We investigated the DNA damage from Auger electrons emitted from incorporated stable iodine (127I), following photoelectric absorption of external x-rays. The effectiveness of the Auger electrons in producing DNA double-strand breaks (DSB) was determined theoretically, using Monte Carlo simulations of the radiation physics and chemistry, and was shown to be in reasonable agreement with DNA damage measured using the comet assay. The DSB yields were measured in CHO cells for 60Co (as a non-Auger-promoting radiation) and for tungsten-filtered 100 kVp x-rays capable of producing Auger electron emission. The theoretical study showed that on average, 2.5 Auger electrons were emitted for N-shell orbital vacancies and up to 10 Auger electrons were emitted from L1-shell vacancies. These Auger bursts produced approximately 0.03 DSB per N-shell vacancy and 0.3 DSB per K-shell or L-shell vacancy. The calculated yield of DSB from Auger cascades per unit dose (1 Gy) in water was approximately 1.7 for tungsten-filtered 100 kVp x-rays, assuming 20% IUdR substitution of thymidine. The comet assay yielded an experimental value of 3.6+/-1.6 per 1 Gy for the same conditions. The Monte Carlo simulations also demonstrated a high complexity of DSB produced by Auger cascades with virtually all DSB from inner shell orbitals (i.e. K, L shells) accompanied by compounded strand breakage and base damage, indicating a difficult lesion to repair. This finding agrees well with comet assay results of DNA repair, where an increase in the DSB yield in IUdR-sensitized cells was shown to persist after a time of 24 h. We conclude that Auger cascades in iodine produce a modest increase in the number of initial strand breaks of the order of 10% but the complex nature of these DSB makes them very difficult to repair or potentially prone to misrepair. The accentuated DNA damage may have major consequences for cell survival and may be exploitable in kilovoltage photon activation therapy (PAT) of tumors sensitized with iodine.

The synthesis, characterization and antileukemic activity of rationally designed amino dimeric naphthoquinone (BiQ) possessing aziridine as alkylating moiety is described. Bis-aziridinyl BiQ decreased proliferation of acute myeloid leukemia (AML) cell lines and primary cells from patients, and exhibited potent (nanomolar) inhibition of colony formation and overall cell survival in AML cells. Effective production of reactive oxygen species (ROS) and double stranded DNA breaks (DSB) induced by bis-aziridinyl BiQ is reported. Bis-dimethylamine BiQ, as the isostere of bis-aziridinyl BiQ but without the alkylating moiety did not show as potent anti-AML activity. Systemic administration of bis-aziridinyl BiQ was well tolerated in NSG mice.

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Background: The clinical outcomes of patients with acute myeloid leukemia (AML) remain unsatisfactory, therefore the development of more efficacious and better-tolerated therapy for AML is critical. We have previously reported the anti-leukemic activity of synthetic halohydroxyl dimeric naphthoquinones (BiQ) and aziridinyl BiQ. Objective: This study aimed to improve the potency and bioavailability of BiQ compounds and investigate the anti-leukemic activity of the lead compound in vitro and in a human AML xenograft mouse model. Methods: We designed, synthesized, and performed structure-activity relationship of several rationally designed BiQ analogues that possess amino alcohol functional groups on the naphthoquinone core rings. The compounds were screened for anti-leukemic activity and the mechanism as well as in vivo tolerability and efficacy of our lead compound was investigated. Results: We report that a dimeric naphthoquinone (designated BaltBiQ) demonstrated potent nanomolar anti-leukemic activity in AML cell lines. BaltBiQ treatment resulted in the generation of reactive oxygen species, induction of DNA damage, and inhibition of indoleamine dioxygenase 1. Although BaltBiQ was tolerated well in vivo, it did not significantly improve survival as a single agent, but in combination with the specific Bcl-2 inhibitor, Venetoclax, tumor growth was significantly inhibited compared to untreated mice. Conclusion: We synthesized a novel amino alcohol dimeric naphthoquinone, investigated its main mechanisms of action, reported its in vitro anti-AML cytotoxic activity, and showed its in vivo promising activity combined with a clinically available Bcl-2 inhibitor in a patient-derived xenograft model of AML.