Protection of committed murine haemopoietic progenitors against BCNU toxicity does not predict protection of primitive, multipotent spleen colony-forming cells : implications for chemoprotective gene therapy

• Published in: Leukemia Vol. 13; no. 11; pp. 1776 - 1783
• Main Authors: CHINNASAMY, N, RAFFERTY, J. A, LASHFORD, L. S, CHINNASAMY, D, MARGISON, G. P, THATCHER, N, DEXTER, T. M, FAIRBAIRN, L. J
• Format: Conference Proceeding Journal Article
• Language: English
• Published: London Nature Publishing 01.11.1999; Nature Publishing Group
• Subjects: Alkylating agents; Alkylation; Animals; Anticancer properties; Antineoplastic Agents - toxicity; Biocompatibility; Biological and medical sciences; Bone marrow; Carmustine - toxicity; Cells, Cultured; Clastogenicity; Clinical trials; Colonies; Colony-forming cells; Colony-Forming Units Assay; DNA alkyltransferase; Drug Resistance, Neoplasm; Drug toxicity and drugs side effects treatment; Erythrocytes; Erythrocytes - cytology; Erythrocytes - drug effects; Erythrocytes - enzymology; Gene therapy; Genetic Therapy; Granulocytes - cytology; Granulocytes - drug effects; Granulocytes - enzymology; Guanine - analogs & derivatives; Guanine - pharmacology; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - enzymology; Humans; Immunohistochemistry; Leukocytes (granulocytic); Macrophages; Macrophages - cytology; Macrophages - drug effects; Macrophages - enzymology; Male; Medical sciences; Mice; Micronucleus Tests; Mutagens - toxicity; Mutation; N,N'-bis(2-chloroethyl)-N-nitrosourea; Nucleotidyltransferases - antagonists & inhibitors; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; O6-benzylguanine; Pharmacology. Drug treatments; Progenitor cells; Resistant mutant; Spleen; Spleen - cytology; Spleen - drug effects; Spleen - enzymology; Spleen - metabolism; Temozolomide; Toxicity; Toxicity: blood; Transduction, Genetic; Tumors; Antineoplastic agent; Animal model; Nitrosoureas; Toxicity; Stem cell; Hematopoietic cell; Hemopathy; Prevention; Gene; Bone marrow; CFU-GM-Cell; Enzyme; Transferases; Carmustine; Rodentia; Genetic transfer; CFU-S-Cell; In vivo; Methylated-DNA-protein-cysteine S-methyltransferase; Vertebrata; Mammalia; Methyltransferases; Mouse; Animal; Genetic engineering; Transduction; Gene therapy
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2401584

The effect of expression of an O6-benzylguanine (O6-beG)-resistant mutant (hATPA/GA) of human O6-alkylguanine-DNA alkyltransferase (ATase) on the in vivo toxicity and clastogenicity of the anti-tumour agent N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) to murine bone marrow has been investigated. When compared with control animals, the bipotent granulocyte-macrophage colony-forming (GM-CFC) progenitor population of the hATPA/GA transduced mice were somewhat more resistant to BCNU (1.4-fold, P = 0.047) and this effect was more significant in the presence of the ATase inactivator O6-beG (3. 5-fold, P = 0.001). The polychromatic erythrocytes were also significantly protected against BCNU-induced clastogenicity both in the presence (P < 0.001) and absence of O6-beG (P < 0.05). The primitive, multipotent spleen colony-forming cells (CFU-S) in these animals also showed moderate (1.6-fold, P = 0.034) protection in the absence of O6-beG but in the presence of the inactivator they remained as sensitive to BCNU toxicity as those in the control animals (P = 0.133). This result contrasts with previous findings demonstrating significant hATPA/GA-mediated, O6-beG-resistant protection against the toxicity and clastogenicity of a number of O6-alkylating agents, including temozolomide, fotemustine and chlorozotocin. The possibility that our strategy for protective gene therapy may be highly agent and cell-type specific is unexpected and has possible implications for clinical trials of this approach using BCNU or related agents.