This paper explores the factors involved in assessing the value of a tumour-marker test in differential diagnosis and patient monitoring. The difficulties have been grossly underestimated, and in the past it has been tacitly assumed that an association between the tumour-marker level and the presence of malignancy is sufficient to prove the usefulness of the test. Part 1 investigates in depth the principles of design of a study to evaluate a tumour-marker test, bearing in mind the ultimate aim of improving the patient's prognosis. The preliminary research carried out on the tumour marker, the laboratory assay technique itself and the "normal" range of levels or the use of a proposed critical level, are all reviewed. The clinical side presents many problems, including the precise definition of the medical situation in which the addition of a new test may assist, and the estimation of the overall size of this problem. Some examples from studies are given. The general principle of evaluating a tumour marker by considering the clinical situation first without, and then with, a tumour-marker result, is stressed. Part 2 gives some practical advice on the setting-up, administration and analysis of such studies.

Ehrlich ascites tumour cells grown in mice have a cell-surface trypsin-like neutral protease (TLNP) which is not inhibited by high-mol.-wt inhibitors of trypsin. This enzyme is inhibited by low concentrations of zinc, which may be removed by chelating agents, with the consequent return of enzymic activity. Gold, provided as the drugs aurothiomalate or auranofin, also inhibits TLNP. The gold can be removed from the enzyme by incremental addition of thiols. The mechanisms of gold transfer to the active site to cause inhibition and subsequent removal of gold with reactivation of TLNP, have been shown to be controlled by reversible thiol-exchange reactions.

When the clonogenic survival of mouse haemopoietic stem cells (CFU-S) and leukaemia L1210 cells growth as ascites tumours are compared after being heated in vitro and assayed in vivo by spleen-colony assay, there is no significant difference in the terminal slopes of the survival curves. The shoulders of the survival curves differ, but this may be explained by differences in cell kinetics. By contrast, L1210 leukaemic marrow cells are considerably more susceptible to the lethal effects of hyperthermia (43 degrees C) than either normal marrow stem cells or L1210 leukaemic cells grown as ascites tumours. Moreover, the killing of L1210 ascites cells by hyperthermia can be enhanced by heating L1210 ascites cells with an equal number of normal marrow cells, or as upernatant removed from heated marrow cells. Most cells in lukaemic marrow are normal, and it is postulated that the increased thermal sensitivity of L1210 cells in leukaemic marrow is caused by diffusible factors (e.g. lysosomal enzymes) released by heating normal marrow cells. Images Fig. 8 Fig. 9

In a clinical investigation of observed postoperative survival, 563 patients have been registered for primary surgical treatment of colorectal cancer since 1974. The potential prognostic factors examined within the first days of hospitalization for primary resection included age of the patients, operability, location of the tumour, tumour extension and the preoperative serum CEA level. Statistical treatment of the data revealed that each of the clinical parameters except tumour location covers ranges associated with highly significant differences in survival of the patients. The preoperative serum CEA level gave prognostic information in addition to operability or tumour extension. The prognostic significance of the preoperative CEA level was still evident when selected subgroups of patients with distinct resectability and tumour extension were examined. The results indicate that the preoperative serum CEA level is an independent prognostic parameter.

Phototherapy in the presence of haematoporphyrin derivative has been shown to have a preferential effect on malignant tumours when compared to normal tissue. This communication presents a comparison of the sensitivity to photochemotherapy in vitro of different cell lines. Asynchronous populations of cells were exposed to light in the presence of haematoporphyrin derivative, and found to be inactivated with a comparable efficiency. The lines were of human, Chinese-hamster or mouse origin and had different abilities to form tumours after heterotransplantation into nude mice or transplantation into syngeneic, immunosuppressed mice. Synchronized cells from 4 of the lines showed a similar variation in sensitivity to light throughout the cell cycle. Cells near the middle of interphase showed the highest sensitivity, whilst cells in early G1 were found to be least sensitive towards treatment with haematoporphyrin derivative and light.