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Biomedical subjects

B W Hancock

Publications and source records attributed to B W Hancock.

At least 19 recordsLinked to original sources
PubMed1992

Variable expression of the interleukin-2 receptor alpha chain and MYC genes in lymphocytes from renal cell carcinoma patients treated with interleukin-2.

We have studied the expression of the interleukin-2 receptor alpha chain, c-MYC and L-MYC genes in lymphocytes obtained from four renal cell carcinoma patients undergoing an interleukin-2 clinical trial. Two of these patients exhibited stable disease after the interleukin-2 therapy and two exhibited progressive disease. Analysis of mRNA levels by dot blot hybridization indicated that changes in the expression of both the interleukin-2 receptor alpha chain and c-MYC genes were erratic and varied widely between patients. L-MYC expression was not observed in any sample. There appeared to be little correlation between the changes in gene expression and parameters such as thymidine incorporation, the proportion of CD25 positive cells present or cytotoxic activity. The situation in vivo therefore appears to be more complex than would be predicted from in vitro studies.

Antigens, CD↗
PubMed1992

Cytogenetic analysis of a United Kingdom series of non-Hodgkins lymphomas.

We describe cytogenetic analyses of cells derived from 40 non-Hodgkins lymphoma (NHL) node biopsies, 23 of which were from patients who had not been treated before biopsy. We noted that the chromosomes most frequently gained were X (32%), 12 (27%), and 3 (24%). Monosomies were much less common; loss of chromosome 13 (13.5%) was most frequent. Structural abnormalities primarily involved chromosomes 14 (70%), 1 (40.5%), 18 (38%), 6 (35%), and 17 (22%). Low-and high-grade disease showed similar patterns of structural changes; however, a markedly greater number of chromosome gains were associated with low-grade disease. Biopsy samples from patients who had previously been treated showed an increased frequency of structural abnormalities, as well as a significantly larger number of chromosome gains. The importance of these observations, particularly with regard to possible oncogene involvement in lymphoma evolution, is discussed.

Aneuploidy↗
PubMed1992

The augmentation of lymphokine-activated killer activity following pulsing of human peripheral blood mononuclear cells with recombinant human interleukin-2.

The short-term exposure of peripheral blood mononuclear cells (PBMC) to recombinant human interleukin-2 (rhIL-2) at 37 degrees C leads to the generation of lymphokine-activated killer (LAK) activity similar in magnitude to that obtained by the exposure of PBMC to rhIL-2 continuously for 3-5 days. In order to investigate whether the required signal for LAK induction occurred during the short exposure to rhIL-2 or at a later point in the induction phase, PBMC were exposed to rhIL-2 for 1 h at 4 degrees C and then exposed to a low-pH wash to remove bound IL-2 from its receptor. PBMC treated in such a way showed increased LAK activity and proliferation compared to cells exposed to rhIL-2 alone. Expression of the p55 (alpha) subunit of the IL-2 receptor was also increased. In order to cause the augmentation, a lowering of the pH below 4.0 was necessary, and exposure of PBMC to low pH alone (in the absence of rhIL-2) failed to cause activation. Another relevant feature was a transient increase in the expression of the p75 subunit of the IL-2 receptor (beta chain) immediately following the exposure to low pH and the release of interferon gamma, tumour necrosis factor alpha and IL-6; activation was blocked by the inclusion of neutralising antisera raised against rhIL-2 and interferon gamma, thus demonstrating that the endogenous release of these cytokines is important for activation.

Cytokines↗
PubMed1992

Treatment of malignant melanoma and renal cell carcinoma with recombinant human interleukin-2: analysis of cytokine levels in sera and culture supernatants.

In this study we evaluated the clinical response of 12 patients with malignant melanoma and renal cell carcinoma (RCC) following administration of recombinant human interleukin-2 (rhIL-2) by continuous infusion. Serum samples taken before, during and following sequential courses of IL-2 were assayed for the presence of tumour necrosis factor alpha (TNF-alpha) IL-1 alpha, IL-6 and interferon gamma (IFN-gamma) and the presence or changes in these cytokines were examined with respect to clinical response data: our results did not show any direct correlation between the parameters measured and clinical outcome. In addition, peripheral blood mononuclear cells (PBMC) derived from 3 RCC patients were cultured in a serum-free environment and the resulting supernatants assayed for the production of these cytokines and compared to the corresponding serum levels. During one or more courses of treatment only 1 patient, who had metastatic bone disease, demonstrated detectable serum TNF-alpha; serum IL-6 levels were elevated in a proportion of all patients studied and a sustained IL-6 response occurred in a patient who had complete disease remission; IL-1 alpha was detected in the serum of 3 RCC patients; IFN-gamma could not be detected in any serum sample tested. Cytokine levels in sera and supernatants derived from 3 RCC patients were compared but no correlation was found: TNF-alpha and IL-6 were shown to be present at much higher concentrations in supernatants when compared to sera whereas the levels of IL-1 alpha were almost undetectable. This lack of correlation is probably due to the presence of "interfering" proteins in sera which either depress or enhance the ability to detect cytokines in sera using enzyme immunoassays.

