Activation of mitomycin C by NADPH:cytochrome P-450 reductase

Mitomycin C is an alkylating agent used in cancer chemotherapy that shows some specificity towards hypoxic cells. The therapeutic effects of this compound are thought to result from its metabolic activation by enzymes such as NADPH:cytochrome P-450 reductase. In a previous report we described a Chinese hamster ovary cell line resistant to mitomycin C, which had a decreased NADPH:cytochrome P-450 reductase activity coupled with a lower rate of mitomycin C metabolism. In order to provide further evidence that the lower reductase activity is a factor in the resistance mechanism, we incorporated NADPH:cytochrome P-450 reductase into cytotoxicity assays and showed that it significantly sensitizes cells to mitomycin C. Also, the difference in drug sensitivity between the wild-type and drug-resistant Chinese hamster ovary cells was no longer observed. In addition to these studies, we expressed a rat liver NADPH:cytochrome P-450 reductase cDNA in a Salmonella typhimurium strain, LR5000. The bacteria expressing the rat NADPH: cytochrome P-450 reductase showed increased sensitivity to mitomycin C when incubated with this compound under aerobic conditions. However, under hypoxic conditions increased sensitivity was not observed. This parallels the previous finding with mitomycin C-resistant Chinese hamster ovary cells. These data provide direct evidence for the role of NADPH:cytochrome P-450 reductase in the cytotoxic action of this mitomycin C under aerobic but not hypoxic conditions and suggest that reduced levels of this enzyme can lead to drug resistance. P-450 reductase expressed in S. typhimurium may provide a valuable tool for evaluating the role of this enzyme in the toxicity of drugs activated through a one electron reduction pathway.     

Vascular amyloidosis causing spontaneous mediastinal haemorrhage with haemothorax.

Bleeding diathesis is a recognised complication of amyloid disease. Localised and generalised bleeding manifestations are usually associated with intravascular coagulopathy related to isolated or multiple coagulation factor deficiencies. Recently, there have been reports of haemorrhage due to amyloid deposition in blood vessel walls and in the perivascular region leading to increased fragility and poor haemostasis. We report a case of spontaneous mediastinal haemorrhage due to amyloid involvement of vascular tissue in the absence of coagulopathy.     

3 cases of longitudinal stress fracture of the tibia

A 62-year-old man rose from a crouched position with a twisting motion and developed pain in the lower third of his left tibia. 2 weeks later, radiographs were normal. Pain persisted and 3 months later radiographs revealed a longitudinal lucency in the distal tibia on the lateral view and a corresponding thin sclerotic band on the AP view suggesting a stress fracture (Figure). The leg was immobilized in a cast. A CT scan confirmed a healing stress fracture with endosteal and subperiosteal new bone formation. The cast was removed at 6 weeks, radiographs showed healing and the patient has remained asymptomatic.     

Oculomotor nerve and muscle abnormalities in congenital fibrosis of the extraocular muscles

Congenital fibrosis of the extraocular muscles is an autosomal dominant congenital disorder characterized by bilateral ptosis, restrictive external ophthalmoplegia with the eyes partially or completely fixed in an infraducted (downward) and strabismic position, and markedly limited and aberrant residual eye movements. It has been generally thought that these clinical abnormalities result from myopathic fibrosis of the extraocular muscles. We describe the intracranial and orbital pathology of 1 and the muscle pathology of 2 other affected members of a family with chromosome 12-linked congenital fibrosis of the extraocular muscles. There is an absence of the superior division of the oculomotor nerve and its corresponding alpha motor neurons, and abnormalities of the levator palpebrae superioris and rectus superior (the muscles innervated by the superior division of the oculomotor nerve). In addition, increased numbers of internal nuclei and central mitochondrial clumping are found in other extraocular muscles, suggesting that the muscle pathology extends beyond the muscles innervated by the superior division of cranial nerve III. This report presents evidence that congenital fibrosis of the extraocular muscles results from an abnormality in the development of the extraocular muscle lower motor neuron system.     

Reconstruction of the sternum and anterior chest wall using autologous tissues

We have described the successful reconstruction of a completely resected anterior chest wall using autologous tissues. This case demonstrates feasibility despite known potential contamination and serious postoperative physiologic dysfunction.