Conditional epidermal expression of TGFbeta 1 blocks neonatal lethality but causes a reversible hyperplasia and alopecia.
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To study the role of transforming growth factor type beta1 (TGFbeta1) in epidermal growth control and disease, we have generated a conditional expression system by using the bovine keratin 5 promoter to drive expression of the tetracycline-regulated transactivators tTA and rTA, and a constitutively active mutant of TGFbeta1 linked to the tetO target sequence for the transactivator. This model allows for induction or suppression of exogenous TGFbeta1 with oral doxycycline. Maximal expression of TGFbeta1 during gestation caused embryonic lethality, whereas partial suppression allowed full-term development with neonatal lethality characterized by runting, epidermal hypoproliferation, and blocked hair follicle growth. With complete suppression, phenotypically normal double transgenic (DT) mice were born. Acute induction of TGFbeta1 in the epidermis of adult mice inhibited basal and follicular keratinocyte proliferation and reentry of telogen hair follicles into anagen. However, chronic expression of TGFbeta1 in adult DTs caused severe alopecia characterized by epidermal and follicular hyperproliferation, apoptosis, as well as dermal fibrosis and inflammation. Readministration of doxycycline to tTA DT mice caused hair regrowth within 14 days. The mRNA and protein for Smad7, an inhibitor of TGFbeta signaling, were up-regulated in the epidermis and hair follicles of alopecic skin and rapidly induced in rTA mice in parallel with the TGFbeta1 transgene, suggesting that the hyperproliferative phenotype may result in part from development of a sustained negative feedback loop. Thus, this conditional expression system provides an important model for understanding the role of TGFbeta1 during development, in normal skin biology, and in disease. (+info)
Docetaxel in combination with mitoxantrone and granulocyte colony-stimulating factor as front-line chemotherapy in metastatic breast cancer: a multicenter phase II study.
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PURPOSE: To evaluate the activity and tolerance of docetaxel in combination with mitoxantrone and granulocyte colony-stimulating factor (G-CSF) as front-line treatment in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Fifty-four previously untreated patients with MBC who had bidimensionally measurable disease were enrolled onto the study. Forty-eight (89%) patients had visceral metastases and nineteen (36%) had relapsed within twelve months following adjuvant chemotherapy. Docetaxel (100 mg/m2) was given on day 1 after appropriate premedication and mitoxantrone (20 mg/m2) on day 8. G-CSF (150 mcg/m2/d s.c.) was administered from day 2 to day 6 and from day 9 to day 15. The regimen was repeated every three weeks, on an outpatient basis. RESULTS: In an intention-to-treat analysis, 9 (17%) CRs, 24 (44%) PRs, (overall response rate 61%; 95% confidence interval (CI): 48.1%-74.1%), 12 (22%) SD and 9 (17%) PD were observed. The median duration of response and the median time to tumor progression was 12.5 and 14 months, respectively. The overall median survival was 16.5 months, whilst the probability for one- and three-year survival was 61% and 35%, respectively. Grade 3-4 neutropenia occurred in 37 (69%) patients, and febrile neutropenia in 16 (30%); there was one death due to sepsis. Grade 3-4 thrombocytopenia occurred in four (8%) patients. Grade 2-3 neurosensory toxicity was observed in 8 (15%) patients and grade 2-3 asthenia in 24 (45%). CONCLUSIONS: Docetaxel in combination with mitoxantrone and G-CSF support is an intensified and active front-line regimen for patients with MBC; despite its hematological toxicity, this regimen merits further comparison with other standard anthracycline- and/or taxane-based combinations. (+info)
Impact of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia.
