asta-z-7557 and Neoplasms

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; Cyclophosphamide; Immunotherapy; Leukemia, Experimental; Lymphocytes; Macrophage Activation; Neoplasms; Rats

Mafosfamide is a new oxazaphosphorine that breaks down spontaneously into 4-hydroxy-cyclophosphamide. A phase I trial with cyclohexylamine and lysine salts of mafosfamide was carried out in 16 patients, using weekly IV perfusion. Dose-limiting toxicities were not hematological, but consisted in the development of severe pain along the vein during administration. A particular mucosal syndrome with sneezing and conjunctivitis was seen only after administration of the lysine salt. The dose of 700 mg/m2 per week represents the maximum tolerated dose with this weekly schedule.

Topics: Adult; Aged; Blood Cell Count; Clinical Trials as Topic; Cyclophosphamide; Drug Evaluation; Female; Humans; Infusions, Parenteral; Male; Middle Aged; Neoplasms; Pain

This report describes some experimental and clinical studies showing the following: (1) in animals under protection of mesna the dose of ifosfamide (Ifo) can be increased significantly; (2) fractionated administration of Ifo, cyclophosphamide (CPA), or the stabilized metabolite of cyclophosphamide (ASTA Z 7557) is less toxic than single push-injection of the same total daily dose and therapeutically more effective; and (3) in humans under the protection of mesna the continuous infusions of ifosfamide over 5 days leads to an increase of the MTD compared with single daily short-term infusion and responses in some solid tumors, e.g., soft tissue sarcomas.

Topics: Animals; Clinical Trials as Topic; Cyclophosphamide; Humans; Ifosfamide; Infusions, Parenteral; Kidney; Lethal Dose 50; Male; Mesna; Mice; Mice, Inbred Strains; Middle Aged; Neoplasms

Thirty-three patients with advanced solid tumors were treated by high-dose chemotherapy (combined high-dose melphalan), followed by cryopreserved autologous bone marrow transplantation (ABMT). Thirteen of them had bone marrow (BM) tumor involvement at diagnosis, and BM harvest was purged with 50 micrograms/ml ASTA Z 7557 before cryopreservation. Following incubation, in vitro growth of granulomonocytic colony-forming cells (GM-CFC) was regularly inhibited (greater than 99%). Hemopoietic reconstitution after purged and nonpurged ABMT was studied. All patients experienced engraftment. However, peripheral leukocyte and granulocyte recoveries were delayed significantly in patients receiving purged BM (mean 27 and 26 days) compared with those observed in patients receiving nonpurged BM (mean 18 and 18 days). These results confirm that purged BM, despite GM-CFC depletion after in vitro treatment, ensures engraftment after high-dose chemotherapy, but prolonged pancytopenia is observed and postgraft hemopoietic recovery is delayed. A clinical trial is necessary to evaluate the efficiency of the purging technique in eradicating residual tumor cells.

Topics: Adult; Bone Marrow Transplantation; Child; Colony-Forming Units Assay; Cyclophosphamide; Graft Survival; Hematopoiesis; Hematopoietic Stem Cells; Humans; Neoplasms; Neoplastic Stem Cells; Pancytopenia; Preoperative Care; Transplantation, Autologous

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

Mafosfamide-cyclohexylamine is a new oxazaphosphorine derivative. It was chosen for phase-I clinical testing because of an expected higher therapeutic index and lack of complete cross resistance in animal tumors compared to cyclophosphamide. The schedule consisted of a single iv dose repeated every three weeks. The compound was found to cause as it's dose limiting toxicity severe pain along the injected vein and acute irritation of mucous membranes. The maximal tolerated dose was around 1000 mg/m2 given as a slow infusion over 2-3 hours. Hematological toxicity was mild. A limited phase-I study with the lysine salt of mafosfamide showed an identical type of toxicity. Mafosfamide given iv in a high-dose intermittent schedule is of little interest for further clinical trials. It is probable, that the severe venous pain and the mucosal irritation are caused by the high local concentration of 4-hydroxy-cyclophosphamide or by a metabolite. An oxazaphosphorine derivative undergoing slower hydrolysis therefore leading to lower active drug concentrations within the injected vein may be more promising.

Topics: Adult; Aged; Antineoplastic Agents; Cyclophosphamide; Drug Evaluation; Female; Humans; Leukocyte Count; Male; Middle Aged; Neoplasms

The ability of ASTA Z 7557 to inhibit colony formation in vitro by 6 human tumor cell lines and 3 methyl-cholanthrene-induced murine fibrosarcomas was compared to that of cyclophosphamide, 4-hydroperoxy-cyclophosphamide, BCNU, cisplatin, mitomycin C, doxorubicin, and 5-fluorouracil, as a function of dose, and duration of exposure. All drugs except cyclophosphamide were active in a dose and time dependent manner against all cell lines. ASTA Z 7557 and 4-hydroperoxy-cyclophosphamide at equimolar concentrations had similar antiproliferative activities. The stabilities of ASTA Z 7557 and 4-hydroperoxy-cyclophosphamide as measured by cytotoxic activity remaining after incubation at various times at 37 degrees in complete tissue culture medium containing 10% fetal calf serum were identical. At initial concentrations of 20 microM, cytotoxic activity of both compounds began to decline after two hours of incubation and all activity was lost after 24 hours of incubation. In vitro, ASTA Z 7557 produced, at least, additive cytotoxic activity with cisplatin, the combination of cisplatin plus doxorubicin, and human lymphoblastoid interferon.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Division; Cell Line; Cell Survival; Colony-Forming Units Assay; Cyclophosphamide; Fibrosarcoma; Humans; Mice; Neoplasms; Tumor Stem Cell Assay