[Mechanism of occurrence of secondary tumors by antitumor drugs].
Due to the innovations in various aspects of cancer therapy, the time has come when more than half of cancer patients survive 5 years. However, secondary cancer, especially leukemias arising among the survivors and threatening their lives, has become a serious problem. In the present paper I focus on chemotherapeutics, especially DNA topoisomerase II inhibitors such as etoposide and adriamycin, presumed to be the causative agents, and their mode of intervention in the catalytic action of this enzyme. I describe the molecular basis of chromosomal translocations inherent in therapy-related secondary leukemias, and present a hypothesis for the molecular mechanism underlying the occurrence of the disease; namely, that poison-type topoisomerase II inhibitors stabilize the reaction intermediate covalent enzyme-DNA cleavage complexes, called "cleavable complexes," which in turn trigger the mobilization of various DNA damage repair and recombination systems to cope with the damage. The recombinant which acquires a growth advantage over others then overproliferates to become the leukemogenic population.
Andoh
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Dept. of Bioengineering, Soka University Faculty of Engineering, Tokyo, Japan.
D000970:Antineoplastic Agents / Q000009:adverse effects*; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects; D004260:DNA Repair; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000235:genetics; D004317:Doxorubicin / Q000009:adverse effects*; D005047:Etoposide / Q000009:adverse effects*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007938:Leukemia / Q000209:etiology* / Q000235:genetics; D051788:Myeloid-Lymphoid Leukemia Protein; D016609:Neoplasms, Second Primary / Q000209:etiology* / Q000235:genetics; D011519:Proto-Oncogenes; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; D014178:Translocation, Genetic
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D005047:Etoposide; D004317:Doxorubicin; D011495:Histone-Lysine N-Methyltransferase; D004250:DNA Topoisomerases, Type II