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Sodium phenylbutyrate (PB) is an aromatic fatty acid with cytostatic and differentiating activity against malignant myeloid cells (ID(50), 1-2 mM). Higher doses induce apoptosis. Patients with myelodysplasia (n = 11) and acute myeloid leukemia (n = 16) were treated with PB as a 7-day continuous infusion repeated every 28 days in a Phase I dose escalation study. The maximum tolerated dose was 375 mg/kg/day; higher doses led to dose-limiting reversible neurocortical toxicity. At the maximum tolerated dose, PB was extremely well tolerated, with no significant toxicities; median steady-state plasma concentration at this dose was 0.29 +/- 0.16 mM. Although no patients achieved complete or partial remission, four patients achieved hematological improvement (neutrophils in three, platelet transfusion-independence in one). Other patients developed transient increases in neutrophils or platelets and decrements in circulating blasts. Monitoring of the percentage of clonal cells using centromere fluorescence in situ hybridization over the course of PB administration showed that hematopoiesis remained clonal. Hematological response was often associated with increases in both colony-forming units-granulocyte-macrophage and leukemic colony-forming units. PB administration was also associated with increases in fetal erythrocytes. These data document the safety of continuous infusion PB and provide preliminary evidence of clinical activity in patients with myeloid malignancies. (+info)
A new strategy for modulating chemotherapy-induced alopecia, using PTH/PTHrP receptor agonist and antagonist.
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Parathyroid hormone (PTH) related peptide (PTHrP) and the PTH/PTHrP receptor (PTH/PTHrP-R) show prominent cutaneous expression, where this signaling system may exert important paracrine and/or autocrine functions, such as in hair growth control. Chemotherapy-induced alopecia - one of the fundamental unsolved problems of clinical oncology - is driven in part by defined abnormalities in hair follicle cycling. We have therefore explored the therapeutic potential of a PTH/PTHrP-R agonist and two PTH/PTHrP-R antagonists in a mouse model of cyclophosphamide-induced alopecia. Intraperitoneal administration of the agonist PTH(1-34) or the antagonists PTH(7-34) and PTHrP(7-34) significantly altered the follicular response to cyclophosphamide in vivo. PTH(7-34) and PTHrP(7-34) shifted it towards a mild form of "dystrophic anagen", associated with a significant reduction in apoptotic (TUNEL+) hair bulb cells, thus mitigating the degree of follicle damage and retarding the onset of cyclophosphamide-induced alopecia. PTH(1-34), in contrast, forced hair follicles into "dystrophic catagen", associated with enhanced intrafollicular apoptosis. We had previously shown that an induced shift in the follicular damage-response towards "dystrophic catagen" mitigates cyclophosphamide-induced alopecia, whereas a shift towards "dystrophic catagen" initially enhanced the hair loss, yet subsequently promoted accelerated hair follicle recovery. Therefore, this study in an established animal model of chemotherapy-induced alopecia, which closely mimics human chemotherapy-induced alopecia, strongly encourages the exploration of PTH/PTHrP-R agonists and antagonists as novel therapeutic agents in chemotherapy-induced alopecia. (+info)
Amifostine protects against early but not late toxic effects of doxorubicin in infant rats.
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The improved prognosis and increased expected lifetime among long-term survivors of childhood malignancies have made these patients especially sensitiveto the late toxicity of cancer therapy and prone to secondary malignancies. Recently, new strategies aiming to protect against cancer treatment toxicity have been developed, including the drug amifostine (Ethyol), which is suggested to protect normal tissues from the toxic effects of radiation and cytotoxic agents. In the present study, the possible protective effect of amifostine against toxicity induced by a single injection of doxorubicin (3 mg/kg) in immature rats was evaluated. Specifically, we evaluated the protection against long-term toxicity and the effects of amifostine on growing immature tissues. Amifostine (50-200 mg/kg) given 15 min before doxorubicin had a significant protective effect against doxorubicin-induced early alopecia in young rats. Significant protection against cataract formation was obtained by the use of low-dose amifostine (50 mg/kg). However, amifostine did not protect young rats against the late toxic effect of doxoubicin on linear growth, body weight, plasma leptin levels, and heart or testicular tissue. Worrisome, and in contrast to earlier studies in adult rats, an increased doxorubicin toxicity actually was observed and mortality was increased when the higher doses of amifostine (100-200 mg/kg) were used. The present results suggest that more data from growing immature animal models are needed to analyze the safety of amifostine treatment and its mechanisms of action before wider clinical use of this drug in pediatric cancer patients is recommended. (+info)
Why do some people look older than they should?
