British Journal of Cancer

Cobb, L M; Humm, J L

doi: 10.1038/bjc.1986.254pmid: 3542006

Antibodies directed against tumour associated antigens provide a means for delivering preferentially cytotoxic radionuclides to the cells of primary and secondary tumours. The factors that influence the effectiveness of the radiation in the tumour compared with its effect on the radiosensitive normal tissues include the specificity of the antibody, the distribution of targeted energy within the tumour and the host's response to the injected foreign antibody. Recently some encouraging results from clinical trials of radioimmunotherapy have been reported in the literature. There is a continual search for more avid and specific antibodies, and the techniques of genetic engineering are being applied to the problem of reducing the antigenicity and mass of the carrier antibody. The improved efficiency of the labelled antibody needs to be supplemented by an identification of those tumours most likely to respond to this form of therapy.

Hawkey, C J; Holmes, C H; Smith, P G; Austin, E B; Baldwin, R W

doi: 10.1038/bjc.1986.255pmid: 3026425

Reactivity of the monoclonal antibody 791T/36 with secondary malignant deposits has been investigated in frozen sections of 74 human liver biopsy specimens. There was no reactivity with hepatocytes but in some instances binding to fibrous tissues and in one case to portal tract lymphocytes was observed. Sections from 9 biopsy specimens contained malignant deposits. In seven of these 791T/36 bound either to malignant cells or to pseudoacinar contents (3 colorectal adenocarcinomas; 1 probable pancreatic adenocarcinoma; 1 medullary cell carcinoma of thyroid; 1 oat cell carcinoma of bronchus and 1 deposit of nodular sclerosing Hodgkins Disease). Two undifferentiated tumours (1 gastric adenocarcinoma and 1 oat cell bronchial carcinoma) showed no antibody binding. The histological pattern of reactivity previously reported with primary tumours appears to be similar in secondary deposits. A wider range of tumours than recognised hitherto binds 791T/36. Whether the binding to fibrous tissue seen in some instances is sufficient to cause diagnostic uncertainty when 791T/36 is used for scanning requires further investigation.

Robinson, A; Williams, A R; Piris, J; Spandidos, D A; Wyllie, A H

doi: 10.1038/bjc.1986.256pmid: 3542007

RAP-5, a monoclonal antibody raised against a p21ras peptide, has been claimed to show immunohistochemical localisation of cells with infiltrative properties in human tumours. We confirmed that this antibody reveals pronounced cellular heterogeneity in human colonic neoplasms but could find no obvious relationship to infiltrative activity. RAP-5 bound to many different cell types, neoplastic and normal. In order to clarify the specificities of RAP-5 we applied it to two cell lines: nontumorigenic hamster fibroblasts in which ras expression is barely detectable, and a vigorously tumorigenic line derived from these fibroblasts by insertion of the human mutated Ha-ras oncogene in a high expression vector. Another antibody to p21ras, Y13-259, clearly distinguished between these cell lines both on immunoblots and immunocytochemically, but RAP-5 did not. Rather, it bound to proteins of a variety of molecular weights in both cell lines. The results show that RAP-5 is unlikely to be a useful reagent for detection of ras associated proteins in human tissues.

Dhokia, B; Pectasides, D; Self, C; Habib, N A; Hershman, M; Wood, C B; Munro, A J; Epenetos, A A

doi: 10.1038/bjc.1986.257pmid: 3801285

A new, simple and sensitive low pH ELISA method has been developed to measure serum levels of tumour associated antigens detectable by monoclonal antibodies HMFG1 and HMFG2. We examined sera from healthy controls, patients with neoplastic and non-neoplastic conditions of breast, liver and gastrointestinal tract. The majority of patients with metastatic breast cancer had elevated serum antigens (69% HMFG1, 72% HMFG2) compared to healthy controls (6.3% HMFG1, 3.0% HMFG2) or patients with benign breast disease (17% HMFG1, 4% HMFG2). There was no discrimination using these assays between patients with neoplastic and non-neoplastic conditions of liver and gastrointestinal tract. This new method promises to be of value in the assessment and management of patients with breast cancer.

Dhokia, B; Canney, P A; Pectasides, D; Munro, A J; Moore, M; Wilkinson, P M; Self, C; Epenetos, A A

doi: 10.1038/bjc.1986.258pmid: 3467785

A new method with a low pH step to dissociate serum complexes has been developed to measure serum levels of antigens associated with ovarian cancer. The antigens are detected by monoclonal antibodies HMFG1 and HMFG2 and have been compared to an existing ovarian cancer associated antigen detected by the antibody CA125. Elevated HMFG1 was found in 56%, and elevated HMFG2 in 65% of 924 sera from 85 patients with ovarian cancer. CA125 was elevated in 85% of these sera. When the three markers were used in conjunction, 95% of sera from patients with ovarian cancer were positive--compared with 7% in sera from healthy control subjects. Therefore, the combination of HMFG1, HMFG2 and CA125 increases the diagnostic accuracy. If all three markers are normal in a patient previously treated for ovarian cancer then no further positive information regarding disease status can be obtained by ultrasound and CT scanning.

