Kenneth C. Calman

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.

NUCLEAR ŒSTROGEN RECEPTORS AND TREATMENT OF BREAST CANCER

Abstract In an attempt to improve the predictive value of œstrogen-receptor measurements in breast-tumour biopsy specimens, œstrogen receptor was measured at both cytoplasmic and nuclear levels. Although 33% of patients had receptors at both levels, another 17% had cytoplasmic but no nuclear receptors. Theoretically, this latter group would not be expected to respond to hormone therapy. 7% had nuclear but not cytoplasmic receptors. The six-month follow-up data for the group of patients with receptors at both cytoplasmic and nuclear levels suggests qualitatively that this group has a good chance of responding favourably to hormone therapy. Much larger numbers must be accumulated before quantitative conclusions can be reached.

Enhancement of Methotrexate Absorption by Subdivision of Dose

SummaryA comparison was made in fasting patients between a single 100 mg oral dose of methotrexate formulated as its sodium salt in a palatable syrup and the same total quantity of drug administered in four divided doses of 25 mg taken at 2-h intervals. Allocation to the order of these treatment schedules was on a random basis. The area under the serum methotrexate concentration-time curve until 50 h was found to be considerably greater after the divided dose regimen, the mean ratio AUC 25 mg x 4/AUC 100 mg being 1.86 (±0.90). There was no significant difference in peak serum methotrexate concentrations or methotrexate half-life estimates between the two regimens, however.The results of this study are consistent with saturation of an intestinal transport process when methotrexate is administered orally in a single large dose.

Effects of polysorbate 80 on the absorption and distribution of oral methotrexate (MTX) in mice.

SummaryThis study is part of a programme of work aimed at improving the bioavailability of oral methotrexate (MTX). In preliminary experiments no significant effect of non-ionic surfactant polysorbate 80 (Tween 80) on absorption of 0.5 mg MTX · kg-1 in NMRI mice was observed except when the drug was given together with 6% polysorbate 80 in solution. Absorption from a higher dose of 3 mg MTX · kg-1 was increased when the drug was administered with 2% or 6% polysorbate 80. Plasma MTX measurements confirmed the significantly higher levels of MTX with 6% polysorbate 80 PO. In subsequent experiments, when Porton mice were used and 4 mg MTX · kg-1 was administered PO, higher plasma and brain levels of MTX were measured in animals given the drug with 6% polysorbate 80, suggesting the enhancement of MTX uptake by this non-ionic surfactant. Although the amount of MTX in the liver and kidney of mice given MTX with polysorbate 80 were not significantly different from the amounts in mice given MTX alone, the lower observed levels suggested that polysorbate 80 perhaps facilitates the elimination of the drug from these organs. The amount of plasma MTX in mice measured 1 h after oral administration of various MTX doses in the presence of 6% polysorbate 80 were significantly higher than the levels in mice given the drug without surfactant, but the significantly higher amounts of MTX in the brain were only observed following the doses of 2 and 6 mg MTX · kg-1.

Specialist training in UK

1852 Vol 350 • December 20/27, 1997 concentrations than non-diabetics, by an average of 4·3% in men and 6·9% in women. Because of this, the Sheffield table targets an annual mean CHD risk of about 3·1% in diabetic men and 3·2% in women, rather than the 3·0% intended. This error is negligible compared with that of not using any formal method of CHD-risk assessment. The Sheffield table will be more inaccurate in individuals whose HDL cholesterol differs substantially from the population mean, and this is stated clearly in the footnotes to the table. A Sheffield table based on the total/HDL cholesterol ratio is available on request for those who wish a more precise assessment of CHD risk. We have not advocated wide use of the total/HDL cholesterol ratio in the Sheffield table because of concern that non-specialist doctors may be uncomfortable with this ratio, and because many laboratories do not report the ratio routinely. Perhaps Jones is jesting when he suggests that laboratories might calculate the risk of CHD from the lipids and clinical information. Our understanding is that most clinicians are reluctant to write the patient’s name on the laboratory request form—will they really provide age, sex, smoking habit, blood pressure, and the presence or absence of diabetes or left-ventricular hypertrophy?

The analysis and animal pharmacokinetics of 1,2,4, triglycidyl urazol using a high-pressure liquid chromatographic technique

SummaryThis article details a procedure for the analysis of TGU by a simple high-pressure liquid chromatographic (HPLC) method. Linearity is maintained over the range from zero to at least 30 μg 1,2,4, triglycidyl urazol (TGU). The sensitivity of the assay is 250 ng/ml. A second peak, as yet unidentified, was setected on the chromatogram and probably represents a metabolite of TGU. The pharmacokinetic profile of TGU in Porton mice shows a first-order elimination process t1/2β of 5 min. The apparent volume of distribution is 0.75 ml and the clearance 0.10 ml/min with a elimination rate constant of 0.14 min.

The Management of Cancer

In the past few years there have been considerable changes in methods of treating cancer. These changes have not simply been due to improvements in techniques or the availability of new drugs. The changes have also been related to the way in which the different forms of treatment have been used. For example, the active and aggressive treatment of small amounts of residual tumour, and the concept of combined modality therapy in which the patient may receive several forms of treatment given in a planned manner.

Clinical Pharmacology of Anti-Cancer Drugs

The pharmacological principles determining the effectiveness of drugs in the treatment of malignant and non-malignant diseases are similar. Thus, drug absorption, binding, distribution, metabolism and excretion determine the concentration of drug at the target site and the duration and intensity of action. However, with anti-cancer drugs, there are frequently extra factors, not commonly encountered with other drugs, which influence the efficacy of treatment. Such special factors are that many anti-cancer drugs: (a) have a very narrow therapeutic index, i.e. a narrow margin between effective dose and lethal dose; (b) are highly unstable; (c) are effective at very low concentrations; and (d) have unusual metabolic pathways.

The Approach to the Patient

As with the treatment of any disease the approach to the patient and the attitudes of the doctor or nurse are of crucial importance. This implies that the same high standards of medical care, investigations and treatment are given to the patient with cancer as would be given to other diseases requiring specialist management. It emphasises the fact that the clinical approach to the patient has, as its foundation, the principles of general medicine.

Identification of Adriamycin and its Metabolites in Human and Animal Tissue and Blood

Adriamycin, an anthracycline antibiotic with a broad spectrum of anti-tumour activity, is metabolized to at least 8 different products in man, all of which have been extracted from patient urine and identified using TLC [l]. These are adriamycinol (AOL), the major metabolite; 5 non-polar aglycones of adriamycin (ADR) and AOL, and two conjugated aglycones. The kinetics of several of the aglycones has been followed in 14 patients using TLC [2].