Cytotoxicity of cis-parinaric acid in cultured malignant gliomas.

The cytotoxic effects of cis-parinaric acid, a plant-derived 18-carbon polyunsaturated fatty acid, were assessed in vitro on normal and neoplastic glia. After being incubated for 24 hours in the presence of 12 mumol/L cis-parinaric acid, 36B10 glioma cultures demonstrated nearly 90% toxicity (unpaired Student's t test, P < 0.001). Similar results were obtained after the exposure of C6 rat glioma cultures, A172 human glioma cultures, and U-937 human monocytic leukemia cultures to cis-parinaric acid. In contrast, fetal rat astrocytes incubated with 12 mumol/L cis-parinaric acid demonstrated no significant toxicity (3% reduction, P = 0.12); fetal rat astrocytes showed only 20% toxicity after exposure to 40 mumol/L cis-parinaric acid (P = 0.001). The cytotoxic effects of cis-parinaric acid were antagonized with the addition of equimolar concentrations of alpha-tocopherol. Enzyme immunoassay of treated 36B10 glioma supernatant fluid for 8-isoprostane (a known oxidative metabolite) demonstrated a 10-fold increase of 8-isoprostane over 24 hours (123.0 +/- 10.3 versus 10.0 +/- 0.7 pg/ml for control, P < 0.001). These studies indicate that cis-parinaric acid may be significantly cytotoxic to malignant glioma cells in concentrations that spare normal astrocytes and that the mechanism of cytotoxicity is related to an oxidative process. The selective cytotoxic effect of cis-parinaric acid we describe represents the first step in the development of new chemotherapeutic agents for gliomas; these new agents act by preferentially enhancing lipid peroxidation in neoplastic cells.

Cytosine arabinoside and mitoxantrone induction chemotherapy followed by bone marrow transplantation or chemotherapy for relapsed or refractory pediatric acute myeloid leukemia.

The purpose of this study was to determine the induction rate, duration of response and toxicity of cytosine arabinoside (1.0 gm/m2 i.v. over 2 h q 12 h x 8 doses days 1 through 4) and mitoxantrone (12 mg/m2 over 1 h daily x 4 doses days 3 through 6) in pediatric patients with acute myeloid leukemia (AML). Patients achieving a complete remission received either bone marrow transplantation or further chemotherapy. Twenty-seven of 37 evaluable patients (73% (95% confidence interval 59-87%)) achieved a complete remission. For all responding patients, the projected median time to relapse is 12 months. The projected 1 and 2 year disease-free survival is 47% (28-66) and 41% (21-61) with a range of follow-up of 0 to 48+ months. The major toxicity was bone marrow suppression and infection. This therapy is very active in pediatric AML and has acceptable toxicity. Some patients treated achieve prolonged survival.

The mechanism of chlorpromazine-induced red blood cell swelling.

1. Chlorpromazine (CPZ)-induced red blood cell (RBC) swelling was investigated by determination of electrolyte, mean cell volume (MCV) and water content changes in CPZ-treated cells. 2. CPZ-induced RBC swelling is dose-, hematocrit- and pH-dependent, and is associated with a net increase in RBC monovalent cation and Cl- contents. 3. The partition coefficient (Kp) for the CPZ-RBC membrane interaction is pH dependent (Kp = 2500 at pH 7.8; Kp = 840 at pH 6.8). 4. Despite the pH dependence of Kp values an equal number of CPZ molecules is required to induce a 12% increase in MCV at pH 7.8 and 6.8.

Comparative studies of phenothiazine derivatives for their effects on swelling of normal and sickle erythrocytes.

1. Three phenothiazines with similar structure; chlorpromazine (CPZ), triflupromazine (TFPZ), and trifluoperazine (TFP), were compared for the potency of swelling of normal red cells and antisickling effect of red cell from patients with sickle cell disease. 2. Normal erythrocytes treated with the phenothiazines became swollen within 60 min, and the percent increase in mean cell volume (MCV) was dose-dependent and varied according to the agent used. 3. The cell swelling was hematocrit-dependent, and pH-dependent. A greater swelling potency was seen at lower hematocrits and higher pH values. 4. The swelling was also dependent on the pKa values of these chemicals. TFP with the lowest pKa induced the highest degree of swelling while CPZ with the highest pKa induced the lowest. 5. The un-ionized fraction of the phenothiazines at a given pH was directly related to potency of the swelling. 6. The cell swelling was directly related to the binding affinities of the phenothiazines to calmodulin. 7. The antisickling effect of these compounds using sickle red cells, numerically estimated by an automated image analysis system, was found in the same order as that of swelling potency: TFP > TFPR > CPZ.

