Contact allergy to trimethylolpropane triacrylate (TMPTA) in an aziridine plastic hardener

4 workers developed hand and face dermatitis when exposed to a floor top coal. This contained a polyurethane arid a polyfunctional aziridine hardener and additives. The aziridine hardener was made by reacting propyleneimine with a polyfunctional acrylate, trimethylolpropane triacrylate (TMPTA). All 4 reacted to the hardener and to TMPTA, which is present in excess, 2 of them also reacted to pentacrythritol triacrylate (PETA), which can be used in the production of aziridine hardeners. TMPTA and PETA cross-react, and are known sensitizers in UV-hardening acrylates.
The present finding shows that well-known sensitizers can be found in hidden sources when used in a quite different chemical process.     

Receptor status (ER and PgR) determined with histochemical and biochemical methods in breast carcinoma]

Recently, a method similar to ER.ICA has been proposed for the progesterone receptor (PgR) using two monoclonal antibodies, JZB39 and KD68, specific for human PgR and characterized by a molecular weight of 95 and 120 Kd, respectively. A series of 73 breast cancer patients was studied with regards to ER and PgR using both immunocytochemical (ICA) and biochemical (DCC) assays. Results showed no substantial differences between the two methods when considering common clinical-pathological parameters. Overall agreement between ICA and DCC methods was found: 79% for PgR and 78% for ER. A slight quantitative correlation was also observed between the "score values" of the ICA method and the Fmol content of ER and PgR using the Brave-Pearson test (r = 0.49 for PgR; r = 0.43 for ER). Specificity of PgR.ICA method was 77% for PgR and 72% for ER; sensitivity was 82% and 83%, respectively. The ICA method is a reliable technique to assess PgR presence as well as ER. Further studies are necessary to evaluate the prognostic role of nuclear PgR.     

Spontaneous Reversal of P‐Glycoprotein Expression in Multidrug Resistant Cell Lines*

Abstract: Increased expression of P‐glycoprotein encoded by the mdr‐1 gene is a well‐characterised mechanism for resistance to cancer chemotherapeutic drugs in cell lines. However, the P‐glycoprotein expression after removal of the selection pressure has not fully been elucidated. The stability of P‐glycoprotein expression in the presence (+) and absence (?) of vincristine (30 or 150 nM) was studied in multidrug resistant K562 cell lines (VCR30+, VCR150+, VCR30? and VCR150?) for 11 months. The P‐glycoprotein protein and mdr‐1 mRNA levels were determined at regular intervals using flow cytometry and real‐time PCR, respectively. Chemosensitivity to a panel of antineoplastic drugs was measured using an MTT assay. The presence of vincristine (VCR30+ and VCR150+) resulted in high and stable levels of P‐glycoprotein and mdr‐1 mRNA during the whole period compared to wild type. As for the VCR30? and VCR150? subcultures, the expressions of P‐glycoprotein and mdr‐1 mRNA were stable for five months, and then the levels decreased rapidly. Concomitantly, the sensitivity to drugs known as P‐glycoprotein substrates was restored. In conclusion, resistant cells growing in the presence of the inducing drug have a stable P‐glycoprotein expression and resistance level, but removing the inducing drug may result in a sudden and rapid lowering of P‐glycoprotein and mdr‐1 mRNA levels as long as five months after drug withdrawal.     

Pharmacodynamic differences between species exemplified by the novel anticancer agent CHS 828

When a candidate drug enters clinical trials, decisions regarding dosing are mainly based on animal data. Occasionally, toxicity problems are faced in the clinic because of unexpected species differences in pharmacokinetics or pharmacodynamics between humans and preclinical species. Fludarabine and topotecan are examples of such drugs. In the first clinical trials of the new agent CHS 828, the maximum tolerated dose was reached earlier than expected from animal data. This paper discusses the issue of species differences in the development of anticancer drugs, and preclinical models for detection and quantification of such differences. Pharmacokinetic and hematological toxicity data of CHS 828 from studies in rats and humans are presented. In vitro sensitivity to CHS 828 and some established cytotoxic agents was measured in lymphocytes from humans and rats and in a panel of human and rodent cell‐lines. 10–100 times higher CHS 828 exposure was tolerated by rats than by patients. In both in vitro cell systems, CHS 828 showed higher potency in human cells compared to rodent cells. A species difference was evident also for fludarabine, but not for doxorubicin and cisplatin. CHS 828 pharmacokinetics were similar across species. In conclusion, the lower tolerance of CHS 828 in humans than in rats could be detected in vitro in cultures of peripheral lymphocytes. Preclinical studies of species differences could help the interpretation of in vivo effect studies as well as the choice of starting dose for clinical trials. We suggest peripheral lymphocytes from different species as a potential model system for such studies. Drug Dev. Res. 61:218–226, 2004. © 2004 Wiley‐Liss, Inc.     

Evaluation of osteopontin as biomarker for pancreatic adenocarcinoma.

