Giuseppe Bogliolo

The in vitro and in vivo effect of recombinant interferon α‐2a on circulating haemopoietic progenitors in polycythaemia vera

In four patients with polycythaemia vera (PV) who received interferon alpha (IFN‐α) (3 MU subcutaneously three times a week) for 5 months, peripheral blood levels of granulocyte‐macrophage colony‐forming units and erythroid burst‐forming units were assessed monthly. Circulating progenitors significantly decreased throughout the treatment period. Moreover, we observed an inhibitory activity of IFN‐α on haemopoietic progenitor cells (HPC) from patients with PV in vitro.

Regional pharmacokinetic selectivity of intrapleural cisplatin

The pharmacokinetics and toxicity of cisplatin were investigated in 3 patients affected by malignant mesothelioma who received 90 mg/m2 of the drug intrapleurally. The mean area under the pleural Pt concentration versus time curve (AUC) [12.83 (S.D. 4.06) mg.min/ml] was about 50 times greater than that detected in plasma [0.27 (0.03) mg.min/ml], indicating a clear pharmacological advantage for this route of administration. The mean plasma total Pt concentration was 1.1 micrograms/ml and the apparent total body clearance was 268 (101) ml/min. Platinum plasma pharmacokinetic data measured following intrapleural cisplatin administration (4 patients) were compared with those observed in 7 patients treated intravenously with the same dose of cisplatin (90 mg/m2) under the same modalities of hydration. Intrapleural administration of cisplatin resulted in significantly lower plasma total partial AUC (P less than 0.05) and prolonged plasma levels of filterable Pt compared with intravenous administration. No difference between the two routes of cisplatin administration in the renal clearance (S.D.) of filterable Pt [132 (64) ml/min and 122 (39) ml/min for intravenous and intrapleural cisplatin, respectively] were observed. None of the mesothelioma patients developed clinical symptoms or signs of pleural inflammation. The intrapleural treatment did not produce haemotoxicity and the emetic toxicity was lower compared with that observed in patients receiving cisplatin intravenously.

Effect of diethyldithiocarbamate on toxicity of doxorubicin, cyclophosphamide and cis-diamminedichloroplatinum (II) on mice haemopoietic progenitor cells

DBA/2NCr1BR F1 mice received a single i.v. injection of doxorubicin (4.32, 7.20 or 12.00 mg kg-1), cyclophosphamide (70, 120 or 200 mg kg-1) or cis-diamminechloroplatinum (5.4, 9.0 or 15.0 mg kg-1), alone or 2 h before an i.p. injection of 1,000 mg kg-1 of diethyldithiocarbamate (DDTC). Twenty-four hours after, survival of bone marrow colony forming units-spleen and granulocyte-macrophage colony forming cells, was determined. On the whole, administration of DDTC reduced the toxic effect of the three anticancer drugs on haemopoietic progenitors. The effect was in general more evident at the lower than at the higher doses of the antitumour drugs.

Dexamethazone-induced acute tumor lysis syndrome in a T-cell malignant lymphoma.

We report a case of steroid-induced acute tumor lysis syndrome and review the literature. A 60-year-old woman was started on steroid therapy for dyspnea due to bilateral pleural effusion and a large mass involving the anterior mediastinum. The final diagnosis was precursor T-lymphoblastic lymphoma-leukemia. Following steroid therapy, the patient developed acute renal failure and laboratory evidence of metabolic changes induced by massive cytolysis. She received vigorous hydration, diuretic and allopurinol therapy, and haemodialysis. Her diuresis, renal function and laboratory data returned to normal within 2 weeks. A review of the medical literature on T-cell lymphoma revealed only one similar case of steroid-induced acute tumor lysis syndrome, a life-threatening metabolic emergency. This risk should be kept into account in the management of patients with lymphoproliferative disorders.

