asta-z-7557 and perfosfamide

Topics: Adolescent; Adult; Animals; Bleomycin; Bone Marrow; Bone Marrow Transplantation; Cell Separation; Child; Child, Preschool; Clinical Trials as Topic; Cyclophosphamide; Drug Evaluation; Etoposide; Graft vs Host Disease; Hematopoietic Stem Cells; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Lysophosphatidylcholines; Methylprednisolone; Neoplasms, Experimental; Phospholipid Ethers; Pyrimidinones; Transplantation, Autologous; Transplantation, Isogeneic

Topics: Adolescent; Adult; Animals; Bleomycin; Bone Marrow; Bone Marrow Transplantation; Cell Separation; Child; Child, Preschool; Clinical Trials as Topic; Cyclophosphamide; Drug Evaluation; Etoposide; Graft vs Host Disease; Hematopoietic Stem Cells; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Lysophosphatidylcholines; Methylprednisolone; Neoplasms, Experimental; Phospholipid Ethers; Pyrimidinones; Transplantation, Autologous; Transplantation, Isogeneic

Adriamycin (ADR), 4-hydroperoxycyclophosphamide (4-OOHCYP) and the new cyclophosphamide derivative AZ 7557 (AZ) were tested for their effects on the release of the Interleukins IL-2 and IL-1 from rat spleen cells and peritoneal exudate macrophages respectively. ADR was found to enhance IL-2 release and less effectively IL-1 release. 4-OOHCYP and AZ were found to inhibit IL-2 release but had no effect on IL-1 production. It is suggested that the modulation of IL-2 levels by these drugs is unlikely to be mediated by their effects on IL-1.

Topics: Animals; Antineoplastic Agents; Ascitic Fluid; Cyclophosphamide; Doxorubicin; In Vitro Techniques; Interleukin-1; Interleukin-2; Male; Rats; Rats, Inbred Lew; Spleen

Ex vivo bone marrow treatment prior to autologous bone marrow transplantation for acute leukemia or solid tumors (known for their frequent medullary metastatic dissemination) has provoked a great deal of hope and enthusiasm. If, as in most cases, the feasibility of various methods (exposure to chemical products, monoclonal antibodies and complement-dependent cytolysis, immuno-magnetic procedures) has been confirmed, no study to date has shown the efficacy. Only randomized studies will result in such a proof, on the condition that all the specific technical parameters of each method have been perfectly defined. The clinical results of pilot evaluation studies for the prevention of graft-versus-host reaction through the elimination of T lymphocytes in the donor graft have been encouraging. They have shown the feasibility and efficacy of different methods of T cell depletion. One point however remains controversial: is it necessary or not to eliminate all T lymphocytes? After a depletion which is too efficient, the difficulties involved in grafting the donor's hematopoietic cells on the recipient represent a new problem, e.g., in allogenic grafts for acute leukemia (host-versus-graft). In order to resolve the problem of these take failures (10 to 20% of the published series except for Royal Free Hospital and Besançon) it appears necessary to redefine the conditioning regimen prior to allogenic bone marrow transplantation.

Topics: Antibodies, Monoclonal; Antigens, Neoplasm; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cell Separation; Centrifugation, Density Gradient; Cyclophosphamide; Graft vs Host Disease; Humans; Lectins; Leukemia; Lymphocyte Depletion; Methylprednisolone; Neoplasms; Neprilysin; Pilot Projects; Plant Lectins; Ricin; Soybean Proteins; T-Lymphocytes; Transplantation, Autologous; Transplantation, Homologous

The ex vivo sensitivity of murine pluripotent hematopoietic stem cells (CFU-S) and myeloid progenitor cells (CFU-GM) to 4-hydroperoxycyclophosphamide, ASTA Z 7557, phosphoramide mustard, acrolein, melphalan, and cis-platinum was determined in the absence and presence of known (disulfiram, diethyldithiocarbamate, cyanamide) or suspected [ethylphenyl(2-formylethyl)phosphinate] inhibitors of aldehyde dehydrogenase activity. As compared to CFU-GM, CFU-S were less sensitive to the oxazaphosphorine agents, 4-hydroperoxycyclophosphamide and ASTA Z 7557. The two cell populations were approximately equisensitive to acrolein as well as to the non-oxazaphosphorine cross-linking agents, phosphoramide mustard, melphalan and cis-platinum. All four inhibitors of aldehyde dehydrogenase activity potentiated the cytotoxic action of the oxazaphosphorines toward CFU-S; they did not potentiate the cytotoxic action of acrolein or the non-oxazaphosphorines toward these cells. The inhibitors did not potentiate the cytotoxic action of the oxazaphosphorines, non-oxazaphosphorines, or acrolein toward CFU-GM. Pyridoxal, a substrate for aldehyde oxidase, did not potentiate the cytotoxic action of oxazaphosphorines toward CFU-S. Cellular NAD-linked aldehyde dehydrogenases are known to catalyze the oxidation of the major transport form of cyclophosphamide, 4-hydroxycyclophosphamide/aldophosphamide, to an inactive metabolite, carboxyphosphamide. Our observations suggest that (1) aldehyde dehydrogenase activity is an important determinant of the sensitivity of a cell population to the oxazaphosphorines, (2) CFU-GM lack the relevant aldehyde dehydrogenase activity, and (3) the phenotypic basis for the relative insensitivity of CFU-S to oxazaphosphorines is the aldehyde dehydrogenase activity contained by these cells.

