Mechanisms of spontaneous human cancers.

The causes of much of human cancer remain obscure. The fraction that is spontaneous is unknown and cannot be calculated until all known external causes have been accounted for. This is not a feasible proposition.

Cohort analysis of mortality rates as an historical or narrative technique.

A history of cohort analysis has been given, and it has been pointed out that the bulk of the literature on the subject has dealt with concepts that assume either that graduation and possibly extrapolation are desirable, preferably in conformity with some formula expressing what is implicitly accepted as a "law of mortality", or that, whether or not a fixed pattern of mortality exists, the intensity of mortality risk is largely determined in early life. The view is advanced that either concept alone, is, or both concepts together are, inadequate and may lead to an improper assessment of the nature-nurture complex, since environment and therapeutic measures are constantly changing. The plea is made for the technique of cohort analysis to be used as a narrative or historical technique, and for a synthesis of knowledge derived from social history, medical history, and cohort analysis to be made to interpret the narrative.

Differences in the levels and pattern of DNA-adduct labelling in human cell lines MCL-5 and CCRF, proficient or deficient in carcinogen-metabolism, treated in vitro with bile from familial adenomatous polyposis patients and from unaffected controls.

In patients with familial adenomatous polyposis (FAP), duodenal adenomas cluster around the ampulla and their distribution closely resembles mucosal exposure to bile, suggesting a role for bile in their development. Previous studies using 32P-postlabeling to detect DNA adducts, have provided evidence to support this hypothesis. We have now investigated the role of metabolic activation in influencing the levels and patterns of adduct formation by incubating precolectomy gallbladder bile from FAP patients and bile from unaffected controls with human lymphoblastoid cell lines that are metabolically proficient (MCL-5), or deficient (CCRF).

cis-Diamminedichloroplatinum(II)-induced cell death through apoptosis in sensitive and resistant human ovarian carcinoma cell lines.

We have studied the effects of the chemotherapeutic drug cis-diamminedichloroplatinum(II) (cis-platin) on three human ovarian carcinoma cell lines - one sensitive to the drug (CH1), one with acquired resistance (CH1cisR) and one with intrinsic resistance (SKOV-3). Previous work has shown that the 50% inhibitory concentrations (IC50 values) after a 2-h exposure to the drug are: CH1, 2.5 microM; CH1cisR, 7.

Primary structure of the variable regions encoding antibody to NG2, a tumour-specific antigen on the rat chondrosarcoma HSN. Correlation of idiotypic specificities with amino acid sequences.

Eight syngeneic rat monoclonal antibodies that recognize structurally overlapping epitopes on the chondroitin proteoglycan NG2, a tumour-specific antigen on the chemically induced rat chondrosarcoma HSN, have been analysed for the sequence of their immunoglobulin heavy (H) and light (L) chain variable (V) regions. This analysis defined five groups of antibodies which are very similar for both the H and L chains and revealed that a wide range of different V regions are capable of binding to the same antigenic determinant. However, three mAbs, 11/160, ALN/12/17 and ALN/9/94, which recognize a sequential epitope, were found to use almost identical heavy (V-D-J) and light (V-J) chains in regions demonstrating an exclusivity in specific protein-protein interaction for this particular epitope.

High pH reduces DNA damage caused by bile from patients with familial adenomatous polyposis: antacids may attenuate duodenal polyposis.

Patients with familial adenomatous polyposis (FAP) develop periampullary duodenal tumours, suggesting that bile contributes to their formation. The hypothesis that bile contains carcinogens has been tested by looking for DNA adducts (markers of carcinogen exposure) in the duodenum of patients with or without FAP and by determining whether bile can produce DNA adducts in vitro. Using 32P-postlabelling to detect adducts, there was an excess (compared with unaffected patients) of DNA adducts in the duodenum of FAP patients and an excess of DNA adducts in the small bowel of rats treated with FAP bile, while bile from FAP patients formed significantly more DNA adducts in vitro than did bile from controls.

