Human Malignant Diseases Research Articles

Localization of a lymphocyte-specific protein tyrosine kinase gene (lck) at a site of frequent chromosomal abnormalities in human lymphomas.

The murine lck gene is closely related to a family of cellular protooncogenes and encodes a lymphocyte-specific, membrane-associated protein tyrosine kinase. We and others have demonstrated that the lck gene is rearranged and overexpressed in the murine lymphoma LSTRA, most likely as a result of the insertion of Moloney murine leukemia virus DNA immediately adjacent to the gene. We now report that the lck gene is located at the distal end of murine chromosome 4 and on human chromosome 1 at position 1p32-35 near a site of frequent structural abnormalities in human lymphomas and neuroblastomas. These results raise the possibility that structural alteration of the lck gene through chromosomal rearrangement may contribute to transformation in human malignant disease.

Immunotoxins.

AbstractImmunotoxins are hybrid molecules formed by coupling antibody molecules to powerful toxins of plant or bacterial origin. In experimental systems, immunotoxins have been found to kill cancer cells with great potency and specificity. This article reviews the current status of immunotoxins and some of the problems that have to be overcome before they can be used to treat human malignant disease.

Oncogenes. A possible role for cancer genes in human malignant disease.

A small class of normal cellular genes has the potential to transform cells malignantly. These cellular oncogenes have been identified by their similarity to the transforming genes of oncogenic RNA viruses (retroviruses), and by their ability, under certain circumstances, to transform cells into which they have been transferred. Cellular oncogenes are not normally tumorigenic and, indeed, appear to be critically involved in normal cellular processes, possibly at the level of growth regulation. However, it appears that a number of mechanisms exist whereby these oncogenes can become malignantly activated, leading to uncontrolled cellular proliferation. The evidence implicating cellular oncogenes in human malignant disease is reviewed.

The Relation of Oncogenesis and Cytogenetics in Leukemia and Lymphoma

Recent advances in both molecular biology and cancer cytogenetics have provided valuable tools for the study of human oncogenesis. Cellular homologues of viral transforming genes (oncogenes) have been mapped to precise sites on human chromosomes, many of which are involved in specific chromosome translocations in human malignant diseases. Moreover, specific chromosome abnormalities, such as the Ph1 chromosome, have diagnostic implications. Sufficient data are now available for both acute myeloid and lymphoid leukemia so that the patient's response to therapy and survival can be correlated with the karyotype; it was also shown that the karyotype of the leukemic cells provides significant independent prognostic information. This review summarizes the specific translocations of human leukemias and lymphomas, their clinical implications, and the cellular oncogenes associated with them. Possible mechanisms of oncogenesis and future areas of investigation are also discussed.

Evidence for two distinct c-src loci on human chromosomes 1 and 20.

A number of proto-oncogenes have recently been localized to the chromosomal segments that are the breakpoints in the specific rearrangements noted in human malignant diseases. Moreover, rearranged forms of several proto-oncogenes have been identified in malignant cells; in several instances, the proto-oncogene has undergone an alteration as a result of a nonrandom chromosomal rearrangement. One proto-oncogene that has yet to be associated with human neoplastic disease is c-src, the cellular homologue of the transforming sequence of Rous sarcoma virus (RSV). By somatic cell hybridization, c-src has been mapped to chromosome 20, but its precise location was not determined. We have now mapped this gene by using in situ hybridization of the cloned human c-src probe to human mitotic chromosomes. We report here that the human genome contains two loci with strong homology to the coding regions of this oncogene, at 1p34-p36 and 20q12-q13. It is noteworthy that these chromosomal regions are frequently involved in the structural rearrangements observed in haematological malignant diseases.

Monoclonal antibody to cytokeratin for use in routine histopathology.

CAM 5.2 is a murine monoclonal antibody, raised against the colon carcinoma cell line HT29, which recognises lower molecular weight intracellular cytokeratin proteins within secretory epithelia. Extensive indirect immunohistochemical studies have confirmed that this antibody stains formalin fixed (and freshly frozen) normal and malignant human tissue in a consistent manner. Reliable staining of conventionally processed pathological tissues provides more accurate identification and staging of human malignant epithelial diseases.