Topics: Acrolein; Aldehyde Dehydrogenase; Animals; Bone Marrow Cells; Cisplatin; Colony-Forming Units Assay; Cyanamide; Cyclophosphamide; Disulfiram; Ditiocarb; Drug Synergism; Granulocytes; Hematopoietic Stem Cells; Male; Melphalan; Mice; Mice, Inbred BALB C; Nitrogen Mustard Compounds; Organophosphorus Compounds; Phosphinic Acids; Phosphoramide Mustards

Topics: Animals; Bone Marrow; Bone Marrow Transplantation; Burkitt Lymphoma; Cell Line; Cell Separation; Cyclophosphamide; Hematopoietic Stem Cells; Humans; Leukemia; Leukemia, Experimental; Mice; Rats

The sensitivity of cultured L1210 and P388 cells sensitive (L1210/0, P388/0) and resistant (L1210/OAP, P388/CLA) to oxazaphosphorines, to 4-hydroperoxycyclophosphamide, ASTA Z-7557, phosphoramide mustard, and acrolein was determined in the absence and presence of known (disulfiram, diethyldithiocarbamate, cyanamide) or suspected [ethylphenyl(2-formylethyl)phosphinate] inhibitors of aldehyde dehydrogenase activity. The L1210/OAP cell line is resistant specifically to the oxazaphosphorines; P388/CLA cells are partially cross-resistant to other cross-linking agents. All four inhibitors of aldehyde dehydrogenase activity potentiated the cytotoxic action of the oxazaphosphorines, 4-hydroperoxycyclophosphamide and ASTA Z-7557, against L1210/OAP and P388/CLA cells; in the presence of a sufficient amount of inhibitor, sensitivity was essentially fully restored in both cases. The inhibitors did not potentiate the cytotoxic action of the nonoxazaphosphorines, phosphoramide mustard and acrolein, against these cell lines. The cytotoxic action of the oxazaphosphorines and nonoxazaphosphorines against L1210/0 and P388/0 cells was not potentiated by any of the aldehyde dehydrogenase inhibitors. Inhibitors of xanthine oxidase or aldehyde oxidase activities did not potentiate the cytotoxic action of the oxazaphosphorines against L1210/OAP cells. These observations strongly suggest that (a) aldehyde dehydrogenase activity is an important determinant with regard to the sensitivity of a cell population to the oxazaphosphorines; (b) L1210/0 and P388/0 cells lack the relevant aldehyde dehydrogenase activity; (c) the phenotypic basis for the resistance to oxazaphosphorines by L1210/OAP cells is aldehyde dehydrogenase activity; and (d) the major reason that P388/CLA cells are resistant to oxazaphosphorines is aldehyde dehydrogenase activity.

Topics: Aldehyde Dehydrogenase; Animals; Cell Line; Cross-Linking Reagents; Cyanamide; Cyclophosphamide; Disulfiram; Drug Resistance; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Mice

Certain biological effects exerted by 4-hydroperoxycyclophosphamide and by 2,4-tetrahydrocyclohexylamine (ASTA-Z-7557), utilized in vitro in the therapy of leukemias and lymphomas to eliminate the occult tumor cells in autologous marrow transplantations, were studied in human lymphocytes cultured in vitro. The data show that these drugs exert mutagenic activity eliciting unscheduled DNA synthesis (reparative synthesis) after DNA damage and cause about tenfold higher frequency of sister chromatid exchanges than controls. Furthermore, they exert strong toxic effects, measured as tritiated thymidine uptake inhibition, on mitogen-stimulated dividing cells even if pretreated during the nonproliferative phase of the cell cycle in which the toxic activity of the drugs is not detectable. Data obtained with doses of the drugs similar to those used in the therapy are discussed in terms of the therapeutic use of these chemicals.

Topics: Cell Survival; Cells, Cultured; Cyclophosphamide; DNA Replication; Dose-Response Relationship, Drug; Humans; Kinetics; Lymphocytes; Metaphase; Mutagens; Sister Chromatid Exchange

Topics: Cells, Cultured; Cyclophosphamide; Dose-Response Relationship, Drug; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute