**2.2 Enhancing radiation therapy with radiosensitizers**

Radiosensitizing agents are molecules that enhance the dose of ionizing radiation delivered to a patient's tumor. The optimal clinical radiosensitizer (a) lowers the required dose of ionizing radiation, (b) increases its antitumor effect, and


*List of commonly used radiosensitizing methods/agents for combination with radiotherapy in various tumor types. The last four are emboldened to denote their current use in ongoing clinical trials.*

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ionizing radiation.

*NQO1-Bioactivatable Therapeutics as Radiosensitizers for Cancer Treatment*

(c) synergistically kills cancer cells. To date, no radiosensitizer has met these demands. Many radiosensitizers have been used clinically (**Table 1**, normal text) with limited success, or are currently in clinical trial (**Table 1**, bold text). These include suppressors of radioprotectors (e.g., thiol) [4], molecules releasing cytotoxic substances when radiolyzed [5], thymine/cytidine analogs [6], oxygen mimic

In the late 1980s, our laboratory began searching for DNA repair modulators that synergize with ionizing radiation to kill cancer cells more effectively. The goal was to thwart cancer cells' ability to repair IR damage, to avoid the survival of IR-resistant malignant cells that have undergone potentially lethal damage repair (PLDR). One of those compounds was (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-

We found that just four micromolar β-lapachone inhibited single-strand DNA break repair in cancer cells exposed to DNA-damaging agent methyl methane sulfonate [9, 10], killing 99% of cells at an exposure time 90–120 min [11].

Additionally, we found that combining β-lapachone with ionizing radiation in Hep2 cells increased double-strand breaks and dramatically lowered the dose of radiation required for cell death, highlighting β-lapachone as a potent radiosensitizer [12]. In the 1990s and early 2000s, we conducted subtraction-hybridization screening to isolate X-ray inducible genes to investigate ionizing radiation resistance and found Xip3, also known as NQO1 [13]. Dicoumarol, an NQO1 inhibitor, specifically blocked β-lapachone's toxicity, indicating that the radiosensitizer may be bioactivated by this enzyme. As NQO1 is specifically expressed in tumor cells, this indicated a promising use of β-lapachone as a cancer therapeutic with or without

NQO1 is a Phase II detoxification enzyme that reduces ROS levels in cancer cells. NQO1 converts quinones into stable intermediate hydroquinones that are exported out of the cell by conjugation [10]. Most solid cancers, including non-small cell lung and pancreatic cancers (>85%), prostate, colon, and breast cancers (60%) and head and neck cancers (40%) overexpress NQO1 5- to 200- fold above normal tissue. Corresponding levels of catalase in these cancers were strikingly reduced, impacting the ability of cancer cells to eliminate ROS [14]. Overexpression of NQO1 appears to

Though NQO1 detoxifies most quinones through two-electron oxidoreduction, a few quinones undergo a rapid futile redox cycle response, generating an unstable intermediate hydroquinone that spontaneously reverts back to its original form using two oxygenation steps and creating two superoxides. Deoxynyboquiones (DNQ ), KP372 agents, and β-lapachone are three classes of NQO1-bioactivatable drugs currently known [16]. Recently, Napabucasin, an orphan drug in clinical trials for pancreatic and cervical cancer, has also been reported to be bioactivated by NQO1 [17]. Though mitomycin C and streptonigrin are metabolized by NQO1,

**4. Mechanism of action for NQO1-bioactivatable therapies**

**4.1 NQO1 vs. catalase ratio and specificity**

stabilize HIF-1alpha and promotes metastasis [15].

*DOI: http://dx.doi.org/10.5772/intechopen.90205*

sensitizers [7], and DNA repair inhibitors [8].

**3. β-Lapachone, a DNA repair inhibitor**

b]pyran-5,6-dione), also known as β-lapachone [9].

**3.1 Initial discovery of β-lapachone's effect on DNA repair**

#### **Table 1.** *Clinical radiosensitizers.*

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(c) synergistically kills cancer cells. To date, no radiosensitizer has met these demands. Many radiosensitizers have been used clinically (**Table 1**, normal text) with limited success, or are currently in clinical trial (**Table 1**, bold text). These include suppressors of radioprotectors (e.g., thiol) [4], molecules releasing cytotoxic substances when radiolyzed [5], thymine/cytidine analogs [6], oxygen mimic sensitizers [7], and DNA repair inhibitors [8].
