Chemoimmunotherapy with low dose vinorelbine and interleukin-2 in treatment of patients with metastatic renal cell carcinoma.

Systemic therapies employed in patients with metastatic renal cell carcinoma (MRCC) include chemotherapy to immunomodulatory cytokines (interleukin 2 [IL-2], interferon alpha [INFalpha]), chemoimmunotherapy, adoptive immune therapy and anti-angiogenic therapy. Despite this range of treatment alternatives, the optimal therapy for MRCC patients is far from being established. Thus, attempts with novel therapeutic approaches implementing new drug combinations are justified. We conducted a phase II evaluation of a combination of vinorelbine and IL-2, both at low doses, in 30 patients with MRCC. The rationale of the combination was to damage the tumor tissue to the extent necessary to make it more immunogenic while, at the same time, to obtain an efficient immune response through the concomitant administration of IL-2. The treatment, given in different dose combinations and administration times, resulted feasible, with no renal, neurological or hematological toxicity. The overall survival of the whole group of patients is higher than that usually observed following treatment with immunotherapies (18.2 versus 13.3 months, respectively). While the limited number of treated patients does not allow advancing conclusions on the effective activity of the adopted protocol, the results observed are encouraging.

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.

Effect of H2 antagonists cimetidine and famotidine on the hemotoxicity of cyclophosphamide.

A comparison between the effects of H2 antagonists Cimetidine and Famotidine on the hemotoxicity of Cyclophosphamide in vivo in DBA/2NCrBl mice is described. Hemotoxicity of anticancer drug was determined by peripheral blood leukocytes, bone marrow cells and bone marrow CFU-S, GM-CFC. Results show that Famotidine does not increase Cyclophosphamide hemotoxicity while Cimetidine enhances the toxicity of the anticancer drug only on normal pluripotent hemopoietic stem cells.

Occurrence of spontaneous malignant lymphoma in the course of idiopathic myelofibrosis.

The spontaneous development of malignant non-Hodgkin lymphoma in a patient with idiopathic myelofibrosis is described. The tumor appeared 3 years after clinical diagnosis of the latter. Implications of the association between myeloproliferative and lymphoproliferative disorders at a pathogenetic level are briefly discussed.

Toxicity of trimetrexate on hemopoietic progenitor cells in normal mice.

Single increasing doses of methotrexate (MTX) and trimetrexate (TMQ) were administered to normal mice. Survival of hemopoietic progenitor cells assayed as CFU-S and GM-CFC was determined 24 hr after drug injection. The survival of each population in TMQ-treated animals was not statistically different from that observed in mice treated with MTX. No difference was observed in time-survival curves of hemopoietic progenitor cells comparing TMQ to MTX. TMQ toxicity at the hematological level thus seems comparable to that of MTX.

Experimental study on bone marrow CFUs following anticancer drug administration to plethoric mice.

The effect of some cycle-dependent anticancer drugs on CFUs has been studied in transfused polycythemic mice. In untreated animals during passive plethora erythropoiesis is depressed but the content of CFUs per femur remains constant. In treated plethoric mice the femural content of CFUs is similar or higher than that found in treated controls after administration of adriamycin, vinblastine, cyclophosphamide, it is lower when the mice receive azathioprine or hydroxyurea. These results suggest that suppression of erythropoiesis does not uniformly affect the susceptibility of pluripotent stem cells to anticancer drugs. Interpretation of the reported findings is difficult as it must take into account a complex interplay of a number of factors.

The effects of chronic administration of cyclophosphamide on haemopoietic stem cells.

The effects of cyclophosphamide given for 18 weeks in small daily doses on CFU-S, CFU-C, and CFU-E content in mice bone marrow and spleen were studied. In the bone marrow, after an initial drop, the stem cell content rises above the normal values and remains there throughout a long period. In the spleen the stem cell content shows an initial several fold increase followed by a steady decline. It seems possible that this behaviour reflects a compensative effect to the toxic action of the drug at more differentiated levels of the haemopoietic cells.

Effect of bleeding on in vivo 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.