Enhanced K-cell activity in the peripheral blood of patients with malignant disease.

We have analysed the influence of human malignant, inflammatory and infectious disease on the capacity of peripheral lymphocytes to mediate antibody-dependent haemolysis. The application of an enzyme-like kinetic model for measurement of maximal cytotoxic function has permitted reproducible and sensitive determinations of the K-cell function. The results show that malignant disease is associated with enhancement of ADCC capacity.

Expression of major histocompatibility antigens and leucocyte infiltration in benign and malignant human breast disease.

The reactivity of murine monoclonal antibodies (McAbs) directed against the monomorphic determinants of Class I and Class II antigens of the major histocompatibility complex (MHC), and against antigens expressed by discrete populations of leucocytes was studied using the indirect immunoperoxidase technique on serial tissue sections of 16 benign and 17 malignant primary human breast tumours. Class I antigens (detected by the McAb 2A1) were consistently associated with stromal leucocytes, fibroblasts and vascular endothelium, but expression on epithelial cells particularly of malignant provenance, was more variable. Class II antigens (detected by TDR 31.1) were present upon a variety of cell types which also included sporadic expression on malignant and benign epithelia. The distribution of leucocytes grossly monitored with 2D1 (reactive with a common leucocyte antigen) was largely interepithelial and periductal in benign lesions. Leucocytes were generally more numerous in malignant tumours, where they were largely confined to the stroma. The majority (approximately 75%) of leucocytes were T lymphocytes (reactive with UCHT1), some of which appeared to react with TDR 31.1 and were therefore activated. Ratios of helper/inducer (OKT4+) and suppressor/cytotoxic (OKT8+) subsets generally exceeded unity in malignant neoplasms. There was no correlation between the extent and distribution of T cells and the HLA status of the epithelial cells. Leucocytes detected by the monoclonal antibody OKM1 which reacts with monocytes/macrophages, granulocytes and large granular lymphocytes were numerically few and again mainly confined to the stroma. In a limited number of tests, leucocytes detected with HNKl, reactive with a differentiation antigen expressed on some cells which mediate natural and antibody-dependent cellular cytotoxicity in vitro although detectable interepithelially in benign tumours, were virtually absent from malignant tissue. HNK1 also cross-reacted with myoepithelial cells in the ducts of benign lesions.

Identification of the Constant Chromosome Regions Involved in Human Hematologic Malignant Disease

Specific consistent chromosome translocations are regularly observed in certain human leukemias and lymphomas. For the myeloid leukemias, the constant recombinants are: the long arm of 9 to chromosome 22 in chronic myeloid leukemia, the long arm of 21 to chromosome 8 in acute myeloblastic leukemia, and the long arm of 17 to chromosome 15 in acute promyelocytic leukemia. Three related translocations are seen in Burkitt lymphoma and B cell acute lymphocytic leukemia; in each one, chromosome 8 is involved with chromosome 2, 14, or 22. Analysis of a complex translocation affecting chromosomes 8 and 14 indicates that the translocation of chromosome 8 to chromosome 14 is the critical constant rearrangement. The analysis of the DNA at the translocation sites of these chromosomes, rather than the reciprocal of each translocation, appears to be the most productive focus for initial study. The various immunoglobulin loci are located in chromosomes 2, 14, and 22, the chromosomes regularly involved in translocations in Burkitt lymphoma and B cell acute lymphocytic leukemia.

Monoclonal antibodies in oncology.

Molecular biology has made tremendous strides over the last five years. The new biology allows us to prepare monoclonal antibodies to defined antigens; to detect, isolate and clone specific genes; and to insert these genes into defined sites in different cells giving new functions to old organisms. These revolutionary developments have been followed closely by researchers, businessmen, politicians and philosophers, as well as by those involved in the clinical care of patients. Although our understanding of human molecular biology is increasing rapidly, it is the development of monoclonal antibodies that has the most immediate application in the clinic. There have been several reports of their use in the diagnosis, localisation and treatment of human malignant disease. This review describes developments that are likely to have direct relevance to patient care in the near future.

