Increasing DNA repair capacity in bone marrow by gene transfer as a prospective tool in cancer therapy.
Resistance of tumor cells to alkylating anticancer agents that produce adducts at the O6 position of guanine in DNA, the O6-alkylating agents, correlates with the expression of O6-alkylguanine-DNA alkyltransferase (ATase). O6-benzylguanine and related pseudosubstrates are able to inactivate human ATase in vitro and in vivo and they are being tested as chemotherapeutic adjuvants for enhancing the effectiveness of O6-alkylating drugs. On the other hand, the clinical consequences of ATase depletion may be fatal for some sensitive systems e.g. hematopoiesis. To overcome this problem, strategies for the protection of primary bone marrow cells by targeted transfer of pseudosubstrate-resistant ATase genes have been considered and recently achieved at the laboratory level. This approach could therefore be now extended to a clinical cancer gene therapy program.
Kleibl
K
K
Cancer Research Institute, Slovak Academy of Sciences, Bratislava.
Margison
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GP
D000478:Alkylation; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology* / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D018736:DNA Adducts; D004249:DNA Damage; D004260:DNA Repair; D004351:Drug Resistance / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D018390:Gene Targeting; D018014:Gene Transfer Techniques; D006147:Guanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000201:enzymology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000628:therapy*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; C064976:O(6)-benzylguanine; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase