4-HPR modulates gene expression in ovarian cells

Ovarian cancer has a high rate of recurrence and subsequent mortality following chemotherapy despite intense efforts to improve treatment outcomes. Recent trials have suggested that retinoids, especially 4-(N-hydroxyphenyl) retinamide (4-HPR), play an important role as a chemopreventive agent and are currently being used in clinical trials for ovarian cancer chemoprevention as well as treatment. This study examines the mechanism of its activity in premalignant and cancer cells. We investigated the modulation of gene expression by 4-HPR in immortalized ovarian surface epithelial (IOSE) cells and ovarian cancer (OVCA433) cells with DNA microarray. Real time RT-PCR and western blotting were used to confirm the microarray results and metabolic changes were examined with optical fluorescence spectroscopy. 4-HPR resulted in an up-regulation of expression of proapoptotic genes and mitochondrial uncoupling protein in OVCA433 cells and modulation of the RXR receptors in IOSE cells, and down-regulation of mutant BRCA genes in both IOSE and OVCA433 cells. 4-HPR had a larger effect on the redox in the 433 cells compared to IOSE. These findings suggest that 4-HPR acts through different mechanisms in premalignant ovarian surface cells and cancer cells, with a preventive effect in premalignant cells and a treatment effect in cancer cells.     

Clinical significance of altered expression of retinoid receptors in oral precancerous and cancerous lesions: relationship with cell cycle regulators

Alterations in expression of retinoid receptors are implicated in human cancers. We hypothesized that altered expression of retinoic acid receptors (RARalpha,beta,gamma) and retinoid X receptor RXRalpha and their relationship with cell cycle regulators (p53, p16, p21) is associated with development, progression and prognosis of oral cancer. Immunohistochemical analysis of RAR alpha, beta, gamma and RXRalpha proteins was carried out on serial sections from 244 oral squamous cell carcinomas (OSCCs), 102 potentially malignant lesions (65 hyperplasias, 37 dysplasias), 83 matched histologically normal oral tissues and 29 normal mucosa from non-exposed individuals without oral lesions and correlated with expression of cell cycle regulators p53, p16 and p21 as well as with clinicopathological parameters. Expression of retinoid receptors RARbeta, RARgamma, RXRalpha and cell cycle regulators p16 and p21 was decreased in majority of oral SCCs as well as in potentially malignant lesions. Multivariate stepwise logistic regression analysis carried out for comparison of non-exposed normal oral mucosa with histologically normal oral tissues from patients with oral lesions showed significant loss of RARbeta or p53 accumulation (RARbeta(-)/p53(+) Odd's ratio, OR = 266.6, p = 0.000); non-exposed normal mucosa from individuals without oral lesions with potentially malignant lesion was RARbeta(-)/p21(-)/p53(+) (OR = 215.7, p = 0.000); matched normal to potentially malignant stage was RARalpha(+)/p21(-) (OR = 4.414, p = 0.005); hyperplasia to dysplasia was RARalpha(+)/p53(+) (OR = 4.72, p = 0.005) and potentially malignant to malignant phenotype was RARalpha(+) (OR = 2.061, p = 0.004). The prognostic relevance of these factors was assessed in 115 of these SCC patients who were followed-up for a maximum period of 94 months (median 21 months). Multivariate analysis using Cox's proportional Hazard's model showed that RARalpha(+)/p21(-) phenotype was associated with shorter disease-free survival (Hazard's ratio, HR = 1.863, p = 0.0471). To our knowledge, this is the first large study showing alterations in expression of retinoid receptors at the protein level at different stages in development and progression of oral SCC. It also underscored the prognostic significance of retinoid receptors and their interactions with cell cycle regulators in multistep oral tumorigenesis.     

Receptor-selective retinoids inhibit the growth of normal and malignant breast cells by inducing G1 cell cycle blockade

Summary Despite advances in treatment, breast cancer continues to be the second leading cause of cancer mortality in women. Statistics suggest that while focus on treatment should continue, chemopreventive approaches should also be pursued. Previous studies have demonstrated that naturally occurring retinoids such as 9-cis retinoic acid (9cRA) can prevent breast cancer in animal models. However, these studies have also shown that these compounds are too toxic for general use. Work from our laboratory showed that an RXR-selective retinoid LGD1069 prevented tumor development in animal models of cancer with reduced toxicity as compared to an RAR-selective retinoid TTNPB. In the present study, we investigated the mechanisms by which receptor-selective retinoids inhibit the growth of normal and malignant breast cells. Our results demonstrate that the synthetic retinoids tested are as effective as 9cRA in suppressing the growth of normal human mammary epithelial cells (HMECs) and estrogen receptor-positive (ER-positive) breast cancer cells. Although the receptor-selective retinoids induce minimal amounts of apoptosis in T47D breast cancer cells, the predominant factor that leads to growth arrest is G1 cell cycle blockade. Our data indicate that this blockade results from the downregulation of Cyclin D1 and Cyclin D3, which in turn causes Rb hypophosphorylation. Non-toxic retinoids that are potent inducers of cell cycle arrest may be particularly useful for the prevention of breast cancer.     