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BACKGROUND: As a component of studies on biological age, the age of subjects from their appearance (perceived age) was estimated. OBJECTIVE: To determine the factors associated with looking older. METHODS: Cross sectional study of London civil servants (318 men, 129 women) in the Department of the Environment study. Perceived age was recorded by an observer and the difference between this age and chronological age was analysed according to 20 different variables. RESULTS: Men had an average perceived age of 0.37 years older than their actual age and women a perceived age of 0.54 years younger. In men, looking older was related to greying of the hair, grade of arcus senilis, and grade of baldness. Less expected, looking older was positively related to total serum cholesterol (p=0.03) and blood haemoglobin (p<0.01). In women, looking older was related to greying of the hair, positively to blood erythrocyte sedimentation rate (ESR), and negatively to serum bilirubin (p=0.01). Looking older was not related to alcohol consumption, employment grade, serum high density lipoprotein cholesterol, glucose, albumin, and calcium in either sex. CONCLUSION: The relationships between looking older and total cholesterol and haemoglobin in men and ESR and bilirubin in women, require further investigation. (+info)
Atrichia caused by mutations in the vitamin D receptor gene is a phenocopy of generalized atrichia caused by mutations in the hairless gene.
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Generalized atrichia with papules is a rare disorder characterized by loss of hair shortly after birth and development of cutaneous cysts. Mutations in the hairless gene (HR) cause this phenotype in both mouse and human. Here we present a case of atrichia with papules in a patient with a normal HAIRLESS gene but with mutations in both alleles of the VITAMIN D RECEPTOR. The patient exhibited vitamin D resistant rickets, which was confirmed by an absent response of her fibroblasts to 1,25-dihydroxyvitamin D3 in vitro. Similar to individuals with HAIRLESS mutations, her skin showed an absence of normal hair follicles and the presence of follicular remnants and cysts. The cyst epithelium contained keratin-15- and keratin-17-positive cells suggesting derivation from the hair follicle bulge and the presence of epithelial stem cells. Although hair loss has been reported in association with hereditary vitamin D resistant rickets, we now characterize this alopecia as clinically and pathologically indistinguishable from generalized atrichia with papules, which was previously thought to be caused only by mutations in HAIRLESS. These findings suggest that VDR and HR, which are both zinc finger proteins, may be in the same genetic pathway that controls postnatal cycling of the hair follicle. (+info)
Multicenter, randomized comparative trial of fludarabine and the combination of cyclophosphamide-doxorubicin-prednisone in 92 patients with Waldenstrom macroglobulinemia in first relapse or with primary refractory disease.
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Few reports are available on the treatment of patients with Waldenstrom macroglobulinemia (WM) and primary or secondary resistance to alkylating-agent-based regimens. From December 1993 through December 1997, 92 patients with WM resistant to first-line therapy (42) or with first relapse (50) after alkylating-agent therapy were randomly assigned to receive fludarabine (25 mg/m(2) of body-surface area on days 1-5) or cyclophosphamide, doxorubicin (Adriamycin), and prednisone (CAP; 750 mg/m(2) cyclophosphamide and 25 mg/m(2) doxorubicin on day 1 and 40 mg/m(2) prednisone on days 1-5). The first end point evaluated was the response rate after 6 treatment courses. Forty-five patients received CAP and 45 received fludarabine. Two patients died before the first course of chemotherapy. No statistical differences were observed between the 2 treatment arms with respect to hematologic toxicity or infections. Mucositis and alopecia occurred significantly more often in patients treated with CAP. Partial responses were obtained in 14 patients (30%) treated with fludarabine and 5 patients (11%) treated with CAP (P =.019). Responses were more durable in patients treated with fludarabine (19 months versus 3 months), and the event-free survival rate was significantly higher in this group (P <.01). Forty-four patients died, 22 in the fludarabine group and 22 in the CAP group. There was no statistical difference in the median overall survival time in the 2 study arms. Fludarabine was thus more active than CAP in salvage therapy of WM and should be tested as first-line therapy in a randomized comparison with alkylating agents. (+info)