ABSTRACT
The cytotoxic activity of human recombinant tumor necrosis factor (rHuTNF) (from 0.01 to 10000 U/ml) was assayed on six human ovarian cancer cell lines and one human cervical carcinoma cell line using a crystal violet assay. rHuTNF was cytotoxic to four cell lines (A2780, A2774, SW626, PA1), while 3 cell lines (IGROV1, SKOV3, Me180) were marginally sensitive to its activity. However, under the same experimental conditions rHuTNF markedly enhanced the cytotoxicity of mitoxantrone, a chemotherapeutic drug targeted at DNA topoisomerase II, in six cell lines. The potentiation of mitoxantrone cytotoxicity was not caused by increased drug accumulation after rHuTNF treatment. No significant increase in cytotoxicity to Me180 cell line was seen when rHuTNF was added to mitoxantrone.
Subject(s)
Mitoxantrone/pharmacology , Ovarian Neoplasms/drug therapy , Tumor Necrosis Factor-alpha/pharmacology , Drug Screening Assays, Antitumor , Drug Synergism , Female , Humans , Recombinant Proteins/pharmacology , Tumor Cells, Cultured/drug effects , Uterine Cervical Neoplasms/drug therapyABSTRACT
Recombinant human tumor necrosis factor (rHuTNF) is a cytokine, with some antitumor activity, released by stimulated monocytes-macrophages. In vivo and in vitro cytotoxicity studies testing the effectiveness of rHuTNF alone or in combination with chemotherapeutic agents have been carried out. We have evaluated the direct cytotoxic effect of rHuTNF on a human epithelial ovarian cancer cell line in vitro (A2774), alone or in combination with Etoposide (VP16) or Doxorubicin (Doxo), some topoisomerase II (Topo II) targeted drugs, or in combination with Cisplatin (CDDP), a not Topo II interactive drug. Our results suggest that rHuTNF is directly cytotoxic and that it is also able to induce a potentiation of VP16- or Doxo-cytotoxicity, but it is unable to potentiate CDDP-cytotoxicity. These data represent a reasonable basis for combining rHuTNF with Topo II inhibitors within phase I studies. The combination regimen could be tested in ovarian cancer patients.
ABSTRACT
Human granulocyte-macrophage colony-stimulating factor (GM-CSF) is a regulatory glycoprotein that stimulates the production of granulocytes and macrophages from committed hematopoietic progenitor cells both in vitro and in vivo. In this report, we show that recombinant human GM-CSF enhances colony formation by nonhematopoietic human ovarian cancer cell lines, IGROV-1, A2774, ME-180, Pa-1 and A2780. GM-CSF also enhanced the colony formation by cells obtained from fresh ascites of a patient with ovarian mucinous cystadenocarcinoma and a patient with serous papillary ovarian carcinoma. Our observations were made with GM-CSF concentrations between 0.1 to 1 ng/ml; these concentrations are equivalent to the dosages generally used for bone marrow recovery after chemotherapy.
Subject(s)
Cell Division/drug effects , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Ascites , Cell Line , Female , Humans , Kinetics , Ovarian Neoplasms , Recombinant Proteins/pharmacologyABSTRACT
Recombinant human tumor necrosis factor (rHuTNF) is a macrophage-secretory protein with antitumor activity. In vivo and in vitro cytotoxicity studies have been carried out to test the effectiveness of rHuTNF alone or in combination with chemotherapeutic agents. We have evaluated the direct cytotoxic effect of rHuTNF on a human epithelial ovarian cancer cell line in vitro (A2774), alone, or in combination with mitoxantrone (Mit), a topoisomerase II (Topo II) targeted drug. Our results not only suggest that rHuTNF is directly cytotoxic, but also that it is able to induce a very strong potentiation of Mit cytotoxicity.
Subject(s)
Mitoxantrone/pharmacology , Ovarian Neoplasms/drug therapy , Tumor Necrosis Factor-alpha/pharmacology , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Drug Synergism , Female , Humans , Recombinant Proteins/pharmacology , Tumor Cells, Cultured/drug effectsABSTRACT
This report describes the use of skin substitutes in the treatment of deep partial skin thickness burns in childhood. These are lesions that, if treated inadequately, can result in severe scarring. However, if treated appropriately, they can heal without any sequelae, which is obviously crucial for aesthetic and psychological reasons. This review contains children admitted to the authors' Burn Unit over a 5-year period (1984-88) with deep partial skin thickness lesions which were treated with synthetic and/or biosynthetic skin substitutes and without surgical procedures. This group of children has been compared with another group hospitalized for burns of the same depth and treated with conventional closed wound management. First, short-term results are presented, highlighting healing time, followed by the long-term results from an aesthetic and functional viewpoint.
Subject(s)
Biocompatible Materials/therapeutic use , Burns/therapy , Coated Materials, Biocompatible , Occlusive Dressings , Burns/etiology , Burns/pathology , Child, Preschool , Cicatrix/prevention & control , Follow-Up Studies , Humans , Infant , Skin Transplantation , Wound HealingABSTRACT
Ovarian cancer is the second most common gynecologic malignancy. Standard therapeutic approaches to this disease, surgery followed by chemotherapy, have produced response rates of up to 80%. However, the five-year survival rate remains around 30%. Recently, Tumor Necrosis Factor (TNF) has received attention as either an alternative or an associated agent for chemotherapy of ovarian cancer. TNF is known to have direct cytotoxic and cytostatic effects on a variety of transformed cell lines "in vitro". Furthermore, TNF is known to enhance significantly the "in vitro" effects of a class of chemotherapeutic agents, specifically those targeted at DNA topoisomerase II. In this work we have investigated TNF-induced cytotoxicity in four established human epithelial ovarian cancer cell lines: A-2774; SV-626; SKOV-3 and Pa-1. TNF mediated cytotoxic activity was observed in a range of concentrations between 1 U/ml and 10-3 U/ml. A-2774 and SV-626 were the two most sensitive lines, especially when exposed to high concentrations of TNF.
Subject(s)
Ovarian Neoplasms/pathology , Tumor Necrosis Factor-alpha/pharmacology , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Humans , Recombinant Proteins/pharmacology , Tumor Cells, Cultured/drug effectsABSTRACT
8-methoxycaffeine (8-MOC) is a caffeine derivative more potent than its parental compound in inducing chromosomal aberrations. 8-MOC has been postulated to produce chromosomal aberrations by DNA topoisomerase II inhibition. The effect of 8-MOC on nuclear DNA were studied by alkaline elution experiments and compared with those of Ellipticine and Adriamycin (ADR). Like Ellipticine and ADR, 8-MOC induced single strand breaks (SSBs), double strand breaks (DSBs), and DNA-protein cross-links (DPCs) in a bell-shaped manner with respect to drug concentration. As in the case of ADR and Ellipticine, 8-MOC induced equal SSB and DPC frequencies. These results could suggest that 8-MOC induces DNA breaks by interacting with DNA topoisomerase II or with a similar DNA metabolism enzyme.