Mutations in the p53 gene in schistosomal bladder cancer: a study of 92 tumours from Egyptian patients and a comparison between mutational spectra from schistosomal and non-schistosomal urothelial tumours.

Much of bladder cancer in East Africa and the Middle East is attributed to chronic urinary infection with Schistosoma haematobium ('schistosomiasis'). Most schistosomal bladder cancer (SBC) is squamous cell carcinoma (SCC) and occurs in the fifth decade of life. In contrast, nonschistosomal bladder cancer (NSBC) in Western countries usually occurs in the seventh decade of life and is largely transitional cell carcinoma (TCC).

Mechanisms of carcinogenesis and individual susceptibility to cancer.

The population can be divided into four groups, or "oncodemes," depending on the relative contributions of environment and genetics to their risk of cancer. These oncodemes are: 1) background (random mutations in normal people); 2) environmental (environmental carcinogens acting on normal people); 3) environmental/genetic (environmental carcinogens acting on genetic susceptibility); and 4) genetic, with genetic susceptibility being more important than environmental exposure. Most cancer probably occurs in oncodemes 2 and 3.

Cisplatin induces apoptosis in a human ovarian carcinoma cell line without concomitant internucleosomal degradation of DNA.

After treatment of the human ovarian carcinoma cell line, CH1, with cisplatin, cells detached from the culture dish in a time- and dose-dependent fashion. These cells showed morphological changes indicative of apoptosis. Their DNA had not been degraded into oligonucleosomal fragments, but the DNA had been cut into larger fragments (30 kbp) of a size associated with chromatin loops.

The role of apoptosis in cell killing by cisplatin: a flow cytometric study.

Cell killing of L1210 cells by cisplatin has been studied using flow cytometry and DNA gel electrophoresis. Ten hours after a supralethal dose of drug (100 microM), extensive apoptosis was induced. Cells were also susceptible to the induction of apoptosis by nutritional deprivation, for example by incubation in arginine-deficient medium.

Uptake and distribution of L-3-[I-125] iodo-alpha-methyl tyrosine in experimental rat tumours: comparison with blood flow and growth rate.

Radiolabelled amino acids combined with positron emission tomography (PET) show promise for the accurate delineation of viable tumour extent and may also provide a rapid and sensitive indicator of response to therapy. We have investigated the potential use of the radioiodinated amino acid analogue L-3-iodo-alpha-methyl tyrosine (IMT) for these purposes using experimental tumours in hooded rats. Preliminary studies using HSN tumours and IMT labelled with iodine-125 demonstrated maximum tumour uptake at 15 min post injection although an improved tumour-to-brain ratio was seen at 24 h due to the relatively poor retention of IMT in normal brain.

Characterization of luminal and basal cells flow-sorted from the adult rat mammary parenchyma.

Differentially expressed membrane antigens have been used to flow-sort viable luminal epithelial and myoepithelial cells from freshly disaggregated adult virgin rat mammary parenchyma. Resulting cultures and clones have been characterized morphologically and by a panel of antibodies that recognise cell-type-specific cytoskeletal antigens in the intact mammary gland. Five clonal phenotypes were recognisable by morphological criteria, three (types 1-3) exclusively associated with sorted luminal epithelial (25.

The vascularity of cutaneous melanoma: a quantitative histological study of lesions 0.85-1.25 mm in thickness.

The vascularity of 107 primary cutaneous melanomas has been characterized by morphometric histological analysis. The lesions selected for study were of thickness 0.85-1.

Isolation and characterization of a monoclonal rheumatoid factor specific for the hinge region of rat IgG2b.

The isolation and characterization of an isotype-specific autoantibody-secreting hybridoma NET/2/3 from rats bearing the syngeneic tumour HSN is described. This rheumatoid factor of the IgM class recognizes an epitope within the hinge region of rat immunoglobulins of the IgG2b subclass which is destroyed by reduction of disulphide bonds. The specificity of NET/2/3, although not allotype-restricted, is highly isotype-restricted, as it does not bind to rat Ig other than IgG2b, nor does it react with the majority of mouse IgG, although some reactivity occurs with mouse IgG3.