Effect of Bleeding on in vivo and in vitro Colony-Forming Hemopoietic Cells

The effect of bleeding on spleen colony-forming units (CFU-S) and on in vitro colony-forming cells with colony-stimulating factor (CFU-C) and erythropoietin (CFU-E) has been evaluated. The in vivo and in vitro colony-forming cells of the bone marrow show a decrease which for the CFU-E, CFU-C follows a short-lived increase. In the spleen, all progenitor cells assayed have shown a significant and sustained increase.

Failure of N-acetylcysteine to protect against cis-dichlorodiammine-platinum(II)-induced hematopoietic toxicity in mice

In view of the results showing a decrease in cis-dichlorodiammineplatinum(II) (cis-DDP) nephrotoxicity after administration of thiol donors, this study was carried out to test the possibility that N-acetylcysteine (NAC) was active against myelodepressive effects of the anticancer drug. Cis-DDP (15.5 mg/kg body weight, i.v.) was administered to control mice and to mice treated simultaneously or 1 h later with NAC (800 mg/kg body weight, i.v.). At various times after treatment, up to 11 days, assessments were made of peripheral blood cell levels and bone marrow progenitor cell (CFUs and CFUc) concentrations. Cis-DDP caused a decrease in hemopoietic precursor cells in the order of that caused by other hemopoietic precursor cells in the order of that caused by other myelodepressive drugs, whereas there was only a slight decrease in peripheral blood WBC. In this experimental setting, NAC administration did not afford significant protection against platinum toxicity on bone marrow precursors or peripheral blood cells.

Pulmonary toxicity in mice after high-dose methotrexate administration with and without leucovorin rescue.

Interstitial lung lesions were induced in mice by high-dose methotrexate with high frequency. They appeared early after treatment; their onset, evolution and recovery parallelled those of lesions to the hemopoietic tissues and the intestine. The pathogenesis of methotrexate lung toxicity in mice is discussed. Leucovorin rescue was ineffective in preventing the lung lesions induced by high-dose methotrexate.

The effect of N-acetylcysteine on toxicity of cyclophosphamide and doxorubicin on murine hemopoietic progenitors.

The effect of N-acetylcysteine on hemopoietic stem cells was studied. The drug was given to mice untreated and injected with a single dose of cyclophosphamide or doxorubicin. The results show that the antioxidant drug N-acetylcysteine does not induce any significant decrease in the cytotoxic effect of cyclophosphamide or doxorubicin.

Production of tumor necrosis factor and granulocyte colony stimulating factor by bone marrow accessory cells in myelodysplastic patients

Abstract:  This paper reports on the production of tumor necrosis factor (TNF) and granulocyte macrophage colony‐stimulating factor (GM‐CSF) by cultured mononuclear adherent cells derived from bone marrow of 25 patients affected by myelodysplastic syndrome (MDS) of different FAB subtypes. Mean production of GM‐CSF was much lower than in controls, without significant differences among different subtypes. Mean production of TNF was similar in MDS patients and in controls, but noteworthy differences were observed between patients with RA, RAEB and RAEB‐t and patients with RARS and CMML. Growth of bone marrow granulocyte macrophage and erythroid progenitors did not correlate with TNF and GM‐CSF production, although in MDS subtypes with higher GM‐CSF levels, colony growth was slightly higher than in subtypes with lower GM‐CSF production.

Circulating hematopoietic progenitor cells in polycythemia vera: the in vivo effect of hydroxyurea.

The in vivo effects of hydroxyurea (HU) on circulating erythroid (BFU-E) and granulocyte-macrophage progenitors (CFU-GM) in patients with polycythemia vera (PV) have been evaluated. HU induced a strong decrease of both BFU-E and CFU-GM in the first month of treatment. During the following 4 months of treatment the level of circulating progenitors remained at very low values, until the end of the period of observation. HU activity involved both erythroid and myeloid committed progenitors and both erythropoietin-stimulated (normal) and endogenous (derived from the abnormal PV clone) BFU-E.