Learning to knock out male infertility.

In vivo disposition of Adriamycin (ADR) is characterized by rapid uptake into most tissues and long tissue transit time due to high affinity but slowly reversible binding to nuclear DNA (Harris & Gross, 1975; Terasaki et al., 1984). The role of drug metabolism in this scheme has not been fully elucidated (Chan et al., 1978). There is reason to believe that uptake of ADR into solid tumours behaves independently of the factors that govern its distribution into tissues. For instance, ADR was detected in only the outermost 4 to 6 layers of cells of intra-abdominal ovarian tumours, indicating a penetration problem not normally associated with tissues (Ozols et al., 1979). Also, tumour cells develop resistance to ADR believed to involve active extrusion of the drug from cells (Dano, 1973). Studies on the uptake of ADR into solid human tumours in vivo have been limited because of the obvious problem of obtaining sufficient numbers of specimens for meaningful evaluation. Also, these studies have tended to compare drug concentrations in tumours with unrelated tissues. In this paper we have attempted to study several aspects of the disposition of ADR in solid human tumours in vivo: (a) dose/response, by sampling from tumours with different known responses to ADR; (b) tumour drug uptake, by comparing ADR concentrations in tumours with adjacent normal tissue and blood; (c) intracellular binding; and (d) tumour metabolism. Tumour and normal tissue specimens were obtained from post-operative resections and open biopsies from a total of 36 patients admitted to Glasgow Royal Infirmary. Gastric carcinoma and adjacent normal mucosa were from partial and full gastrectomies; colorectal carcinoma and adjacent normal colon mucosa were from anterior resections and partial colectomies and breast carcinoma was from breast lumpectomies. Breast cancer metastases were from axilla node biopsies with evidence of tumour nodules. Liver biopsy specimens from gastric and colorectal cancer patients and 5 ml of venous blood from all patients were sampled simultaneously with tumour resection. A low dose of commercially available ADR (25 mgm2, Farmitalia, Milan, Italy) was administered i.v. operatively 30 min before tumour resection (27 min+16 min s.d.). Resections and biopsies were immediately taken to the pathology department from histological sectioning and 1-2 g tumour visibly clear of necrosis and normal tissue, 1-2 g mucosa and 0.5 g liver were immediately frozen to-60°C with solid CO2 for determination of drug and metabolite content. ADR and metabolite concentrations of all samples were …