scholarly journals O 6-Benzylguanine Potentiates the In Vivo Toxicity and Clastogenicity of Temozolomide and BCNU in Mouse Bone Marrow

Blood ◽  
1997 ◽  
Vol 89 (5) ◽  
pp. 1566-1573
Author(s):  
Nachimuthu Chinnasamy ◽  
Joseph A. Rafferty ◽  
Ian Hickson ◽  
John Ashby ◽  
Helen Tinwell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Antitumor Agents ◽  
Alkylating Agents ◽  
Micronucleus Assay ◽  
Hematological Toxicity ◽  
Mouse Bone Marrow ◽  
Macrophage Colony ◽  
Lower Magnitude ◽  
Marrow Cellularity

The effects of treatment of mice with O6-benzylguanine (O6-BeG) on the levels of O6-alkylguanine-DNA alkyltransferase (ATase) in the hematopoietic compartment and on the in vivo sensitivity of hematopoietic progenitor cells to the toxic and clastogenic effects of the antitumor agents 1,3-bis(2-chloroethyl)-nitrosourea (BCNU) and temozolomide were studied. When the overall effects of BCNU alone or with O6-BeG pretreatment were compared, dose potentiating factors of 4.17 for marrow cellularity, 4.57 for granulocyte macrophage-colony forming cells (GM-CFC) and 8.25 for colony forming unit-spleen (CFU-S) in O6-BeG pretreated versus nonpretreated animals were observed. A similar trend of dose potentiation was observed for temozolomide, although it was of lower magnitude: 1.20 for marrow cellularity, 1.63 for GM-CFC, and 1.68 for CFU-S. When the clastogenic effects of BCNU and temozolomide were examined in the mouse bone marrow micronucleus assay, a significantly (P < .05 to .001) higher frequency of micronuclei formation was observed in mice that received O6-BeG pretreatment compared with mice that received no pretreatment. These data suggest that the use of O6-BeG as a tumor-sensitizing agent before treatment of patients with O6-alkylating agents may lead to more severe hematological toxicity and possibly to an increased incidence of secondary leukemias as a result of elevated mutation frequencies in these patients.

scholarly journals O 6-Benzylguanine Potentiates the In Vivo Toxicity and Clastogenicity of Temozolomide and BCNU in Mouse Bone Marrow

Blood ◽  
1997 ◽  
Vol 89 (5) ◽  
pp. 1566-1573 ◽  
Author(s):  
Nachimuthu Chinnasamy ◽  
Joseph A. Rafferty ◽  
Ian Hickson ◽  
John Ashby ◽  
Helen Tinwell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Antitumor Agents ◽  
Alkylating Agents ◽  
Micronucleus Assay ◽  
Hematological Toxicity ◽  
Mouse Bone Marrow ◽  
Macrophage Colony ◽  
Lower Magnitude ◽  
Marrow Cellularity

Abstract The effects of treatment of mice with O6-benzylguanine (O6-BeG) on the levels of O6-alkylguanine-DNA alkyltransferase (ATase) in the hematopoietic compartment and on the in vivo sensitivity of hematopoietic progenitor cells to the toxic and clastogenic effects of the antitumor agents 1,3-bis(2-chloroethyl)-nitrosourea (BCNU) and temozolomide were studied. When the overall effects of BCNU alone or with O6-BeG pretreatment were compared, dose potentiating factors of 4.17 for marrow cellularity, 4.57 for granulocyte macrophage-colony forming cells (GM-CFC) and 8.25 for colony forming unit-spleen (CFU-S) in O6-BeG pretreated versus nonpretreated animals were observed. A similar trend of dose potentiation was observed for temozolomide, although it was of lower magnitude: 1.20 for marrow cellularity, 1.63 for GM-CFC, and 1.68 for CFU-S. When the clastogenic effects of BCNU and temozolomide were examined in the mouse bone marrow micronucleus assay, a significantly (P < .05 to .001) higher frequency of micronuclei formation was observed in mice that received O6-BeG pretreatment compared with mice that received no pretreatment. These data suggest that the use of O6-BeG as a tumor-sensitizing agent before treatment of patients with O6-alkylating agents may lead to more severe hematological toxicity and possibly to an increased incidence of secondary leukemias as a result of elevated mutation frequencies in these patients.

