Platelet activating factor receptor antagonists improve the efficacy of experimental chemo- and radiotherapy

Platelet activating factor is a lipid mediator of inflammation, and in recent decades, it has emerged as an important factor in tumor outcomes. Platelet activating factor acts by specific binding to its receptor, which is present in both tumor cells and cells that infiltrate tumors. Pro-tumorigenic effects of platelet activating factor receptor in tumors includes promotion of tumor cell proliferation, production of survival signals, migration of vascular cells and formation of new vessels and stimulation of dendritic cells and macrophages suppressor phenotype. In experimental models, blocking of platelet activating factor receptor reduced tumor growth and increased animal survival. During chemotherapy and radiotherapy, tumor cells that survive treatment undergo accelerated proliferation, a phenomenon known as tumor cell repopulation. Work from our group and others showed that these treatments induce overproduction of platelet activating factor-like molecules and increase expression of its receptor in tumor cells. In this scenario, antagonists of platelet activating factor markedly reduced tumor repopulation. Here, we note that combining chemo- and radiotherapy with platelet activating factor antagonists could be a promising strategy for cancer treatment.

Increased Anti-tumor Effect by a Combination of HSV Thymidine Kinase Suicide Gene Therapy and Interferon-gamma/GM-CSF Cytokine Gene Therapy in CT26 Tumor Model

The potential therapeutic benefit of introducing IFN-gamma and GM-CSF genes in combination with the HSVtk suicide gene into subcutaneously implanted CT26 tumor cells was compared with that from each treatment alone. Cells, unmodified or retrovirally transduced with HSVtk or IFN-gamma/GM-CSF genes, were inoculated subcutaneously into syngeneic BALB/c mice in various combinations. HSVtk gene, with intraperitoneal ganciclovir treatment, reduced tumor volume by 81% at locally inoculated tumor sites (p<0.01) and by 25% at distantly inoculated tumor sites (p=0.052). IFN-gamma/GM-CSF genes showed a 56% tumor volume reduction at local tumor sites (p<0.01) and 15% volume reduction at remote tumor sites, although this was not statistically significant. The combination of HSVtk (with GCV) and IFN-gamma/GM-CSF genes showed an 81% volume reduction at local tumor sites (p<0.01) and a 43% volume reduction at remote tumor sites (p<0.01). Thus, the combination of HSVtk and IFN-gamma/GM-CSF gene therapy produced greater therapeutic efficacy than either treatment alone.

Restoration of Adriamycin and Vincristine Dependent Tumoricidal Activity by Interferon in Mice with Implanted Tumor Cells

The survival of implanted tumor cells in mice which had been treated with interferon in combination with either adriamycin or vincristine was evaluated. While the majority of tumor cells implanted into normal mice failed to survive (52.1 to 63.5%), most of those implanted into mice which had been pretreated with either adriamycin or vincristine survived. If the mice were secondarily treated with interferon, the ability of adriamycin or vincristine to inhibit the survival of implanted tumor cells was restored within 24 hours. Restoration of tumoricidal activity by interferon treatment was more evident in the adriamycin pretreated mice. Peritoneal macrophages isolated from mice pretreated with both interferon and adriamycin had an increased tumoricidal activity, when compared with those isolated from mice treated with adriamycin alone. This interferon dependent enhancement of tumoricidal activity was comparable with that obtained by treating mice with lymphokines a product of Con A treated lymphocytes isolated from BCG treated mice. These results suggested that both adriamycin and vincristine may damage the macrophages required for the natural host defense mechanism and allow the implanted tumor cells to survive. Interferon may, however, protect the macrophages from drug induced damage.

Imunoterapia ativa específica e imunoquimioterapia adotiva em tumores experimentais: açäo da interleukin - 2

Uma preparaçäo de proteínas de membrana plasmática de células tumorais obtidas por processo original de vesículaçäo de membrana celular é usada como antígeno específico do tumor. Em sistema singênico protegeu 80% dos camundongos contra inóculo tumoral. Inóculo tumoral jé estabelecido, em início de crescimento, é curado em 70 a 80% com inoculaçäo de antígeno de membrana com afjuvante, em tumores experimentais de camundongo. A imunoterapia adotiva específica, isto é, a transferência de linfócitos pré-sensibilizados, näo protegeu camundongos contra tumor já desenvolvido. A imunoquimioterapia adotiva, transferência de linfócitos de baço de animal imunizados pelo tumor + 1 dose de ciclofosfamida foi eficiente, curando 80% dos animais com tumor singênico já estabelecido, sendo que a ciclofosfamida apenas retarda temporariamente o crescimento tumoral. Este projeto näo tem aplicaçäo clínica, pois para o doente näo se dispöe de linfócitos isogênicos sensibilizados especialmente contra seu câncer. Está sendo tentada a substituiçäo de linfócitos T sensibilizados por "Interleukin-2" + ciclofosfamida. A "Interkeukin-2" é obtida in vitro por açäo de macrófago + linfócito T helper + concanavalina A. Experiência preliminares em tumores experimentais deram nítido retardamento do crecimento dos mesmos. Este produto está sendo purificado e concentrado e produzido especificamente com antígeno do próprio tumor