Improving radiation therapy efficacy considering DNA repair, TP53 mutations, microscopic heterogeneity, and low- and high-dose apoptosis

All radiation types produce δ -rays of about a ≈1 keV or less that can impart MGy doses to 10-nm-size volumes of DNA. These events can produce severe dual double-strand breaks (DDSB) at the periphery of nucleosomes in single events particularly in heterochromatic DNA. These DDSBs are the most common multiply damaged sites, and their probabilities generally determine the biological effectiveness and therapeutic responses. The recent understanding that most normal tissues with intact TP53 genes generally are low-dose hypersensitive (LDHS) and low-dose apoptotic (LDA) implies that the well-known universal clinical fractionation window at ≈2 Gy/Fr defines the optimal tolerance level of most organs at risk and not the optimal tumor dose per fraction at least when using intensity-modulated radiation therapy (IMRT). Interestingly, practically all cancer cells are linked to genomic instability in some DNA repair, cell cycle, or growth control genes like TP53 that is affected in more than 50% of all tumors. Unfortunately, this often gives tumor cells a low-dose radiation-resistant (LDRR) phenotype. The fractionation window is due to the low-dose and linear energy transfer (<i>LET</i>) initiation of full DNA repair capability after ≈½ Gy or 18 DSB, and we should use this acquired repair advantage in normal tissues to its full extent up to ≈2.3 Gy where the high-dose apoptosis (HDA) starts to set in. Understanding quantum biological cure implies that light ions should truly have the lowest possible <i>LET</i> in normal tissues to retain the classical fractionation window but have a high <i>LET</i> only in the gross tumor region. Carbon ion therapy substantially benefits from the last ≈10 GyE of the treatment being delivered by low <i>LET</i> (electrons or photons) to minimize normal tissue damage, get a steepest possible dose response, and maximize complication-free cure. Interestingly, this also necessitates the use of the lightest ions with a low <i>LET</i> in normal tissues, allowing quantum biology-optimized molecular radiation therapy with He-Li-B ions, with minimal adverse therapeutic effect in normal tissues and the highest possible apoptosis, senescence, and cell kill in the tumor!