Characterization of syngeneic rat monoclonal antibodies to the HSN tumor using syngeneic monoclonal anti-idiotopic antibodies.

Twelve syngeneic anti-idiotopic mAb (anti-idiotypic/idiotopic antibodies Ab2)) were prepared from CBH/Cbi rats immunized with one of three monoclonal anti-HSN antibodies (Ab1) (11/160, ALN/11/53, or ALN/16/53) specific for the HSN tumor. The sera of the rats used for hybridoma production and all of the monoclonal Ab2 specifically inhibited the binding to HSN of the immunizing Ab1 only. It is concluded that, in this completely syngeneic system, only the private idiotopes associated with the antibody-combining site were immunogenic.

Characterization in vitro of luminal and myoepithelial cells isolated from the human mammary gland by cell sorting.

Luminal and myoepithelial cells have been separated from normal adult human breast epithelium using fluorescence activated cell sorting. Their isolation was based on the exclusive expression of two surface antigens, epithelial membrane antigen (EMA) and the common acute lymphoblastic leukaemia antigen (CALLA/CD10/neutral endopeptidase 24.11).

Isolation and characterization of a serologically defined tumour membrane antigen from a chemically-induced rat sarcoma, HSN.

Polypeptides containing the tumour antigenic determinant present on the external domain of a membrane antigen of the 3-4 benzpyrene-induced rat fibrosarcoma HSN have been isolated and purified. Following cleavage from intact cells with trypsin, the peptides were purified by immunoaffinity chromatography and SDS-PAGE. Three polypeptides of molecular weight 120, 45 and 42 kDa were obtained that bound the specific rat monoclonal antibody (MAb) 11/160 in Western blots.

Tissue distribution of DNA adducts in CDF1 mice fed 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ).

Male and female CDF1 mice were administered a single oral dose of 3 mumol of the food mutagens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) or 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and killed 24 h later. DNA was isolated from the livers, lungs, kidneys, colon and forestomach and analysed by 32P-postlabelling for the presence of IQ and MeIQ adducts. Several adduct-enrichment procedures were investigated, including ATP-deficient labelling conditions, butanol extraction and nuclease P1 digestion, and only the ATP-deficient procedure was found to produce the same adduct pattern on polyethyleneimine--cellulose TLC as the standard procedure.

Rat monoclonal antibodies to the external domain of the product of the C-erbB-2 proto-oncogene.

With the breast carcinoma cell line BT 474 used as a source of antigen, four rat monoclonal antibodies (MAbs) (3 IgG2a and I IgA) have been prepared against the external domain of the product of the c-erbB-2 proto-oncogene. All 4 antibodies stain frozen sections of tissues that over-express the product of the c-erbB-2 proto-oncogene, and competitive binding assays showed that the antibodies recognized 2 non-overlapping epitopes. Representative antibodies from the two groups (ICR12 and 13) were shown to specifically immunoprecipitate a 190 kDa protein from 35S-methionine-labelled breast carcinoma cells where the c-erbB-2 is amplified (BT 474 and MDA-MB 361).

Metabolism of 3-hydroxychrysene by rat liver microsomal preparations.

3-Hydroxychrysene, a metabolite of the polycyclic aromatic hydrocarbon (PAH) chrysene, was metabolised by rat liver microsomal preparations obtained from Arochlor 1254-pretreated rats. Eight major metabolites were isolated by high performance liquid chromatography and characterised by u.v.

Effects of 1-ethynylpyrene and related inhibitors of P450 isozymes upon benzo[a]pyrene metabolism by liver microsomes.

The effects of three aryl acetylenes, 1-ethynylpyrene (EP), 2-ethynylnaphthalene (EN) and 3-ethynylperylene (EPE), upon the metabolism of benzo[a]pyrene (BaP) by microsomes isolated from rat liver were investigated. These aryl acetylenes all inhibited the total metabolism of BaP. Formation of BaP 7,8-dihydrodiol and BaP tetrol products by microsomal preparations from rats that had been pretreated with 3-methylcholanthrene (3MC) were preferentially inhibited.