British Journal of Cancer

Muñoz, N; Bosch, X; Kaldor, JM

doi: 10.1038/bjc.1988.1pmid: 2831924

The human papillomavirus has emerged over the past decade as the leading candidate to be the sexually transmitted aetiological factor in cervical cancer. Although it appears that papillomavirus types 16 and 18 are associated with a higher risk of advanced cervical neoplasia, most of the evidence comes from studies which do not satisfy basic epidemiological requirements, and are therefore difficult to interpret. The most significant problems are the small sample size, potentially biased selection of study subjects, the difficulties in cytologically distinguishing precancerous lesions from papilloma infection of the cervix, the unknown specificity and sensitivity of the various hybridisation methods for determining papillomavirus infection status, and the statistical analyses and presentation of results. On the basis of the existing studies, one is forced to conclude that, while experimental data suggest an oncogenic potential for HPV, the epidemiological evidence implicating it as a cause of cervical neoplasia is still rather limited.

Breimer, LH

doi: 10.1038/bjc.1988.2pmid: 3279995

Murphy, P; Alexander, P; Senior, PV; Fleming, J; Kirkham, N; Taylor, I

doi: 10.1038/bjc.1988.3pmid: 3348947

The sites of tumour development for 6 rat tumours injected into syngeneic rats via different vascular routes was determined. Xenografts of human tumours were also injected intra-arterially (i.a.) into immunosuppressed rats. Following intravenous (i.v.) and intraportal (i.ptl.) injection of cells tumour colonies localized in lung and liver respectively due to tumour cell arrest. Arterially injected radiolabelled cells disseminated and arrested in a similar distribution to cardiac output and did not 'home' to any organs. Following arterial injection of unlabelled tumour cells colonies grew in many organs. While the pattern of growth for a particular tumour varied with the cell dose, the 'arterial patterns' for all of the tumours studied followed a similar pattern. Some organs (eg adrenals, ovaries and periodontal ligament) were consistently preferred, others (eg skin and skeletal muscle) only supported tumour growth following the delivery of large numbers of cells, while in some tissues (eg spleen and intestines) tumour never grew. Viable tumour cells could be demonstrated by bioassay in many organs for up to 24h after i.a. injection. However tumour growth only occurred in certain organs and the pattern of this growth was not related to the number of tumour cells arrested or their rate of autolysis. This site preference could be expressed quantitatively as the probability of an arrested cell developing into a tumour and was considered a 'soil effect'. Site preference was not directly related to organ vascularity. Organ colonisation was promoted by steroid treatment but the mechanism was unclear and was not secondary to T-cell immunosuppression or prostaglandin synthesis suppression. The adrenal glands were preferred sites of tumour growth but pharmacological manipulation of adrenal function did not alter tumour growth to this organ. Sites of injury and healing were preferred sites of tumour colonisation and this could not be accounted for by increased delivery of tumour cells to these regions. The possibility that the macrophage component of the inflammatory response promoted tumour growth was suggested from studies in which the interval between trauma and inoculation of tumour cells was varied as well as by promotion of intraperitoneal (i.p.) tumour growth by a macrophage infiltrate.

Glaves, D; Huben, RP; Weiss, L

doi: 10.1038/bjc.1988.4pmid: 3279993

Estimates were made of the rates at which cancer cells were released directly into the renal vein in patients undergoing radical nephrectomy for primary renal cancer. Cancer cells were counted in blood samples taken from the renal vein using a density gradient centrifugation procedure, and identified using immunocytochemical techniques, on the basis of their cytoskeletal intermediate filament proteins. Cancer cells were released as single cells and multicell emboli in 8/10 patients, in numbers varying widely between 14-7509 emboli ml-1 of blood. Despite a calculated median input into the metastatic process of 3.7 x 10(7) cancer cells per day for at least 180 days, only 3/10 patients had extraperitoneal metastases prior to surgery and only 1 of the remaining disease-free patients subsequently developed distant metastases over a maximum 35 month period. These results are discussed in terms of primary tumour kinetics and metastatic inefficiency.

Elvin, P; Kerr, IB; McArdle, CS; Birnie, GD

doi: 10.1038/bjc.1988.5pmid: 2450556

We have constructed cDNA libraries from the poly(A)+ RNA of normal colonic mucosa and a liver metastasis from a colonic adenocarcinoma. Differential screening of these libraries using 32P-labelled cDNAs transcribed from poly(A)+ RNAs isolated from specimens of four normal colonic mucosae, five adenocarcinomas, and three liver metastases by Grunstein-Hogness and dot-blot hybridization has identified a number of recombinant cDNA clones homologous to mRNAs that appear to differ significantly in abundance between normal and neoplastic colon and metastases. These cDNA clones, and others identified in the libraries, may be of considerable importance both as diagnostic tools and in defining the phenotypic changes associated with tumour progression and metastasis.

