Low-density lipoprotein metabolism in mice with soft tissue tumours.

This study examines the potential value of low-density lipoprotein (LDL) as a vehicle for directing cytotoxic drugs to tumour cells in mouse model systems. Control and MAC 13 tumour-bearing NMRI mice were injected with tracer doses of 125I-labelled native and cyclohexanedione-modified 131I-labelled LDL. 18 h later the animals were killed and the radioactivities assimilated by various tissues were measured relative to plasma activity at the time of death. These values were used to calculate specific tissue receptor-mediated LDL uptake. All tissues expressed receptors but the liver and adrenal gland were particularly active. In tumour-inoculated animals, the neoplastic lesions were second only to liver in their net assimilation of LDL. CFLP mice bearing virus-induced parotid adenomata gave results similar to those obtained in NMRI animals. In order to improve the selectivity of LDL assimilation we attempted to downregulate LDL receptors in the liver and adrenal gland by administration of the bile acid sodium taurocholate or by subcutaneous injection of hydrocortisone sodium succinate. These manoeuvres together reduced uptake of the lipoprotein into both organs without affecting tumour activity.

Further evidence that the site of the breakpoint in the major breakpoint cluster region (M-bcr) may be a prognostic indicator.

A break in chromosome 22 within the major breakpoint cluster region (M-bcr) is a characteristic of Philadelphia chromosome-positive CML. We have determined the zone of the breakpoint in 80 chronic myelogenous leukemia (CML) patients and have confirmed our previous observation that a relationship does exist between the subregion of the breakpoint within the M-bcr and the average length of the chronic phase of the disease. Patients with a 3' breakpoint have a statistically shorter chronic phase (25 months) than patients with a 5' break (55 months). Thus, a molecular analysis of the M-bcr may provide a prognostically useful indicator of the probable length of the chronic phase, although the underlying mechanism of blast transformation, and the role (if any) of the hybrid phl-abl mRNA, is still unclear.

Comparative cellular uptake and cytotoxicity of a complex of daunomycin-low density lipoprotein in human squamous lung tumour cell monolayers.

In an attempt to target cytotoxic drugs to tumour cells daunomycin-low density lipoprotein (LDL) complexes were synthesised. Human squamous lung tumour cells in vitro have large numbers of high affinity cell surface LDL receptors (Vmax = 19 ng LDL/micrograms cell protein per 24 hr; Km = 23 micrograms/ml). Cellular uptake of daunomycin and LDL-daunomycin was rapid and approached equilibrium by approximately 3 hr. Intracellular daunomycin concentrations were similar at each time point regardless of whether free drug or the complex was used. The degree of intracellular drug metabolism differed markedly with significantly higher production of daunomycinol following exposure to free daunomycin for 90 min. Daunomycin and LDL-daunomycin were equally cytotoxic in vitro (respective clonogenic ID90s of 1 microgram/ml and 0.7 microgram/ml). Fluorescence microscopy indicated that both free daunomycin and LDL-daunomycin have a punctate, granular distribution within the cytoplasm.