Comparison of estradiol receptor investigations and histochemical investigations on enzymes in human mammary cancers.

The best way to predict the responsiveness of human breast carcinomas to hormone therapy is to investigate the estradiol receptor-binding abilities of these tumors. This binding induces many hormone-regulated changes in the activities of several enzymes. Therefore, enzyme activities after short-term organ culture exposed to added hormones were tested to see whether a correlation of enzyme activities exists with estradiol receptor binding. The results from both the estradiol receptor investigations and histochemical investigations on enzymes revealed a high degree of conformity, which confirms the existence of such a correlation. However, for this reason histochemical investigations on enzymes cannot eliminate the discrepancy between the experimentally verified existence of estradiol receptor binding and the response of mammary tumors to hormone therapy, which is not higher than 50-60%.

Complex regulation of the DNA-binding activity of p53 by phosphorylation: differential effects of individual phosphorylation sites on the interaction with different binding motifs.

The tumor suppressor protein p53 exists in different phosphorylation states depending on the cellular environment and perhaps the stage of the cell cycle. These different phosphorylation states can be mimicked in the baculovirus expression system by employing the phosphatase inhibitor okadaic acid. Hyperphosphorylation of p53, particularly of Ser313 and/or Ser309, stimulated its DNA binding activity (Fuchs, Hecker and Scheidtmann, Eur. J. Biochem. 228, 625, 1995). Here we show that hyperphosphorylation of p53 has different effects on its DNA-binding activity, depending on the phosphorylation sites and the binding motif: (i) Phosphorylation of amino-terminal sites appeared to reduce binding to the RGC consensus motif, whereas additional phosphorylation of both, Ser313 and Ser309 led to enhanced binding. (ii) Upon hyperphosphorylation, binding to the RGC motif was enhanced whereas binding to the p53 response element of the bax1 gene promoter was diminished. (iii) DNA binding was also greatly enhanced by antibodies Pab 122 and 421 directed against the carboxyl terminus, but this latter effect was superimposed by the phosphorylation state of p53. Thus, the DNA binding activity of p53 appears to be regulated in a complex way in that (i) binding to a given sequence motif may be regulated by differential phosphorylation and/or by interaction with other factors; (ii) binding to different motifs may be modulated in opposite ways. Thus, the different genes that are regulated by p53 may be differently affected by these parameters.

Photocatalytic Properties of TiO2 Thin Films Modified with Ag and Pt Nanoparticles Deposited by Gas Flow Sputtering.

In this work, a gas flow sputtering (GFS) process which allows the production and deposition of metal nanoparticles (NPs) in a vacuum environment is described. Aim of the study is to prove the potential of this technology for the fabrication of new TiO2 films with enhanced photocatalytic properties. For this purpose, Ag and Pt NPs have been produced and deposited on photocatalytic float glass coated with TiO2 thin films by magnetron sputtering. The influence of the process parameters and of the metal amount on the final properties of the particles (quantity, size, size distribution, oxidation state etc.,) was widely investigated. Moreover, the effect of the NPs on the photocatalytic activity of the resulting materials was evaluated for the case of the decomposition of stearic acid (SA) during UV-A irradiation. The reduction of the water contact angle (WCA) during the irradiation period was measured in order to test the photo-induced super-hydrophilicity (PSH).

Phase II study of paclitaxel and cisplatin in patients with non-small cell lung cancer.