Treatment of advanced squamous cell carcinoma of the head and neck with isotretinoin: a phase II randomized trial

Summary Retinoids, the analogs of vitamin A, are active in vitro and in vivo against squamous cell carcinoma in animals and against certain epithelial precancers and cancers in humans. These data led us to design a prospective, multi-institutional, randomized phase II trial of isotretinoin in advanced head and neck squamous cell carcinoma. We randomly assigned 40 patients to receive isotretinoin or methotrexate, the best-studied and most active single agent for this disease. Overall, the study patients had extremely poor prognoses, i.e., low performance statuses and recurring disease after surgery and/or irradiation. Three objective responses (16%), including one complete response, occurred in the 19 evaluable isotretinoin-treated patients. Only one minor response (5%) occurred in the methotrexate-treated group. Toxicity occurred with both drugs, but was manageable and never life threatening in the retinoid group. These results and the established activity of retinoids in oral leukoplakia (a precursor of head and neck cancer) indicate the need for further study of this class of drugs in head and neck cancer.     

Retinamide-Induced Apoptosis in Glioblastomas is Associated with Down-Regulation of Bcl-xL and Bcl-2 Proteins

Summary Glioblastomas are among the most difficult neoplasms to treat with continued poor prognosis for long-term survival. Glioblastomas have developed effective mechanisms to resist chemotherapy including levels anti-apoptotic proteins, Bcl-xL and Bcl-2. Chemotherapy agents that promote down-regulation of Bcl-xL and Bcl-2 may enhance sensitivity to chemotherapy in glioblastomas. The ability of the synthetic retinoid N-(4-hydroxyphenyl) retinamide to modulate these anti-apoptotic proteins and to enhance apoptosis and chemotherapy was examined in glioblastoma cells. Expression of Bcl-2 family member proteins Bcl-xL and Bcl-2 were assessed in glioblastomas from three cell lines including U87, U251, and U138. Cells were treated with either retinamide alone or in combination with the chemotherapy agent, BCNU. The incidence of apoptosis was determined with flow cytometry analysis (FACS). Based on Western blots the levels of Bcl-2 and Bcl-xL were decreased in glioblastoma cells after treatment with retinamide. Retinamide treatment resulted in increased ratios of deamidated verses transamidated levels of Bcl-xL in U87 cells. BCNU chemotherapy combined with retinamide markedly down-regulated levels of both Bcl-xL and Bcl-2 proteins in glioblastoma and enhanced the incidence of apoptosis in U87 cells. These studies demonstrate that modulation of levels of the anti-apoptotic proteins, Bcl-xL and Bcl-2, may enhance the sensitivity of glioblastoma toward chemotherapy.     

药物治疗瘢痕疙瘩的应用研究

瘢痕疙瘩是一种难治性的异常瘢痕,目前药物治疗是一种比较常规的方法。作者查阅了国内外近年的相关文献资料进行分析与综述,阐述各类药物治疗瘢痕疙瘩的机制和临床应用情况。临床使用最广泛的药物包括皮质类固醇激素、抗代谢药、免疫调节剂、类维生素A。另外钙通道阻滞剂、抗组胺药等对治疗瘢痕疙瘩也有一定的疗效。药物在治疗和预防瘢痕疙瘩复发方面有重要的用途和意义。     

Medical treatment of hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a common skin disease affecting an estimated 2% of the population. It causes significant symptoms and is notoriously difficult to treat. In this article, the current medical therapy is reviewed. At the present time, therapy appears to be based on an interpretation of the disease as either infectious or a form of acne. The understanding of the pathogenesis of HS suggests that these are not adequate models in order to understand the disease and this may explain the insufficiency of currently available medical treatment. The literature is sparse and there is a shortage of randomised, controlled trials. Three small, randomised, controlled trials have suggested that clindamycin, tetracycline and oestrogens and cyproteroneacetate may have an effect in some patients. Preceiving HS as an inflammatory skin disease suggests the use of general immunosuppressive drugs in the treatment of this condition. This approach, using both traditional immunosupressants and monoclonal antibodies, has been assessed in a small number of patients and appears to have some potential. However, the main source of evidence for this are case series and there is a strong need for more formal studies in this potentially debilitating disease.     

Allergic contact dermatitis caused by topical antiacne drugs

Acne is a chronic inflammatory disease for which a long-lasting therapy, very often with topical drugs, is necessary. Despite the fact that several topical antiacne drugs (in particular, tretinoin, benzoyl peroxide, clindamycin and erythromycin) are used for many years, often on broad skin surfaces and for long periods of time, their potential for contact sensitization is low. Their potential for phototoxic and photoallergic reactions is also low. Much more frequent is irritant contact dermatitis caused by some of these drugs, in particular, retinoids and benzoyl peroxide, for which the short contact therapy has been recently suggested.