Hormone Manipulation in the Therapy of Human Malignant Disease

Hormone Manipulation in the Therapy of Human Malignant Disease Get access JNCI: Journal of the National Cancer Institute, Volume 64, Issue 2, February 1980, Page 399, https://doi.org/10.1093/jnci/64.2.399 Published: 01 February 1980

Hormone manipulation in the therapy of human malignant disease

Hormone manipulation in the therapy of human malignant disease

Hl histones of various human organs and tumors

The histones of 75 human tissues were examined by polyacrylamide gel electrophoresis. A new minor Hl histone called Hl h was found in every case and is proposed to be characteristic of human tissue. The previously described minor Hl histone, Hla, was not detectable in lymph nodes or spleen. The amount of Hl h and Hla relative to the principle Hl band varied from tissue to tissue. As compared to the normal tissue, the amount of Hl h was increased and the Hla decreased in cancers. The sole exception was one hepatocellular carcinoma in which the Hla was increased in the tumor. In two cases of carcinoma of the breast the Hla was decreased to an almost undetectable level. No changes in the other histones were found. These observations may be useful in the diagnosis and prognosis of human malignant disease as well as in forensic medicine.

Some aspects of the role of viruses in cancer

The cells of tumours induced by many oncogenic DNA viruses, or cells transformed in vitro, contain virus-specific T and transplantation antigens; these have been described for SV40 virus, polyoma virus and adenoviruses. The investigation of viruses as causes of malignant disease in man has sought to establish whether tumour cells possess these virus-specific proteins; however, to date and with the limitations of present techniques, this enquiry has not demonstrated the above viruses as causal of human cancer. More recent studies with herpesvirus type 2 (HSV-2) have shown this virus to transform animal and human cells in culture, and induce cancer in experimental animals: for these reasons, many researchers have suggested that this agent may be an agent of some forms of cancer, in particular carcinoma of the cervix. The possible association of HSV-2 with human malignant disease is discussed.

Activation of latent Epstein–Barr virus by antibody to human IgM

EPSTEIN-BARR VIRUS (EBV) is the causative agent of most infectious mononucleosis1 and is also associated with two human tumours, Burkitt's lymphoma (BL)2 and nasopharyngeal carcinoma2. Lymphoid cell lines of B-cell origin have been established from patients with these diseases, and from lymphocytes transformed in vitro by EBV3. In lymphoid cell lines the lytic viral cycle is usually repressed even though the cells carry multiple copies of the EBV genome. These cells therefore provide a valuable model for the study of latent EBV infection. Although EBV is ubiquitous, its association with human malignant disease is to a large extent both ethnically and geographically restricted2 and it is therefore of interest to understand the host factors involved in the regulation of the expression of the latent EBV genome. In infectious mononucleosis, EBV infection is associated not only with a specific anti-EBV antibody2 and T-lymphocyte response4 but also with an increase in nonspecific IgM production5. EBV-infected B lymphocytes produce polyclonal Ig (ref. 6) and the majority of established EBV genome-positive lymphoid cell lines possess surface IgM (ref. 7). We report here that treatment of several human lymphoid cell lines with antisera to human IgM activates the latent EBV genome to give a marked increase in EBV-specific early antigen (EA). Also, in some cell lines this treatment induces an increase in virus capsid antigen (VCA).

Toxicity manifestations following intravenous Corynebacterium parvum administration to patients with ovarian and cervical carcinoma

Manifestations of clinical toxicity were evaluated following 341 courses of intravenous Corynebacterium parvum adjuvant immunotherapy in patients with ovarian and cervical carcinoma. Most patients exhibited symptoms of minor toxicity, which decreased in intensity as subsequent courses of therapy were administered. Temperature elevations to 38.5° C. were the most objectively measured signs of toxicity but temperature elevations greater than 38.5° C. occurred following only 20.5 per cent of the infusions. Blood pressure alterations were not a serious problem and no serious central nervous system or renal toxicity was noted. The minor side effects should not preclude the use of C. parvum as an immunopotentiating agent if it is shown to be beneficial in the treatment of human malignant disease.

Letter: Suppressor cells and human malignant disease.

Letter: Suppressor cells and human malignant disease.

Tumor antigens and tumor-host relationships.

