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Microsatellite instability (MSI) represents one specific pattern of genomic instability and is one of the genetic lesions most frequently detected in human neoplasia. Although MSI has been found to be associated with a wide variety of solid cancers, its involvement in lymphoid malignancies is virtually unexplored. In this study, we have investigated the presence of MSI in chronic lymphoproliferative disorders by comparing the pattern of nine microsatellite repeats (two tetranucleotides, two trinucleotides, and five dinucleotides) on autologous germline and tumor DNA of 23 patients, including 17 with B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL), four with hairy cell leukemia, one with lymphoplasmacytoid lymphoma, and one with T-cell chronic lymphocytic leukemia. All samples at diagnosis displayed a germline pattern of the microsatellites examined, thus suggesting that MSI is not involved in the pathogenesis of these lymphoproliferations. Also, no microsatellite alterations were observed in consecutive samples of B-CLL/SLL obtained from the same patient at various stages of the disease both before and after chemotherapy. Conversely, alterations in 3/9 microsatellite repeats were detected in one case of Richter's syndrome which had evolved from a pre-existent B-CLL/SLL phase. Overall, the low frequency of MSI among chronic lymphoproliferative disorders adds further weight to the common view that the mechanisms and patterns of genomic instability in lymphoid neoplasia differ markedly from those commonly observed in solid cancers. [ABSTRACT FROM AUTHOR]

R-Verapamil (R-VPM), an enantiomer of racemic verapamil (VPM), has been recently reported to possess an activity equivalent to VPM in reverting drug resistance in vitro, without showing remarkable cardiovascular toxicity in animal models, even in doses three times higher than VPM. In this study, we assessed the effects of R-VPM in vitro, on clonogenic leukemia cells (CFU-L) from 15 patients with acute nonlymphoid leukemia (ANLL) at diagnosis, and on bone marrow erythroid (BFU-E) and myeloid (CFU-GM) progenitors from 15 healthy volunteers. On CFU-L, continuous exposure to VPM or R-VPM alone showed a slight inhibitory activity; in combination with daunorubicin (DNR), R-VPM proved more effective (mean IC50 of DNR: alone = 24.53 ng/ml +/- 6.2 SE, + VPM = 18.8 ng/ml +/- 4.6 SE, +R-VPM = 17.9 ng/ml +/- 4.8 SE). On CFU-GM, both VPM and R-VPM were minimally toxic at the lowest concentration used, but 30 microM VPM were significantly more toxic than R-VPM at the same dose (residual growth = 39.2% +/- 6.5% vs. 71.8% +/- 9.3% with R-VPM, p = 0.005). On BFU-E, both VPM and R-VPM caused more consistent growth inhibition; at high doses, VPM was again more toxic than R-VPM (33.4% +/- 12.8% vs 53.4% +/- 10.4% residual growth at 30 microM, p = 0.03). DNR toxicity on bone marrow was more greatly enhanced by VPM than R-VPM, and this difference was statistically significant on erythroid progenitor colony growth (p = 0.04). In conclusion, in comparison to VPM, R-VPM appeared to be at least equally effective on leukemic clonogenic cells and less toxic on normal bone marrow precursors, thus suggesting a possible safe use in vivo, even in concentrations that cannot be achieved with VPM, owing to its toxic effects. [ABSTRACT FROM AUTHOR]

The introduction of hematopoietic growth factors into the management of leukemia can influence the outcome of treatment in several ways, depending on the sensitivity and the response of normal and leukemic cells. In this paper we report on the effects of the administration of Escherichia coli-produced, human recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) in 15 adult patients with acute nonlymphocytic leukemia (ANLL) resistant to first-line treatment or in relapse. GM-CSF was given at a dose of 5-10 micrograms/kg/day as a 6-h i.v. infusion, prior to chemotherapy (CHT) (for 7 days) and after CHT (until evidence of failure or of remission). In the pre-CHT period there was a clear trend towards an increase of circulating neutrophils (PMN) and/or blast cell count (median 0.3 vs. 1.0 x 10(9)/l for PMN, and 0.5 vs. 2.3 for blast cells). After chemotherapy, in the patients who achieved complete remission (CR), the median time to a PMN count greater than 0.5 x 10(9)/l and greater than 1 x 10(9)/l was 16 days (range 13-27) and 19 days (range 13-42) respectively. The outcome of treatment was CR for 8/15 (53%), death during induction for 3/15 (20%), and failure for 4/15 (27%). All failures occurred in patients with an increase of blast cell count during pre-CHT GM-CSF administration. Toxicity and side effects were minor, apart from an acute respiratory syndrome that developed twice in the same patient, at doses of 10 and 3 micrograms/kg/day. These data suggest that investigation of GM-CSF in the treatment of ANLL is worth pursuing, with special attention to GM-CSF effects prior to chemotherapy. [ABSTRACT FROM AUTHOR]

PTT-119, a new synthetic alkylating compound, has shown a marked 'in vitro' inhibitory effect on chronic myeloid leukemia (CML) granulo-monocytic precursors (CFU-GM) at doses greater than 5 µg/ml. Based on previous experiences of synergistic associations between alkylating drugs and biological modifiers, we tested the effects of low doses of PTT-119 (from 0.1 to 1 µg/ml) in concert with alpha, gamma, or alpha + gamma interferons and compared to IFNs alone, in order to investigate an alternative choice for treatment of CML patients in chronic phase. Our results showed a significantly higher CFU-GM cloning inhibition after addition of 100 or 1,000 U/ml of alpha IFN to 0.1 µg/ml PTT-119 (from 39.6% ± 26.6 SD to 80.7% ± 10 SD and 91.5% ± 8 SD, respectively), while gamma IFN resulted in only a slight increase in colony growth inhibition when compared to the drug used alone. The association of alpha plus gamma IFN coupled with PTT-119 treatment did not significantly improve the results observed after exposure of leukemic progenitors to PTT-119 and alpha IFN alone. We conclude that a combined treatment with PTT-119 and IFN is probably worth testing both for purging methods before autologous bone marrow transplantation and for in vivo administration in chronic myeloid leukemia. [ABSTRACT FROM AUTHOR]