Few cytotoxic agents tested in adequate phase II trials involving patients with non-small cell lung cancer have produced single-agent response rates greater than 15%. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is one of them, with reported response rates ranging from 21% to 36%. Platinum-based regimens have been key to the development of the most effective combination therapies for NSCLC. We are currently investigating the efficacy and toxicity of combining paclitaxel (175 mg/m2) given by 3-hour infusion, followed by cisplatin (75 mg/m2) via 1-hour infusion, on a 21-day schedule for the treatment of 75 chemotherapy-naive patients with stage IIIB (17.3%) or stage IV (82.6%) non-small cell lung cancer. Patient characteristics include a median age of 58 years (age range, 28 to 75 years) and a median Eastern Cooperative Oncology Group performance status of 2; 19 patients (25.3%) are women and 56 (74.7%) are men. All patients received standard prophylactic premedication as well as adequate hydration. To date, 75 subjects and 328 courses are evaluable for toxicity. Hematologic toxicities have been moderate; grade 3 or 4 neutropenia occurred in 37% of cycles (50% of patients), and grade 3 or 4 thrombocytopenia was observed in only 2% of cycles (2% of patients). Other notable toxicities were World Health Organization grade 2 or 3 alopecia and nausea/vomiting. Grade 1 or 2 peripheral neuropathy occurred in 26% and grade 3 or 4 in only 1% of all courses. Of 67 patients evaluable for response, complete remission was noted in three (5%) patients, partial remission in 25 (37%) patients, stable disease in 22 (33%) patients, and progressive disease in 17 (25%) patients. These results suggest that combination paclitaxel/cisplatin is active and well tolerated in the treatment of non-small cell lung cancer.

Interim Analysis of a Phase II study of epirubicin and paclitaxel as first-line therapy in patients with metastatic breast cancer.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane to be used routinely in clinical practice, has aroused considerable interest for its high single-agent activity in breast cancer and its novel mechanism of action. The 4' epimer of doxorubicin, epirubicin is an agent with high activity against breast cancer but a lower rate of toxic side effects, especially cardiotoxic events, than its parent compound. Although the paclitaxel/doxorubicin combination has yielded response rates between 63% and 94% in phase I/II studies, some severe cardiotoxic events were reported. The rationale for our study was to evaluate the paclitaxel/epirubicin combination, focusing mainly on cardiotoxicity. In all, 57 patients with metastatic breast cancer entered the study, 28% of whom had primary metastatic breast cancer with large tumors at the primary site. Half of the patients had received adjuvant chemotherapy. Study medication consisted of 60 mg/m2 epirubicin given intravenously over 1 hour, followed by paclitaxel 175 mg/m2 administered as a 3-hour intravenous infusion after premedication with steroids, antihistamines, and H2 antagonists. The main toxicity was neutropenia (World Health Organization toxicity index grade 3/4, 72%). Other hematologic side effects were rare and no febrile neutropenia was reported. Peripheral neuropathy, arthralgia, and myalgia were mild (only World Health Organization grade 1 and 2). All patients had alopecia. The paclitaxel dose was escalated to 200 mg/m2 in eight patients, four of whom received a further escalation to 225 mg/m2. Severe neutropenia necessitated dose reductions in eight patients. No cardiac adverse events were reported. Of 41 patients evaluable for response, seven had complete remissions and 21 had partial remissions (68%). An additional 12 patients (29%) had stable disease. The combination of paclitaxel 175 mg/m2 and epirubicin 60 mg/m2 can be administered safely to patients with metastatic breast cancer. Although response was not the primary end point of this trial, the response data are nonetheless encouraging and suggest that further evaluation of the role of this combination in the first-line treatment of metastatic breast cancer is warranted.

Preliminary results of a phase II study of epirubicin and paclitaxel as first-line treatment in patients with metastatic breast cancer.

