**5.1 Advantages of NQO1-bioactivatable drugs vs. other radiosensitizers**

The major advantage of using NQO1-bioactivatable drugs as radiosensitizers is the tumor selectivity afforded by the drugs themselves. Synergy is afforded by a number of tumor-selective responses to the drugs. First, the dependence of the drugs on NQO1 levels is perfect for the specific treatment of various difficult-totreat human cancers, including non-small cell lung, pancreatic, breast, prostate, and head and neck cancers. Tumor selectivity requires approximately 100 units of enzyme activity, whereas lower levels of NQO1 results in mild metabolomic alterations used for the treatment of metabolic syndromes [34]. Second, the minimum time of exposure of 30–120 min fits the pharmacokinetics of the drug. It should be noted that all studies thus far indicate that the drugs have to be available immediately after or at the same time as exposure with IR. Pre-treatment prior to IR is ineffective. Third, synergy between NQO1-bioactivatable drugs and IR occurs due to PARP1 hyperactivation causing massive NAD+ and ATP loss, preventing repair of the DNA damage created by IR. NQO1-bioactivatable drugs are highly specific to tumors, causing little normal tissue toxicity, which is unaffected by IR treatment [14, 16, 20, 25, 31]. Preclinical in vivo data suggest that radiosensitization trials with NQO1-bioactivatable drugs are warranted for non-small cell lung, pancreatic, breast prostate, and head and neck cancers.

#### **5.2 Future directions for NQO1-bioactivatable drugs**

A clinical trial of radiation sensitization effects of the new drug, isobutyldeoxynyboquione (IB-DNQ ), against non-small cell lung (NSCLC) and/or pancreatic adenocarcinomas (PDAC) is warranted. These cancers are almost uniformly NOQ1 over-expressive and they have routinely low levels of catalase [14]. We have developed CLIA assessments of NQO1 status and enzymatic levels for these studies. The pharmacokinetics of IB-DNQ in these cancers, particularly in NSCLC and PDAC cancers, is relatively short at about 6 h, but long enough for sensitization of tumors to the NQO1-bioactivatable drug + IR. Biomarker and DSB repair kinetics are ongoing in our laboratory in preparation for these radiosensitization studies.