Ifosfamide-induced hyperpigmentation.

BACKGROUND: Pigmented banding of the nails and hyperpigmentation of hands and feet may occur during cyclophosphamide therapy. Ifosfamide, an analogue of cyclophosphamide, might be expected to cause similar pigmentary changes, but, to the knowledge of the authors, there are no reports of this. METHODS: The authors describe skin pigment changes in a 5-year-old patient receiving ifosfamide, MESNA, and etoposide for the treatment of relapsed Wilms tumor. RESULTS: A review of the literature concerning cyclophosphamide-induced pigmentary changes is presented, along with a discussion of the possible correlation of renal dysfunction with pigmentary changes. CONCLUSIONS: This case should alert health care providers to this uncommon adverse effect of ifosfamide.

Cytotoxic effect of cis-parinaric acid in cultured malignant cells.

Parinaric acid, a naturally occurring 18-carbon fatty acid containing 4 conjugated double bonds, is toxic to human monocytic leukemia cells at concentrations of 5 microM or less. Conditioning of the medium reduces the cytotoxic effect, suggesting that parinaric acid and not a metabolite is the active agent. The mechanism of parinaric acid toxicity appears to involve lipid peroxidation because the toxic action can be blocked by the addition of butylated hydroxytoluene. When U-937 cells are differentiated to the monocytic form, they become resistant to as much as 30 microM parinaric acid. This difference in sensitivity may be explained in part by the fact that the undifferentiated cells take up 3 to 4 times more parinaric acid. Concentrations of parinaric acid less than 5 microM are also toxic to human THP-1 monocytic leukemia, HL-60 human promyelocytic leukemia, and Y-79 human retinoblastoma cells. Measurements of protein synthesis indicate that differentiated U-937 cells, confluent cultures of human fibroblasts, bovine aortic endothelial cells, and CaCo-2 colonic mucosal cells are much less sensitive to parinaric acid than the malignant cell lines tested, suggesting that the cytotoxic action may be selective for rapidly growing malignant tumors. Thus, parinaric acid may be the prototype of a new class of lipid chemotherapeutic agents that contain a conjugated system of double bonds and act by sensitizing tumor cells to peroxidation.

Elevated common acute lymphoblastic leukemia antigen expression in pediatric immune thrombocytopenic purpura.

Bone marrow examination is often performed in thrombocytopenic children to distinguish immune thrombocytopenic purpura (ITP) from acute leukemia. We describe a patient with thrombocytopenia and 50% common acute lymphoblastic leukemia antigen (CALLA) positivity in his marrow who was subsequently shown to have ITP. CALLA (CD10) is a surface antigen found in early B-lymphocytes and is elevated in most cases of childhood acute lymphoblastic leukemia (ALL). This case prompted us to prospectively study the frequency of immature lymphocyte populations in children with ITP. Fourteen patients with acute ITP and five with other conditions were studied. The two groups were comparable with respect to age: ITP mean, 4.3 (range 0.3-15.5) years; control mean, 5.8 (0.6-13.8) years. The ITP group had a significantly higher percentage of CD10 positive bone marrow lymphocytes (p = 0.007). Five of the 10 patients younger than 4 years of age in the ITP group had CD10 levels of greater than 30%, which is in the leukemic range, whereas none of the control patients had a CD10 levels of greater than 17% (p = 0.003). There was good correlation between CD10 positivity and B4 positivity indicating that both of these markers arise from the same population of immature B-lymphocytes. None of the ITP patients who were older than 4 years had a CD10 level of greater than 30%. We conclude that it is common to have an increase in the proportion of immature lymphocytes in the marrow of young children with ITP. The cause of this increase in CD10 positive cells is unknown.(ABSTRACT TRUNCATED AT 250 WORDS)