Preliminary results of this ongoing phase II study of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) plus epirubicin administered as first-line treatment to women with metastatic breast cancer indicate encouraging response rates and no severe toxicity. Among the 57 patients admitted to this study, 52% had received prior adjuvant chemotherapy (85% with cyclophosphamide/methotrexate/5-fluorouracil), 46% had received radiotherapy, and 30% had received both forms of therapy; 63% of patients were postmenopausal, mainly with poorly differentiated tumors, and 80% presented with > or = 2 metastatic sites. Epirubicin 60 mg/m2 was administered intravenously as a 1-hour infusion followed by paclitaxel 175 mg/m2 infused over 3 hours. Standard premedication was given. Granulocyte colony-stimulating factor support was not used. Neutropenia was evident in 72% of cycles but was not severe. Instances of anemia and thrombocytopenia were rare. Alopecia was universal. All nonhematologic toxicity observed was mild or moderate (peripheral neuropathy, myalgia, nausea, vomiting World Health Organization toxicity grade < 2). At this time, 41 patients are currently evaluable for response, complete and partial remission are evident in seven and 21 patients, respectively. The overall response rate so far is 68%. An additional 12 patients show evidence of stable disease, and one has shown disease progression. Paclitaxel is considered a promising new drug in the adjuvant treatment of patients with metastatic breast cancer. Combining it with epirubicin allows safe administration with no evidence of severe cardiotoxicity. The incidence of adverse cardiac events was much lower than that observed with combinations of paclitaxel and doxorubicin.

Paclitaxel and epirubicin as first-line therapy for patients with metastatic breast cancer.

Paclitaxel (Taxol), has aroused considerable interest for its high single-agent activity in breast cancer and novel mechanism of action. Epirubicin (Farmorubicin), the 4'epimer of doxorubicin (Adriamycin), also has high activity in breast cancer, with the advantage of a lower rate of toxic side effects-especially cardiac effects-compared with its parent compound. The combination of paclitaxel and doxorubicin has yielded response rates between 63% and 94% in phase I/II studies, but authors reported severe cardiac toxic events. The goal for the current study was to evaluate the combination of paclitaxel and epirubicin, focusing mainly on cardiac toxicity. Of a total of 85 patients entered, 68 patients with metastatic breast cancer were evaluable. Nearly 20% had primary metastatic breast cancer with large tumors. Half had received adjuvant chemotherapy. Study medication in Group A consisted of 60 mg/m2 epirubicin given over 1 hour, followed by paclitaxel 175 mg/m2 as a 3-hour IV infusion. In Group B, 90 mg/m2 epirubicin was combined with 175 mg/m2 paclitaxel, delivered as for Group A. The main toxicity in both groups was neutropenia. In Group A, the paclitaxel dose could be escalated to 200 mg/m2 in 15 patients and to 225 mg/m2 in 7 patients; dose reduction due to severe neutropenia was necessary in 11 patients. No cardiac adverse events were reported in Group A. In Group B, only one patient could be escalated to 200 mg/m2 but three patients required a dose reduction. In this group, one patient had a decrease of left ventricular ejection fraction of more than 10% without any clinical signs. Of 43 patients in Group A and 25 in Group B, the response rate was 67% in Group A and 68% in Group B. The duration of response was 8.2 months in both groups. The combination of paclitaxel 175 mg/m2 and epirubicin 60 mg/m2 or 90 mg/m2 can be safely administered. The response data were encouraging and further evaluation is warranted.

Current trends in onychomycosis therapy: a literature review.

Problems with the use of griseofulvin and ketoconazole in the treatment of onychomycosis have led to studies of three new oral antifungal drugs to treat this disease: fluconazole, itraconazole, and terbinafine. These drugs have been superior in relation to a high rate of cure, shorter duration of treatment, minimal adverse effects, and prolonged duration of remission. Although both fluconazole and itraconazole are structurally related to ketoconazole, their triazole ring is more site-specific than the imidazole ring of ketoconazole, which makes these newer drugs less likely to cause liver toxicity. Terbinafine belongs to a new class of compounds called the allylamines, which are fungicidal rather than fungistatic. Terbinafine has become the first line of therapy in Europe and Canada for onychomycosis, and it has recently been approved in the United States in oral form. Itraconazole and fluconazole are available in the United States, but fluconazole is not yet approved for treatment of onychomycosis.