Carcinoma, Renal Cell↗
PubMed1992

Signal transduction in murine B16 melanoma cells.

The relationship between lung colonization and signal transduction was investigated for six B16 melanoma variants. A range of experimental metastatic potential (as determined by lung colonization), forskolin-stimulated cyclic AMP accumulation and FCS-stimulated protein kinase C activity was found. The major findings were that: (1) cells with the highest agonist-stimulated cyclic AMP production were those with the highest level of membrane-associated protein kinase C activity; (2) clones which differed in protein kinase C levels and distribution did so in the presence but not in the absence of foetal calf serum; and (3) no simple relationship was seen between either signal transduction system and lung colonization for all six variants. Altered ras expression was also excluded as an explanation for the differences in signal transduction and lung colonization potential which were observed. We conclude that differences in signal transduction in vitro between these cells do not relate simply to lung colonization potential in vivo.

Animals↗
PubMed1992

LOPP alternating with EVAP is superior to LOPP alone in the initial treatment of advanced Hodgkin's disease: results of a British National Lymphoma Investigation trial.

PURPOSE: The purpose of this randomized trial was to compare the efficacy of eight cycles of chlorambucil, vincristine, procarbazine, and prednisone (LOPP) with four cycles of LOPP that alternate with four cycles of etoposide, vinblastine, Adriamycin (doxorubicin; Familitalia Carlo Erba, Ltd, UK), and prednisone (EVAP) in patients with advanced Hodgkin's disease. PATIENTS AND METHODS: Between June 1983 and December 1989, 594 patients were entered onto the study. Of the 594, 295 patients were allocated to receive LOPP, and 299 were allocated to receive LOPP/EVAP. RESULTS: The complete remission (CR) rates were 57% and 64%, respectively, after initial chemotherapy (difference not significant [NS]), and 65% and 75%, respectively, after the subsequent administration of radiotherapy to residual masses (P less than .01). The procedure associated mortality in the LOPP and LOPP/EVAP arms was 1% and 3%, respectively. The actuarial CR relapse-free survival was significantly greater in the LOPP/EVAP arm (P less than .001) as was the overall survival (P less than .05). The CR relapse-free rate, disease-free survival (DFS) rate, and overall survival rate at 5 years were 52%, 32%, and 66%, respectively, in the LOPP arm, compared with 72%, 47%, and 75% in the LOPP/EVAP arm, respectively. CONCLUSION: These results indicate that LOPP and EVAP is superior to LOPP alone as initial treatment for advanced Hodgkin's disease.

Actuarial Analysis↗
PubMed1991

Malignant melanoma and renal cell carcinoma: immunological and haematological effects of recombinant human interleukin-2.

The immunological and haematological effects of continuous infusion of recombinant human interleukin-2 (rhIL-2) in 6 patients with metastatic melanoma and 6 with disseminated renal cell carcinoma are reported. In patients with malignant melanoma dacarbazine was given before IL-2; in renal cell carcinoma IL-2 alone was given. In malignant melanoma, 1 complete (CR) and 1 partial response (PR) were seen; 2 patients had stable disease (SD) and 2 progressive disease (PD). In renal cell carcinoma 4 patients had SD and 2 PD. Toxicity of IL-2 therapy was minimal. All patients showed increased cytotoxicity, that was not major histocompatibility complex restricted, towards target cells sensitive and insensitive to natural killer cells. These activities varied between individual patients and were less marked in cases of renal cell carcinoma. Cellular proliferative responses increased in all patients, being consistently higher following the first course of therapy, as did HLA-DR, CD16 and CD25 activation marker expression. Hypersegmentation of neutrophils and eosinophilia were commonly observed, and in renal cell carcinoma these changes were accompanied by abnormal lymphocyte morphology.

Aged↗
PubMed1991

Importance of oncogene research to the cancer clinician.

