Recent Advances in the Biology of Heavy-Ion Cancer Therapy# Nobuyuki HAMADA1†*, Tatsuhiko IMAOKA2†, Shin-ichiro MASUNAGA3,

Heavy ions/DNA double-strand break repair/Intratumor quiescent cell population/p53/Bcl-2/Metastasis and angiogenesis /Carcinogenesis. Superb biological effectiveness and dose conformity represent a rationale for heavy-ion therapy, which has thus far achieved good cancer controllability while sparing critical normal organs. Immediately after irra-diation, heavy ions produce dense ionization along their trajectories, cause irreparable clustered DNA damage, and alter cellular ultrastructure. These ions, as a consequence, inactivate cells more effectively with less cell-cycle and oxygen dependence than conventional photons. The modes of heavy ion–induced cell death/ inactivation include apoptosis, necrosis, autophagy, premature senescence, accelerated differentiation, delayed reproductive death of progeny cells, and bystander cell death. This paper briefly reviews the current knowl-edge of the biological aspects of heavy-ion therapy, with emphasis on the authors ’ recent findings. The topics include (i) repair mechanisms of heavy ion–induced DNA damage, (ii) superior effects of heavy ions on radioresistant tumor cells (intratumor quiescent cell population, TP53-mutated and BCL2-overexpressing tumors), (iii) novel capacity of heavy ions in suppressing cancer metastasis and neoangiogenesis, and (iv) potential of heavy ions to induce secondary (especially breast) cancer. 1