[Histochemical and ultrastructural investigations on organ culture of malignant tumors (author's transl)]. / Histochemische und ultrastrukturelle Untersuchungen an Organkulturen von malignen Tumoren

Organ cultures of malignant tumours were histochemically and electronmicroscopically investigated. There was established that follows enzymes show a little activity in cultured tumour cells after 24 and 48 h: succinate dehydrogenase, alkaline phosphatase, adenosine triphosphatase, and nonspecific esterase, whereas NADH-diophorase, lactate dehydrogenase, and acid phosphatase show an essentially higher activity after termination of the cultivation. However, in comparison with the primare tissue, the activities of the last mentioned enzymes are clearly decreased in cultured tumour cells after termination of the cultivation. No changes of cell structures have electronmicroscopically been observed on these cultures of malignant tumours.

[Histochemical demonstration of beta-glucuronidase and leucine aminopeptidase in cultivated aortic endothelial cells (author's transl)]. / Zum histochemischen Nachweis von beta-Glucuronidase und Leucinaminopeptidase in kultivierten Gefässendothelzellen.

With the aid of histochemical techniques, the activity of beta-GD, LAP, NADH-D, and LDH of in vitro cultivated calf aortic endothelial cells were compared with the activity of these enzymes in different tumours in vivo. The relative high level of beta-GD, NADH-D, and LDH in the endothelial cells is comparable with the increased activity of these enzymes in invasive growing tumours. The results were discussed in connection with a possible enzymolytic effect during the invasive growth of capillary endothelial cells in course of neovascularization in vivo.

[Electron microscopical and enzyme histochemical investigation of kidney and liver of the albino rat after cytostatic treatment (author's transl)]. / Elektronenmikroskopische und enzymhistochemische Untersuchungen der Niere und Leber von Albinoratten nach Cytostatikabehandlung.

Within 5 days following treatment with cytostatics (vincristine, vinblastine, trenimon, 5-fluorouracil) enzyme-histochemical and ultrastructural changes occurred in the kidney and liver of Wistar rats. The enzyme activities were influenzed by cytostatics in different ways. It was found that the activity of some enzymes increased whereas that of others decreased. Kidney and liver showed a different response in their enzymatic behaviour. The cytostatics used did not have the same effect. The histochemical changes following injection of cytostatics in juvenile rats do not agree with those in adult ones. The electronmicroscopic findings reveal marked morphological changes of the kidney and liver cells within the first 5 days following injection of cytostatics. From the 8th day on after administration of cytostatics neither histochemical nor ultrastructural changes as compared with the controlls were found.

[The correlation of in vivo and in vitro effect of cytostatics in transplantated tumours of the mouse (author's transl)]. / Zur Korrelation der in vivo- und in vitro-Wirkung von Cytostatika auf Transplantationstumoren der Maus.

In 2 inoculated mouse tumours the conformity of the actions of 4 different cytostatics at 2 dose levels was tested in vitro and in vivo. The histochemical reaction of lactate dehydrogenase and NADH diaphorase was taken as a criterion of the cytostatic action. The investigations showed the tumours used responded to the cytostatics employed. A good conformity of the in vitro and in vivo findings was established. The histochemical assessment of organ cultures following the administration of cytostatics allows to determine the sensitivity of tumours and helps the physician in deciding on an effective therapeutic.

Temporary ectropion due to topical fluorouracil.

A patient with multiple actinic keratoses was treated with the standard regimen of 5 percent fluorouracil cream. The patient noted bilateral ectropion within two weeks of receiving therapy. The ectropion completely resolved with discontinuation of therapy. This is the first reported case of transient ectropion associated with 5-fluorouracil therapy.

Reimbursement for the oral health care of cancer patients.

Oral conditions related to cancer therapy, which are largely preventable, continue to result in considerable morbidity, dysfunction and lost quality of life. Therefore, it is important for dentists to be knowledgeable about the problems of reimbursement for the oral health care of cancer patients and become involved in the issue of access to oral health care for cancer patients.