1-phenyl-2-decanoylamino-3-morpholino-1-propanol chemosensitizes neuroblastoma cells for taxol and vincristine.

In this study, we show that an inhibitor of glycosphin-golipid biosynthesis, D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), increases the chemosensitivity of neuroblastoma tumor cells for Taxol and vincristine. At noneffective low doses of Taxol or vincristine, the addition of a noneffective dose of PDMP resulted in 70% cytotoxicity, indicating synergy. Such an effect was not observed for etoposide (VP16). PDMP caused an early (6 h) increase in ceramide (Cer) levels, but the excess Cer was metabolically removed in the long-term (96 h). However, upon incubation with PDMP in combination with Taxol, but not with etoposide, Cer levels remained elevated at 96 h. These results suggest that neuroblastoma cells are normally able to metabolically remove excess Cer, but lose this capacity upon exposure to microtubule modulating anticancer agents (Taxol or vincristine). In addition, PDMP treatment resulted in a decreased efflux of [14C]Taxol and [3H]vincristine from neuroblastoma cells, similar to treatment with PSC833 or MK571, suggesting an effect of PDMP on the transporter proteins P-glycoprotein and/or multidrug resistance protein. PDMP did not further reduce [14C]Taxol or [3H]vincristine efflux in PSC833-treated cells, although it did further diminish cell survival under these conditions. We conclude that a combined administration of nontoxic concentrations of PDMP and either Taxol or vincristine results in highly sensitized neuroblastoma cells. This appears to involve a sustained elevation of Cer levels, possibly in concert with increased drug accumulation.

Late results of mesocaval interposition shunting for bleeding oesophageal varices.

Survival, encephalopathy and shunt patency were studied in 64 consecutive patients who underwent mesocaval shunting with a wide-calibre Dacron prosthesis. Half of the patients were operated as emergency cases. Operative blood loss in patients who had emergency procedures was significantly higher than during elective operations. Overall, 30-day mortality was 27 per cent. Survival was 61 per cent after 1 year and 39 per cent after 5 years. Serious encephalopathy requiring hospital admission occurred in 5 patients (11 per cent of patients surviving more than 1 month). Shunt patency was assessed by scintisplenoportography and ultrasonography. Cumulative shunt occlusion rate was 16 per cent after 1 year, 33 per cent after 5 years and 52 per cent after 8 years of follow-up. Out of 17 patients with an occluded shunt, 9 had persistent or recurrent bleeding, while 3 patients had recurrent bleeding despite a patent shunt. We conclude that the mesocaval Dacron interposition shunt should not be recommended as the procedure of first choice for portosystemic shunting.

Oral anticoagulants and dextran for prevention of venous thrombosis in orthopaedics.

A hundred and fifty-two patients who were to undergo major orthopaedic surgery were divided into two groups in order to study the value of dextrans administered as adjuvants to oral anticoagulants in the prevention of deep venous thrombosis. The control group had oral anticoagulants only from the evening before the day of operation, aimed at the 15 per cent thrombotest level. The dextran group had peroperative and postoperative dextran infusions as well. Radionuclide venography was used for thrombosis detection. The dextran group had a lower incidence of thrombosis, but more haemorrhagic problems. The incidence of thrombosis was high in both groups.