Regulated degradation of an endoplasmic reticulum membrane protein in a tubular lysosome in Leishmania mexicana.

The cell surface of the human parasite Leishmania mexicana is coated with glycosylphosphatidylinositol (GPI)-anchored macromolecules and free GPI glycolipids. We have investigated the intracellular trafficking of green fluorescent protein- and hemagglutinin-tagged forms of dolichol-phosphate-mannose synthase (DPMS), a key enzyme in GPI biosynthesis in L. mexicana promastigotes. These functionally active chimeras are found in the same subcompartment of the endoplasmic reticulum (ER) as endogenous DPMS but are degraded as logarithmically growing promastigotes reach stationary phase, coincident with the down-regulation of endogenous DPMS activity and GPI biosynthesis in these cells. We provide evidence that these chimeras are constitutively transported to and degraded in a novel multivesicular tubule (MVT) lysosome. This organelle is a terminal lysosome, which is labeled with the endocytic marker FM 4-64, contains lysosomal cysteine and serine proteases and is disrupted by lysomorphotropic agents. Electron microscopy and subcellular fractionation studies suggest that the DPMS chimeras are transported from the ER to the lumen of the MVT via the Golgi apparatus and a population of 200-nm multivesicular bodies. In contrast, soluble ER proteins are not detectably transported to the MVT lysosome in either log or stationary phase promastigotes. Finally, the increased degradation of the DPMS chimeras in stationary phase promastigotes coincides with an increase in the lytic capacity of the MVT lysosome and changes in the morphology of this organelle. We conclude that lysosomal degradation of DPMS may be important in regulating the cellular levels of this enzyme and the stage-dependent biosynthesis of the major surface glycolipids of these parasites.

A special method of intra-arterial infusion for treatment of head and neck cancer.

Immediately after radical neck dissection the external carotid artery is lengthened by an autogenic saphenous vein graft and sutured more proximally to the common carotid artery. All branches of the external carotid artery not contributing to the blood supply in the tumor region are ligated. After the wound has healed, the vascular graft will be easily palpable and can be punctured repeatedly for highly selective intra-arterial chemotherapy of the inoperable primary tumor for a prolonged period of time. The method seems to be practicable, innocuous, and more effective than conventional methods of intra-arterial chemotherapy for head and neck cancer.

[Cytostatic therapy of advanced squamous cell carcinoma of the head and neck. A randomized study comparing cis-dichlorodiammineplatinum(II) and bleomycin with methotrexate and vindesine]. / Zytostatische Therapie von fortgeschrittenen Plattenepithelkarzinomen des Kopf-Hals-Bereiches. Eine randomisierte Studie zum Vergleich von cis-Dichlorodiaminoplatinum-(II) (cis-DDP) und Bleomycin (BLM) gegen Methotrexat (MTX) und Vindesin (VDS).

79 patients were randomized and treated either with cis-DDP 33 mg/kg i.v. day 1 and BLM 15 mg/m2 i.v. continuously day 2-6 (arm A) or less aggressively with MTX 30 mg/m2 i.v. day 1 + 6 and VDS 3 mg/m2 day 2 + 7 (arm B). Patients with inadequate response were further treated with the alternative regimen ("cross over"). Regarding response rates therapy A was superior to B (p = 0.01) respectively p = 0.05 for the cross over patients. Not pretreated in comparison to pretreated patients demonstrated not significantly better results. Pretreated patients had statistically superior response rates with arm A than with arm B (p = 0.05). All other prognostic factors were without any influence on treatment results. CR induced by chemotherapy (2 X) in not pretreated patients could be increased by additional surgery and X-ray therapy (CR = 26X). Survival times demonstrated no difference between both regimes. Chemotherapy was of less influence on median survival times after 39 months than in comparison to post-chemotherapeutically performed surgery +/- radiotherapy in 44 not pretreated patients. Chemotherapy: CR + PR to MR + NC + PD 16 respectively 13 months with 38 respectively 48% survivors (p = 0.25). Surgery +/- radiotherapy: CR + PR median not reached yet, MR + NC + PD 13 months with 60 respectively 18% survivors (p = 0.001).