OBJECTIVES: Pancreatic adenocarcinoma is a deadly disease with an overall 5-year patient survival of less than 5%. This dismal prognosis of pancreatic cancer is largely due to the advanced stage of the disease at presentation. If pancreatic cancer could be diagnosed more readily and accurately using serum markers, patient survival could theoretically be improved by enabling more patients to avail of surgical resection. One candidate tumor marker recently identified by global gene expression analysis of pancreatic cancer is the secreted glycophosphoprotein osteopontin (OPN). In this study, we evaluate OPN as a serum marker of pancreatic adenocarcinoma. METHODS: In situ hybridization for OPN was performed on a pancreatic adenocarcinoma tissue microarray. Serum OPN levels were determined in preoperative sera from 50 patients with pancreatic cancer and 22 healthy control individuals by competitive ELISA. RESULTS: In situ hybridization for OPN performed on a tissue microarray revealed strong OPN mRNA signal in tumor-infiltrating macrophages in 8 of 14 pancreatic adenocarcinomas. In contrast, OPN expression was not seen in the pancreatic cancer cells themselves, nor was it seen in normal pancreatic tissue or in the macrophages distant from the infiltrating cancer. Serum OPN levels, as measured by ELISA, were elevated in the sera of 50 patients with resectable pancreatic adenocarcinoma compared to 22 healthy control individuals (mean +/- SD for OPN was 482 +/- 170 ng/ml and 204 +/- 65 ng/ml, respectively; P < 0.001). Using a cutoff level of 2 SD above the mean for healthy individuals, elevated OPN had sensitivity of 80% and specificity of 97% for pancreatic cancer. In contrast, only 62% of these patients with resectable pancreatic cancer had elevated CA19-9. CONCLUSIONS: Serum OPN may have utility as a diagnostic marker in patients with pancreatic cancer.     

Gemcitabine plus cisplatin for advanced transitional cell carcinoma of the urinary tract: a phase II multicenter trial

PURPOSE: We determined the activity and toxicity of gemcitabine plus cisplatin in patients with inoperable or metastatic transitional cell carcinoma of the urinary tract. MATERIALS AND METHODS: A total of 54 patients with transitional cell carcinoma, measurable disease and Eastern Cooperative Oncology Group performance status 2 or greater were enrolled in this multicenter phase II trial. Previous adjuvant or neoadjuvant therapy for locally advanced disease was acceptable if it had been completed more than 1 year before study entry. Every 4 weeks patients received 1,000 mg./m.2 gemcitabine intravenously on days 1, 8 and 15, and 70 mg./m.2 cisplatin intravenously on day 2. RESULTS: All patients were evaluable for response and toxicity. Notably only 7 of the 54 patients (13%) previously received chemotherapy in an adjuvant or neoadjuvant setting. Overall we observed 26 objective responses (48%), of which 15% were complete. Median time to progression was 23 weeks and median survival was 54 weeks. Treatment was well tolerated. The main toxicities were leukopenia (grade 3 in 28% and grade 4 in 11% of patients), anemia (grade 3 in 34% and grade 4 in 6%) and thrombocytopenia (grade 3 in 14% and grade 4 in 6%). Other relevant side effects were nausea and vomiting in 20% of cases, fever in 24%, alopecia in 22%, renal failure in 7.4% and mucositis in 2%. CONCLUSIONS: Combined cisplatin plus gemcitabine is highly active in advanced transitional cell carcinoma of the urinary tract with manageable toxicity. The response rate, time to treatment failure and overall survival appeared to be comparable to those achieved with combined methotrexate, vinblastine, doxorubicin and cisplatin. Conversely toxicity appeared lower. Evaluation of this regimen in randomized studies with methotrexate, vinblastine, doxorubicin and cisplatin is strongly suggested.     

Uptake and disposition of inhaled methanol vapor in humans.

Methanol is a widely used solvent and a potential fuel for motor vehicles. Human kinetic data of methanol are sparse. As a basis for biological exposure monitoring and risk assessment, we studied the inhalation toxicokinetics of methanol vapor in four female and four male human volunteers during light physical exercise (50 W) in an exposure chamber. The relative uptake of methanol was about 50% (range 47-53%). Methanol in blood increased from a background level of about 20 to 116 and 244 microM after 2 h exposure at 0, 100 ppm (131 mg/m3) and 200 ppm (262 mg/m3), respectively. Saliva showed substantially higher levels than blood immediately after exposure. This difference disappeared in a few minutes; thereafter the concentrations and time courses in blood, urine, and saliva were similar, with half times of 1.4, 1.7, and 1.3 h, respectively. The postexposure decrease of methanol in exhaled air was faster, with a half time of 0.8 h. The methanol concentrations were approximately twice as high in all four types of biological samples at 200 compared to 100 ppm. No increase in urinary formic acid was seen in exposed subjects. Our study indicates non-saturated, dose-proportional kinetics of methanol up to 200 ppm for 2 h. No gender differences were detected. Similar, parallel patterns were seen with regard to the methanol time courses in blood, urine, and saliva, whereas the concentration in exhaled air decreased markedly faster. Thus, apart from blood and urine, saliva also seems suitable for biomonitoring of methanol exposure.