic retinoic acid-binding protein although the metabolite is not all-trans-retinoic acid.
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PMID:Retinoids and mammary gland differentiation. 389 99

The retinoid N-(hydroxyphenyl) retinamide (4-HPR) appears to be a promising tool for chemoprevention of breast carcinoma, and clinical trials to evaluate its effect are in progress. However, its action on tumor cells has remained largely undefined. We report here that 4-HPR induced apoptosis and/or differentiation in breast cancer cell lines, independent of hormone receptor status and retinoic acid receptor expression, although it was slightly more efficient in inhibiting proliferation of estrogen receptor-positive cells. 4-HPR up-modulated expression of several differentiation markers (class 1 HLA, laminin, and beta 1 integrin chain) and down-regulated expression of molecules associated with tumor progression, including the p185/HER2 oncoprotein, the epidermal growth factor receptor, and the M(r) 67,000 laminin receptor. These data suggest that 4-HPR could exert a beneficial effect by inhibiting cell proliferation and modulating breast tumor aggressiveness.
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PMID:Modulation of markers associated with tumor aggressiveness in human breast cancer cell lines by N-(4-hydroxyphenyl) retinamide. 754 8


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