Hematopoietic precursor cells in mice treated with 4-demethoxydaunorubicin and doxorubicin.

The hematologic toxicity of 4-demethoxydaunorubicin (4-dmDNR), a new anthracycline more potent and less cardiotoxic than doxorubicin (Dx), was studied. Dose-survival curves of bone marrow hematopoietic precursor cells (HPC) in situ were determined with the use of (C57BL X C3H)F1 mice and with assays of colony-forming units--spleen, culture, and erythroid--by in vivo and in vitro methods. Time response of HPC was followed in mice treated at days 0, 2, and 5 with 0.75 mg 4-dmDNR/kg of 4.5 mg Dx/kg and in mice receiving 2.23 mg 4-dmDNR/kg or 3.96 mg Dx/kg twice a week for 4 weeks. The dose-survival curves of HPC for 4-dmDNR were exponential. Slight differences in sensitivity among assayed populations were seen. Although the doses of 4-dmDNR required to reduce the survival of HPC to 37% were similar or lower than those of Dx, following intermittent treatment with doses of 4-dmDNR with the same optimal antitumor activity as with Dx, 4-dmDNR seemed to have a lesser effect on hematopoietic progenitors and a greater effect on peripheral blood cells than did Dx. However, during prolonged administration 4-dmDNR appeared to be toxic at every hematopoietic level.

Cellular and Molecular Characterization of Two Cases of Castleman's Disease, Plasma Cell Variant.

We report the cellular and molecular characterization of two cases of Castleman's disease, plasma cell variant, that differed in their clinical presentation and course. Patient 1 had Castleman's disease in association with Kaposis's sarcoma unrelated to human immunodeficiency virus (HIV) infection and died while he was receiving an aggressive chemotherapeutic regimen for Kaposi's sarcoma. Patient 2 had an isolated retroperitoneal lymphoid mass with an adjacent enlarged limph nodes and his symptoms disappeared completely following the surgical removal of both. Pathologic and immunohistochemical analyses in both cases, revealed that there was a massive infiltration of polyclonal plasma cells in the interfollicular areas of the lymph nodes. Immunoglobulin gene rearrangement studies confirmed the polyclonal nature of B-lineage cells in the involved lymph nodes. Southern blot experiments failed to demonstrate the presence of EBV genome copies in the same lymph nodes. These paradigmatic cases lend further support to the notion that Castleman's disease is an extremely heterogeneous entity.

Failure of N-acetylcysteine to protect against cis-dichlorodiammineplatinum(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.

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.

Leucovorin protection on pluripotent hemopoietic stem cells in mice treated with high-dose methotrexate.

Haematologic effects of delayed 16 h administration of leucovorin (LV) following high-dose methotrexate (HDMTX) were analyzed in C57Bl X C3H F1 mice. Results show that 16 h administration of LV significantly reduces the toxic effects of HDMTX on hemopoietic progenitors and bone marrow cells. At 12 days after HDMTX administration, the bone marrow level of CFUs was significantly higher in HDMTX-LV treated mice than in HDMTX treated animals. In comparison with previous data obtained when LV was injected 2 h after HDMTX, the delay in administration of LV does not appear to reduce the protective effect of the vitamin.

Activity of doxorubicin linked to poly-L-aspartic acid on normal murine hematopoietic progenitor cells.

Compared with free doxorubicin, doxorubicin linked to poly-L-aspartic acid shows a reduction in overall toxicity, without loss of its antitumor activity. In this study, the toxicity of the new anthracycline conjugate on hematopoietic precursor cells of normal DBA/2NCrlBR mice was investigated by assays of bone marrow and spleen CFUs and CFUc (colony-forming units in spleen and culture). In vivo dose- and time-survival curves were determined. Results showed that the conjugate is three to ten times less hematotoxic than doxorubicin. Differences in susceptibility between bone marrow and spleen hematopoietic precursor cells to doxorubicin or the conjugate were observed, suggesting further studies on the pharmacokinetics of the new conjugate.

Cytotoxic effect of dose and schedule on normal murine hematopoietic progenitor cells following the administration of 4'-deoxydoxorubicin.

In an experimental setting, 4'-deoxydoxorubicin (4'-deoxy-DX) shows minimal cardiotoxicity as well as the marked antitumoral activity shown by doxorubicin, its parent compound. In this experimental study, the haematologic toxicity of the new anthracycline was investigated by haematopoietic precursor cell (HPC) assays using in vivo (colony-forming units - spleen, CFUs) and in vitro (CFUc-culture) methods with (C57B1 X C3H)F1 mice. Dose-survival curves and time response of HPC in situ following 4'-deoxy-DX administration were determined. In the time-related experiments, the effects of a single dose, an intermittent treatment (Days 0, 2, and 5) and a prolonged biweekly administration were studied. All dose-survival curves were exponential, with statistically significant differences between the effects on the various cell classes. CFUc appeared more sensitive than CFUs. In time-related experiments, 4'-deoxy-DX toxicity for HPC seemed to be relatively mild. However, CFUc sensitivity was again high in comparison with other populations assayed. In long-term administration, the 4-deoxy-DX effects on the haematopoietic system were also rather slight.

[Behaviour of bone marrow and splenic hemopoietic stem cells following administration of anthracyclines]. / Comportamento delle cellule staminali emopoietiche midollari e di quelle spleniche dopo somministrazione di antraciclinici.

The effect of Adriamycin and 4-Eip-Adriamycin was studied on CFUs, CFUc, CFUe of murine bone marrow and spleen. Differences among the bone marrow stem cells and the spleen stem cells have been observed. It seems possible to explain some of these differences admitting a process of redistribution from the bone marrow to the spleen.

Experimental comparative study on myelotoxicity of 4'-deoxy-4'-I-doxorubicin and of doxorubicin.

4'-Deoxy-4'-I-doxorubicin (I-Dx) is 1.5-2 times more potent than doxorubicin (Dx) on some mice tumors and does not seem to be cardiotoxic. A comparison was made of the effects of both anthracyclines on mice bone marrow hemopoietic progenitors (CFU-S, GM-CFC) and peripheral blood cells. The experimental model is based on dose survival and time survival curves following single or repeated (1 weekly administration for 4 weeks) doses. Results indicate slightly higher sensitivity of assayed populations to I-DX than to Dx.

Activity of 4'-epi-doxorubicin on normal hematopoietic precursor cells in mice.

The effects of 4'epi-doxorubicin (4'-epi-DX) on survival of in situ murine bone marrow hematopoietic precursor cells (HPC) were studied. The drug was given to (C57BL X C3H)F1 mice in increasing single doses, in repeated administration (three time in 5 days), or for a long period (twice a week for 10 weeks). Survival of colony-forming units (CFUs, spleen; CFUc, culture; and CFUe, erythroid) was assayed by in vivo and in vitro methods; dose survival curves were exponential. It appears that single doses of 4'epi-DX have a greater impact on murine HPC than single doses of the parent compound. Following repeated administrations, pluripotential stem cells recover better after the derivative than after its parent drug. During prolonged treatment, the bone marrow content of committed progenitors is depleted to a lesser extent in the animals treated with 4;-epi-DX than in those receiving DX. It is, however, possible that, following the same prolonged treatment, this difference is minimal. The conclusion, these experimental data seem to indicate that 4'-epi-DX has lower toxicity in murine HPC than DX and that this is evident mainly after repeated administrations for a short period of time.