Antitumor-activity and toxicity of continuous-infusion versus bolus administration of bleomycin in 2 heterotransplanted human testicular cancer cell-lines.

The continuous infusion of the glycopeptide antibiotic cytotoxic agent bleomycin in comparison to bolus application has been postulated to be associated with increased antitumour activity and decreased toxicity, particularly pulmonary fibrosis. In the treatment of patients with testicular cancer, bleomycin is an essential agent and is currently used in continuous infusion and bolus application schedules in cisplatin-based combination therapy regimens. The current study addresses the antitumour activity and general toxicity of bleomycin given as continuous intraperitoneal infusion versus bolus application in human testicular cancer cell lines heterotransplanted into nude mice. Maximally tolerated doses for each administration route, defined as being the LD20 were applied (8.7 or 17.5 mg/kg days 1-7 continuous intraperitoneal infusion via osmotic mini pump or 40 mg/kg intraperitoneal bolus application on days 1, 5, 9). Bleomycin demonstrated antitumour efficacy at all concentrations used in comparison to untreated controls. There was no significant difference in antitumour activity between continuous or bolus application of bleomycin when the same cumulative doses were compared. Neither was there any difference with respect to bleomycin toxicity with 11 +/- 4 or 12 +/- 5% losses of body weight for continuous infusion regimens compared to 13 +/- 3% for bolus application. In a small subgroup of mice histological examination of the lungs demonstrated no signs of pulmonary fibrosis. In summary, using an established testicular cancer xenograft model in nude mice bolus application of bleomycin was as active as continuous infusion of this drug with no apparent difference in overall toxicity. Current standard treatment regimens using bolus application of bleomycin should not be altered without necessary reasons. Bleomycin pulmonary toxicity needs to be studied in clinical trials taking into account possible drug interactions in combination chemotherapy regimens and additional risk factors for pulmonary toxicity.

Preclinical activity of a new platinum analogue, lobaplatin, in cisplatin-sensitive and -resistant human testicular, ovarian, and gastric carcinoma cell lines.

Lobaplatin [1,2-diamminomethylcyclobutane-platinum(II) lactate] is a new platinum compound with interesting preclinical activity and apparently no nephro- or neurotoxicity that is currently undergoing clinical phase II studies. Little is known about the cross-resistance between cisplatin and lobaplatin. The activity of this new compound in comparison with cisplatin and carboplatin was evaluated in cisplatin-sensitive and cisplatin-resistant human testicular, gastric, and ovarian carcinoma cell lines using 96 h continuous drug exposure in a sulforhodamine-B assay. In three cisplatin-sensitive testicular carcinoma cell lines, lobaplatin and cisplatin showed comparable antitumor activity. The 50% growth-inhibitory concentrations (IC50 values) determined for cisplatin ranged from 0.1 to 0.4 microM, and those found for lobaplatin ranged from 0.25 to 0.5 microM. Carboplatin showed markedly lower cytotoxicity in all cell lines tested. Lobaplatin was not cross-resistant to cisplatin in a 10-fold cisplatin-resistant testicular carcinoma cell line and showed only weak cross-resistance in a 20-fold cisplatin-resistant ovarian carcinoma cell line. In contrast, complete cross-resistance between cisplatin and lobaplatin occurred in two cisplatin-resistant human gastric carcinoma cell lines, which were 3.3- and 9-fold resistant to cisplatin and 3.1- and 6.5-fold resistant to lobaplatin, respectively. Furthermore, lobaplatin showed significant activity against cisplatin-resistant human ovarian and testicular carcinoma xenografts in vivo. These data indicate a high level of activity for lobaplatin at clinically achievable concentrations in ug-sensitive testicular, ovarian, and gastric carcinoma cell lines and a lack of complete cross-resistance to cisplatin. Further clinical development of lobaplatin is clearly warranted.

Carotid artery stump pressure: how reliable is it in predicting the need for a shunt?

Carotid artery stump pressure was measured in 84 cases of carotid endarterectomy. The operations were performed in 71 patients over a period of five years. An altered neurological status during temporary occlusion of the carotid artery, assessed with the patient under local anesthesia, was the sole criterion for shunt placement. Stump pressure (SP) was significantly higher in the 69 unshunted cases (mean of 53.3 mmHg) than the 15 shunted cases (mean of 34.2 mmHg). Shunt was required in two of 41 cases (5%) with SP of greater than 50 mmHg, eight of 36 cases (22%) with SP of 25-50 mmHg, five of seven cases (71%) with SP of less than 25 mmHg. The clinical presentation, including history of prior stroke, and the presence of contralateral disease (including complete carotid occlusion), did not influence the need for a shunt. In this series, carotid artery stump pressure has greater predictive value for shunt requirement when it is greater than 50 mmHg or less than 25 mmHg. However, monitoring the neurological status of the patient in the awake state is still the most reliable method of determining shunt requirement. In our experience, this is associated with minimal morbidity and no mortality.

Cell surface lectins of transplantable human teratocarcinoma cells: purification of a new mannan-specific endogenous lectin.

Fractionation of detergent extracts of transplanted tumors of human teratocarcinoma cells by affinity chromatography yields one predominant protein with apparent molecular weight of 14,000 and further, for less abundant protein with apparent molecular weight of 35,000 from lactose-sepharose and one protein with apparent molecular weight of 68,000 from mannan-sepharose. No further carbohydrate-binding protein can be isolated on columns derivatized with asialofetuin, melibiose and L-fucose, to which the extract is applied successively. Both proteins agglutinate trypsinized, glutaraldehyde-fixed rabbit erythrocytes in the absence of Ca2+ and can thus be defined as endogenous human teratocarcinoma lectins. Inhibition of heterotypic and homotypic aggregation of human teratocarcinoma cells by D-mannose, D-galactose and glycoproteins rich in one of these sugars is consistent with a functional role of these Ca2+-independent lectins in cell aggregation. Visualization of these activities by fluorescent mannosylated and lactosylated markers on the cell surface further supports the cell surface localization of these detergent extractable lectins. The mannan-specific lectin, in particular, has so far not been detected in any mammalian tissue or tumor and is of potential value for a lectin-based diagnosis and therapy of embryonal carcinomas.