scholarly journals Inhibition of Granulocyte-Macrophage Colony-Stimulating Factor Prevents Dissemination and Induces Remission of Juvenile Myelomonocytic Leukemia in Engrafted Immunodeficient Mice

Blood ◽  
1997 ◽  
Vol 90 (12) ◽  
pp. 4910-4917 ◽  
Author(s):  
Per O. Iversen ◽  
Ian D. Lewis ◽  
Suzanne Turczynowicz ◽  
Henrik Hasle ◽  
Charlotte Niemeyer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Juvenile Myelomonocytic Leukemia ◽  
Mouse Bone Marrow ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Myelomonocytic Leukemia ◽  
Stimulating Factor

Abstract Granulocyte-macrophage colony-stimulating factor (GM-CSF ) and tumor necrosis factor α (TNFα) have been implicated in the pathogenesis of the fatal childhood disease termed juvenile myelomonocytic leukemia (JMML). We used a severe combined immunodeficient/nonobese diabetic (SCID/NOD) mouse model of JMML and examined the effect of inhibiting these cytokines in vivo with the human GM-CSF antagonist and apoptotic agent E21R and the anti-TNFα monoclonal antibody (MoAb) cA2 on JMML cell growth and dissemination in vivo. We show here that JMML cells repopulated to high levels in the absence of exogeneous growth factors. Administration of E21R at the time of transplantation or 4 weeks after profoundly reduced JMML cell load in the mouse bone marrow. In contrast, MoAb cA2 had no effect on its own, but synergized with E21R in virtually eliminating JMML cells from the mouse bone marrow. In the spleen and peripheral blood, E21R eliminated JMML cells, while MoAb cA2 had no effect. Importantly, studies of mice engrafted simultaneously with cells from both normal donors and from JMML patients showed that E21R preferentially eliminated leukemic cells. This is the first time a specific GM-CSF inhibitor has been used in vivo, and the results suggest that GM-CSF plays a major role in the pathogenesis of JMML. E21R might offer a novel and specific approach for the treatment of this aggressive leukemia in man.

scholarly journals Inhibition of Granulocyte-Macrophage Colony-Stimulating Factor Prevents Dissemination and Induces Remission of Juvenile Myelomonocytic Leukemia in Engrafted Immunodeficient Mice

Blood ◽  
1997 ◽  
Vol 90 (12) ◽  
pp. 4910-4917 ◽  
Author(s):  
Per O. Iversen ◽  
Ian D. Lewis ◽  
Suzanne Turczynowicz ◽  
Henrik Hasle ◽  
Charlotte Niemeyer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Juvenile Myelomonocytic Leukemia ◽  
Mouse Bone Marrow ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Myelomonocytic Leukemia ◽  
Stimulating Factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF ) and tumor necrosis factor α (TNFα) have been implicated in the pathogenesis of the fatal childhood disease termed juvenile myelomonocytic leukemia (JMML). We used a severe combined immunodeficient/nonobese diabetic (SCID/NOD) mouse model of JMML and examined the effect of inhibiting these cytokines in vivo with the human GM-CSF antagonist and apoptotic agent E21R and the anti-TNFα monoclonal antibody (MoAb) cA2 on JMML cell growth and dissemination in vivo. We show here that JMML cells repopulated to high levels in the absence of exogeneous growth factors. Administration of E21R at the time of transplantation or 4 weeks after profoundly reduced JMML cell load in the mouse bone marrow. In contrast, MoAb cA2 had no effect on its own, but synergized with E21R in virtually eliminating JMML cells from the mouse bone marrow. In the spleen and peripheral blood, E21R eliminated JMML cells, while MoAb cA2 had no effect. Importantly, studies of mice engrafted simultaneously with cells from both normal donors and from JMML patients showed that E21R preferentially eliminated leukemic cells. This is the first time a specific GM-CSF inhibitor has been used in vivo, and the results suggest that GM-CSF plays a major role in the pathogenesis of JMML. E21R might offer a novel and specific approach for the treatment of this aggressive leukemia in man.

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