The view that immunological reactions play a role in modifying or even controlling malignant disease has now gained wide acceptance. This has developed from well­ substantiated investigations showing that many, although by no means all, experi­ mental animal tumors induced by chemical carcinogens or oncogenic viruses, as well as those of unknown (spontaneous) etiology, elicit immune rejection responses against the tumor (I, 2). Consequently, hosts preimmunized against these tumors (e.g. by implantation of radiation-attenuated cells) will reject a subsequent challenge with the same tumor. Comparable evidence for host defenses in human malignant disease is not avail­ able, apart from limited stu4ies indicating that autografted tumor cells do not readily take (3). There are, however, a small number of impressive examples from clinical investigations suggesting, but not ·proving, that in certain circumstances immunological reactions may control malignant disease. These include reports of spontaneous remissions in melanoma, neuroblastoma, and renal cell carcinoma (4), as well as remissions occurring in Burkitt's lymphoma patients receiving minimal chemotherapy (5). Conversely, there is substantial evidence of increased incidences of malignant tumors in patients receiving continuous immunosuppressive therapy follC'wing organ transplantation (6). Finally there is an increasing number of studies showing that procedures designed to heighten patients' general immunocompetence or to specifically boost tumor-immune responses may have therapeutic potential. Broadly speaking, however, the major body of evidence supporting the concept that human tumors express neoantigens similar to those detected in experimental animal tumors has been derived from in vitro assays of cell-mediated and humoral antibody responses to tumor cells (7). In addition there are a number of reports showing that cancer patients exhibit delayed hypersensitivity responses to tumor extracts (8).

Low temperature specific heat anomalies in melanins and tumour melanosomes.

THE melanins are of great interest because of their widespread presence in biological systems. In humans, melanin is found in nearly all areas where energy transduction occurs, for example, skin, inner ear, retina, as well as in several other areas such as the midbrain. The loss of melanin in the substantia nigra (midbrain) has been correlated with Parkinson's disease, and melanin–drug interactions in the stria vascularis (inner ear) have been implicated in deafness (ototoxicity)1–3. Study of the physical properties of the melanins has yielded considerable insight into possible functional roles in biological systems3–5, and has lead to the design of possible new treatments for the human malignant disease, melanoma, based on interactions between ultrasound and melanin binding drugs6,7. These observations have indicated that the melanins play an active, rather than passive, role in biological systems and intensive study of their properties should lead to better understanding of their functions in vivo. Such studies are also lending some insight into problems associated with the solid-state physics of amorphous materials2,5.

Changes of molecular properties associated with the development of resistance against methotrexate in human lymphoblastoid cells

W 1-L 2 human lymphoblastoid cells were exposed, in culture, to progressively increasing concentrations of methotrexate. By this procedure a series of sublines was obtained with varying degrees of resistance to this drug. Membrane transport of folates and antifolates and the activities of folate dependent enzymes were studied in these sublines. Three mechanisms of drug resistance were observed. As in many previous studies, elevated cellular activities of dihydrofolate reductase were found; in some sublines the activity increased over 200-fold. A detailed study was made of the electrophoretic pattern of dihydrofolate reductase in the resistant cells, and the increase in activity was found to be of two kinds; initially electrophoretic form I increased, whereas in cells with the highest enzyme activities predominantly form II was found. The other enzymes tested, thymidine kinase, thymidylate synthetase, serine hydroxymethyltransferase, 10-formyltetrahydrofolate synthetase and 5,10-methylenetetrahydrofolate dehydrogenase, did not change greatly during the course of development of resistance. Serine hydroxymethyltransferase and thymidylate synthetase were both inhibited by methotrexate but these inhibitions were weak. The contributions made by these secondary sites of action to the cytotoxicity of the drug are discussed. A relatively high frequency of mutants was found with impaired membrane transport of methotrexate; these mutants appeared rather late in the course of development of resistance, and in all these cases enzyme and transport mutations occurred together. As in L 1210 mouse leukaemia cells, 5-methyltetrahydrofolate, 5-formyltetrahydrofolate and methotrexate shared a common pathway for uptake into the cell; in contrast to L 1210 cells, we found the predominant change in the V max , rather than the K m, of the transport system of resistant mutants. It seems that resistance involving impaired methotrexate transport during treatment of human malignant disease may be a comparatively frequent phenomenon, and may occur together with elevation of dihydrofolate reductase activity.