For many years a genetic basis has been postulated for cancers and leukaemias. However, this concept has now been strengthened by the discovery of a group of genes (oncogenes) which are specifically associated with neoplasia. These genes have been identified by studies of animal oncogenic viruses, by in vitro transformation studies of mouse fibroblasts, and by molecular analyses of human tumour cells. The oncogenes are altered forms of normal genes (proto-oncogenes) whose protein products are thought to be involved in the regulation of cell proliferation. It appears that the alteration of proto-oncogenes to form oncogenes results in the inappropriate production of normal proteins or in the production of abnormal proteins. It is suggested, therefore, that the presence of such proteins would allow cells to escape from normal cell growth regulation, and as a result produce uncontrolled proliferation. Oncogene research has to date been primarily concerned with identifying oncogenes and assessing their importance in the development of a number of malignancies. Such research is therefore allowing us to build up a framework of genetic changes which define the development of each type of tumour or leukaemia. Furthermore, information concerning the oncogenes is now beginning to be applied diagnostically to help in determining predisposition of an individual to disease, in aiding the accurate staging of disease, in indicating prognosis and in developing markers to detect residual disease after therapy. It is also possible that in the future we may be able to develop new anticancer therapies, for example, based on oncogene protein inhibitors, or anti-oncogene protein antibodies or even gene therapy.

Humans↗
PubMed1991

British National Lymphoma Investigation randomised study of MOPP (mustine, Oncovin, procarbazine, prednisolone) against LOPP (Leukeran substituted for mustine) in advanced Hodgkin's disease--long term results.

From 1979-1983, 299 patients with stage III or IV Hodgkin's disease (HD) were randomised to receive cyclical chemotherapy with MOPP (mustine, Oncovin, procarbazine, prednisone) or LOPP (Leukeran substituted for mustine). Two hundred and ninety patients were evaluable. There was no statistically significant difference between the complete remission (CR) rates (63% for MOPP, 57% for LOPP), percentage of patients remaining disease free at 5 years (38% for MOPP, 35% for LOPP) and overall survival at 5 years (65% for MOPP, 64% for LOPP). On multivariate analysis younger age, grade I histopathology, absence of systemic symptoms, and normal albumin level were favourable prognostic factors for survival. Acute toxicity in the form of nausea/vomiting, myelosuppression, and phlebitis were less with LOPP than MOPP. Deaths in both groups were usually due to disseminated Hodgkin's disease; there were no infective deaths in the absence of Hodgkin's disease. Second malignancies occurred in six patients treated with MOPP--three acute myeloid leukaemia (AML), one non-Hodgkin's lymphoma (NHL), two carcinomas (Ca); with LOPP, four second malignancies occurred (one AML, one NHL, two Ca). These long term results confirm that LOPP is as effective as MOPP, and less toxic, in the treatment of advanced Hodgkin's disease.

Adolescent↗
PubMed1990

Interleukin-2 and cancer therapy.

In summary, this meeting provided a useful overview of state-of-the-art research on IL-2. Significant gains have been made toward understanding the molecular biology and function of IL-2 and its receptors, but much remains to be learned about the intracellular signaling pathway by which IL-2 transduces its biological effects. Likewise, the nature of the lymphocyte subpopulation that responds to IL-2 requires detailed study, since it is now clear that T cells as well as LGLs can mediate non-MHC-restricted killing of tumor cells. Cell trafficking and effector cell activity within the tumor are other important issues to address. We also need to define the mechanism(s) by which IL-2-activated lymphoid cells mediate their antitumor effect in vivo; it is still far from clear whether these cells directly lyse the tumor cells, interrupt the tumor's vascular supply through endothelial cell damage, or produce other cytokines which then activate other cellular pathways. Preclinical data indicate that IL-2, with or without adoptive cellular therapy or in combination with other cytokines or drugs, can cause tumor regression. The success with animal model systems, however, has not always translated to success in the clinical setting-disappointingly, the majority of cancer patients still fail to respond to this treatment. It is hopeful the reasons for this will become apparent as more is learned about the molecular and cellular mechanisms involved in this "new" form of immunotherapy.

Clinical Trials as Topic↗
PubMed1988

Transfer factor in Hodgkin's disease: a randomized clinical and immunological study.

Transfer factor (TF) was prepared from buffy coats obtained from 493 units of blood taken from healthy donors, including individuals convalescent from various viral infections. It was administered to 22 of 47 patients with Hodgkin's disease undergoing treatment and consenting to take part in this randomized study to determine if TF would enhance their immunity and/or reduce the incidence of subsequent infections. Skin test reactivity was markedly enhanced in those patients receiving TF as opposed to placebo but other immunological assessments showed no significant differences between the groups. TF was not shown to be of benefit in the prevention of infections (including varicella/zoster).

B-Lymphocytes↗