Terrier, P; Sheng, Z-M; Schlumberger, M; Tubiana, M; Caillou, B; Travagli, J-P; Fragu, P; Parmentier, C; Riou, G

doi: 10.1038/bjc.1988.6pmid: 3348948

Tumour specimens from 23 patients with thyroid carcinoma, 22 patients with thyroid adenoma, 3 with Graves' disease, and tissues from 8 normal thyroid glands were analyzed by Southern blot hybridization for the physical state of c-myc and c-fos proto-oncogenes. In 4 patients, both the primary tumour and lymph node metastases were analyzed. No amplification or rearrangement of the two proto-oncogenes was detected. Total RNAs were also analyzed. Elevated levels of the 2.4 kb c-myc RNA and of the 2.2 kb c-fos RNA were found in 13/23 (57%) and 14/23 (61%) of the cancer patients, respectively. High levels of c-myc transcripts were more frequently found in thyroid carcinomas with unfavourable prognosis. Concomitant elevated levels of both c-myc and c-fos RNAs were found in 8 cancers. High levels of c-myc RNA were also found in 1 out of 22 specimens of adenoma, in 1 specimen of Graves' disease and in 2 normal thyroid glands. High levels of c-fos RNA were found in 20 of the 22 adenoma samples and in 2 out of 8 normal thyroid tissues. These data indicate that the overexpression of c-myc and c-fos genes is independent of an alteration of the loci. The high levels of c-fos found in adenoma may be associated with the differentiation state of these tumours.

Embleton, MJ; Butler, PC

doi: 10.1038/bjc.1988.7pmid: 3279994

Monoclonal antibodies to proteins encoded by the ras, myb, myc, erb-B, src and PDGF-2 genes were tested for reactivity with normal rat liver, livers from rats fed with 0.06% 2-acetylaminofluorene (AAF), and premalignant lesions and primary liver tumours from rats given AAF alone or a combined treatment with diethylnitrosamine and AAF. Radioimmunoassays were performed with plasma membrane fractions and total soluble subcellular extracts of the tissues, and immunoperoxidase staining was carried out on frozen tissue sections. All of the antibodies were positive in radioimmunoassays, some more strongly than others, and each antibody bound equally to extracts of different kinds of tissue. Immunohistology revealed significant staining of normal liver by 5 of the 6 antibodies, and only minor qualitative differences of the staining pattern in some tumours and hyperplastic nodules. It was concluded that these antibodies were not able to discriminate sufficiently well between normal, premalignant and malignant rat liver to be of value in identifying the precursor cells of malignant tumours.

Lunn, JM; Harris, AL

doi: 10.1038/bjc.1988.8pmid: 2831926

Mechanisms of resistance to the active metabolite 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC) of the drug 5-(3,3-dimethyl-1-triázeno)imidazole-4-carboxamide (DTIC) were studied in three human cell lines with differing amounts of the repair enzyme O6-alkylguanine-DNA alkyltransferase (O6AT). The lines were HT29 (Mer+Rem+), A549 (Mer+Rem-) and VA13 (Mer-). The ability to repair O6 methyl-guanine was directly related to resistance to MTIC (HT29 ID50 650 mumol l-1, A549 ID50 210 mumol l-1, VA13 ID50 15 mumol l-1. MTIC produced DNA single strand breaks over the range of one log of cell kill, but depletion of cellular NAD levels could not be detected until there was greater than 95% cell kill. Inhibitors of the repair enzyme adenosine diphosphoribosyl transferase (ADPRT) potentiated killing by 2-fold in the Mer+ cell lines but not the Mer- line. The enhancement was directly proportional to an increase in DNA strand breaks but not a change in their half-life. Therefore resistance to the clinically used methylating agent MTIC can be partly overcome by inhibiting ADPRT but a role for ADPRT as a suicide mechanism in response to alkylating agent damage is unlikely.

Komatsu, K; Miller, RC; Hall, EJ

doi: 10.1038/bjc.1988.9pmid: 3126790

The modulating effect of 43 degrees C hyperthermia on the induction of oncogenic transformation by the antineoplastic agents, actinomycin D, mitomycin C, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) was examined using the C3H 10T1/2 cell line. For any given level of cytotoxicity, cells exposed to the three chemotherapy agents at 37 degrees C showed similar frequencies of transformation. Transformation frequencies induced by all three drugs were reduced by hyperthermia. The reduction was most pronounced for cells exposed to BCNU, and to a lesser extent, by cells exposed to actinomycin D and mitomycin C. The modulating effects of heat on drug-induced transformation incidence appeared to be independent of whether application of heat and drug was concurrent or sequential.

Yohem, KH; Slymen, DJ; Bregman, MD; Meyskens, FL

doi: 10.1038/bjc.1988.10pmid: 3348949

The radiation response of murine and human melanoma cells assayed in bilayer soft agar and monolayer was examined. Cells from the murine melanoma Cloudman S91 CCL 53.1 cell line and three human melanoma cell strains (C8146C, C8161, and R83-4) developed in our laboratory were irradiated by single dose X-rays and plated either in agar or on plastic. D0 values were the same within 95% confidence intervals for cells from the human melanoma cell strains C8146C, C8161, and R83-4 but were dissimilar for the murine cell line CCL 53.1 Dq values were different for all cells studied. The shape of the survival curve for all four melanomas was not identical for cells assayed in soft agar versus cells grown on plastic. This would indicate that apparent radiosensitivity was influenced by the method of assay although there were no apparent consistent differences between the curves generated by monolayer or bilayer soft agar assays.