Haglund, C

doi: 10.1038/bjc.1986.259pmid: 3467786

CA125 is a tumour marker test based on a monoclonal antibody against an antigen from an ovarian carcinoma cell line. Serum concentrations of CA125 were determined in 95 patients with pancreatic cancer and in 106 patients with benign pancreatic, biliary and hepatocellular diseases. The CA125 concentrations were compared with the CA19-9 and CEA levels. Almost half (45%) of the patients with pancreatic cancer had an elevated CA125 level (greater than 35 U ml-1). Elevated values were also found in benign diseases (24%), especially in patients with pancreatitis and benign hepatocellular diseases, but more seldom in extrahepatic cholestasis. It seems that CA125 is of limited value in the diagnosis of pancreatic cancer. Combination of the CA125 with the CA19-9 test increases the sensitivity only 6% as compared to the CA19-9 assay alone. There may, however, be a use for CA125 in differentiating between obstructive jaundice of benign and malignant origin.

Plowman, P N; Nicholson, R I; Walker, K J

doi: 10.1038/bjc.1986.260pmid: 2948537

Ten previously untreated postmenopausal women with metastatic breast cancer, none of whom had received prior systemic therapy, were treated with the luteinising hormone releasing hormone (LHRH) analogue D-Ser(But)6, Azgly10-LHRH (ICI 118630). Two obtained an objective partial remission, one in bone metastases and one in lung metastases. One patient proved unassessable. Amongst the seven failures, incomplete pituitary gonadotrophin suppression over the relatively short treatment period with the daily injections was noted. The seven patients failing ICI 118630 received tamoxifen and two with high tumour oestrogen receptor values responded. LHRH analogues may provide a novel endocrine therapy for postmenopausal breast cancer although more data are needed. In this study, the monthly depot injection proved superior to daily injections with regard to gonadotrophin suppression, although it is not clear that this provides the mechanism of action.

Ling, L L; Sutherland, R M

doi: 10.1038/bjc.1986.261pmid: 3801286

The hypoxic toxicity and binding of misonidazole (MISO) requires metabolic reduction. The influence of glucose on the toxicity and binding of MISO was studied because glucose is a major substrate for the supply of NADPH through the hexose monophosphate pathway (HMP). Hypoxic EMT6/Ro cells (10(6) cells ml-1) were incubated with varying concentrations of glucose (0.015 mM to 5 mM). The initial rate of glucose transport was found to increase linearly with the extracellular glucose concentration up to 5 mM (0.038 nmol glucose 10(-6) cells sec-1). About 1.5 percent of the total glucose consumed went through the HMP for hypoxic cells in 5 mM glucose. The rate of HMP progressively decreased as the glucose concentration was lowered. When exposed to 5 mM MISO, the HMP was stimulated. This stimulation declined from 3.2 times in 5 mM glucose to barely detectable below 1 mM glucose. Both the hypoxic toxicity and binding of 5 mM MISO to the acid-insoluble fraction were decreased as the concentration of glucose was lowered. Below 0.5 mM glucose, no significant toxicity due to MISO was observed. There was an initial burden of 2.5 nmol MISO 10(-6) cells bound with little toxicity. After this initial burden, the terminal slope was 1.8 mol MISO bound 10(-6) cells (63 percent decrease in the surviving fraction). These results indicate that glucose concentrations lower than 5 mM can decrease the HMP rate and the toxicity and binding of MISO to hypoxic cells, and imply that calibration curves with normal and low glucose concentrations should be used to estimate the possible hypoxic fraction when MISO is used as a hypoxic probe in vivo.

Roizin-Towle, L; Hall, E J; Pirro, J P

doi: 10.1038/bjc.1986.262pmid: 3801287

Misonidazole (MISO) potentiates the cell killing effect of certain chemotherapy agents, but only under hypoxic conditions. The purpose of the present study was to define the range of oxygen concentrations over which chemosensitization by MISO takes place using mammalian cells cultured in vitro, and to compare this with the oxygen levels required for radiosensitization. V-79 hamster cells, attached to permanox dishes, were gassed with known concentrations of oxygen (less than 10 to 200,000 ppm) and treated with 1 and 5 mM MISO for 4 h previous to exposure to the chemotherapy agent, melphalan. In a parallel series of experiments, under the same gassing conditions, cells were irradiated with graded doses of X-rays at various oxygen concentrations. The K factor i.e. the oxygen concentration which defined half the maximum effect was found to be approximately 4776 ppm for radiosensitization and approximately 400 ppm for chemosensitization by MISO. It is evident that a significantly more stringent level of hypoxia is required for chemosensitization by MISO to take place than for radiosensitization.

Erba, E; Pepe, S; Ubezio, P; Lorico, A; Morasca, L; Mangioni, C; Landoni, F; D'Incalci, M

doi: 10.1038/bjc.1986.263pmid: 3801288

The growth inhibitory effects, the reduction of [3H]-TdR incorporation and the perturbation of the cell cycle induced by the new agent mitozolomide on the M14 human melanoma cell line and on the SW626 human ovarian cancer cell line were compared to those produced by BCNU. Flow cytometry showed an interesting difference: at the high concentration mitozolomide induced an accumulation of cells in S middle and S late-G2-M phase of the cell cycle whereas BCNU caused only a block in S late-G2-M. Further studies were aimed at investigating the susceptibility of freshly isolated human ovarian cancer cells to pharmacologically reasonable mitozolomide concentrations. Only in one out of 16 primary cultures of human ovarian cancers was mitozolomide able to induce cell cycle perturbation, suggesting that ovarian carcinoma cells may not be sensitive to this drug.