A cytochrome P450 2B6 meditated gene therapy strategy to enhance the effects of radiation or cyclophosphamide when combined with the bioreductive drug AQ4N

McErlane, Verna; Yakkundi, Anita; McCarthy, Helen; Hughes, Ciara; Patterson, Laurence H.; Hirst, David; Robson, Tracy; McKeown, Stephanie

doi:10.1002/jgm.728

Cited by 29 publications

(20 citation statements)

References 16 publications

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“…Then, we investigated if the delivered siHIF‐1α could suppress HIF‐1α expression under hypoxia and thereafter upregulate the contents of CYP1A1 and 2B6 (two main AQ4N activating enzymes),14 because HIF‐1α can take away the availability of HIF‐1β for AhR binding and thereafter reduce CYP450 expression (Figure 4B) 17. We assayed the expression of HIF‐1α and CYP1A1 and 2B6 using Western blot (Figure 4C–F).…”

Section: Resultsmentioning

confidence: 99%

“…Besides hypoxia, the activation of AQ4N also depends on cytochrome P450 (CYP450) activating reductases, which are also dominantly responsible for the activation of most other HAPs 13. Two main CYP450 enzymes, CYP1A1 and 2B6, are shown to metabolize AQ4N into AQ4 (a potent inhibitor of topoisomerase II) efficiently (Figure S1, Supporting Information) 14. However, O 2 blocks this activation process by outcompeting AQ4N for heme‐centered active site of CYP450, conferring the selectivity of AQ4N in eradicating hypoxic tumor cells 15…”

Section: Introductionmentioning

confidence: 99%

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A Tumor Vascular‐Targeted Interlocking Trimodal Nanosystem That Induces and Exploits Hypoxia

et al. 2018

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Vascular‐targeted photodynamic therapy (VTP) is a recently approved strategy for treating solid tumors. However, the exacerbated hypoxic stress makes tumor eradication challenging with such a single modality approach. Here, a new graphene oxide (GO)‐based nanosystem for rationally designed, interlocking trimodal cancer therapy that enables VTP using photosensitizer verteporfin (VP) (1) with codelivery of banoxantrone dihydrochloride (AQ4N) (2), a hypoxia‐activated prodrug (HAP), and HIF‐1α siRNA (siHIF‐1α) (3) is reported. The VTP‐induced aggravated hypoxia is highly favorable for AQ4N activation into AQ4 (a topoisomerase II inhibitor) for chemotherapy. However, the hypoxia‐induced HIF‐1α acts as a “hidden brake,” through downregulating CYP450 (the dominant HAP‐activating reductases), to substantially hinder AQ4N activation. siHIF‐1α is rationally adopted to suppress the HIF‐1α expression upon hypoxia and further enhance AQ4N activation. This trimodal nanosystem significantly delays the growth of PC‐3 tumors in vivo compared to the control nanoparticles carrying VP, AQ4N, or siHIF‐1α alone or their pairwise combinations. This multimodal nanoparticle design presents, the first example exploiting VTP to actively induce hypoxia for enhanced HAP activation. It is also revealed that HAP activation is still insufficient under hypoxia due to the hidden downregulation of the HAP‐activating reductases (CYP450), and this can be well overcome by GO nanoparticle‐mediated siHIF‐1α intervention.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Tumor Vascular‐Targeted Interlocking Trimodal Nanosystem That Induces and Exploits Hypoxia

et al. 2018

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“…22,23 The RIF-1 tumor is therefore appropriate for the study of AQ4N, which is activated, in hypoxic conditions, as also demonstrated in our previous studies. 18,19 RIF-1 tumor cells (2 Â 10 5 ) were implanted by intradermal injection into the rear dorsum of anesthetized 8-to -10-week-old C3H mice. Established tumors (150-225 mm 3 ) were injected intra-tumorally with 25 mg of CYP1A1/liposomal mix (Mirus polymer, TransIT s in vivo gene delivery kit; Clontech, Cambridge, UK).…”

Section: Transgene Constructsmentioning

confidence: 99%

“…Since AQ4N could only target hypoxic tumor cells, this approach was used in combination with radiation, as an oxic cell killer, as this approach was successful in our previous studies. 7,18,19 Tumor growth curves demonstrated that a single injection of the CYP1A1 transgene followed by exposure to AQ4N (100 mg/kg) and radiation (20 Gy) delayed tumor growth compared to the empty vector controls (Figure 5b). Kaplan-Meier survival curves (Figure 5a) and the mean VQT (Table 2) show that the tumors of untreated mice reached their VQT by 8.8 days.…”

Section: Cyp1a1-enhanced Tumor Growth Delay In Combination With Aq4n mentioning

confidence: 99%

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Tumor-selective drug activation: a GDEPT approach utilizing cytochrome P450 1A1 and AQ4N

et al. 2006

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Drug metabolizing transgene products, which activate bioreductive cytotoxins, can be used to target treatment-resistant hypoxic tumors. The prodrug AQ4N is bioreduced in hypoxic cells by cytochrome P450s (CYPs) to the cytotoxin AQ4. Previously we have shown that intra-tumoral injection of CYP3A4 and CYP2B6 transgenes with AQ4N and radiation inhibits tumor growth. Here we examine the ability of other CYPs, in particular CYP1A1, to metabolize AQ4N, and to enhance radiosensitization. Metabolism of AQ4N was assessed using microsomes prepared from baculovirus-infected cells transfected with various CYP isoforms. AQ4N metabolism was most efficient with CYP1A1 (66.7 nmol/min/pmol) and 2B6 (34.4 nmol/min/pmol). Transient transfection of human CYP1A17CYP reductase (CYPRED) was investigated in hypoxic RIF-1 mouse cells in vitro using the alkaline comet assay. There was a significant increase in DNA damage following transient transfection of CYP1A1 compared to non-transfected cells; inclusion of CYPRED provided no additional effect. In vivo, a single intra-tumoral injection of a CYP1A1 construct in combination with AQ4N (100 mg/kg i.p.) and 20 Gy X-rays caused a 16-day delay in tumor regrowth compared to tumors receiving AQ4N plus radiation and empty vector (P ¼ 0.0344). The results show the efficacy of a CYP1A1-mediated GDEPT strategy for bioreduction of AQ4N.

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Design of anticancer prodrugs for reductive activation

Chen

2008

Medicinal Research Reviews

209

174

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Anticancer prodrugs designed to target specifically tumor cells should increase therapeutic effectiveness and decrease systemic side effects in the treatment of cancer. Over the last 20 years, significant advances have been made in the development of anticancer prodrugs through the incorporation of triggers for reductive activation. Reductively activated prodrugs have been designed to target hypoxic tumor tissues, which are known to overexpress several endogenous reductive enzymes. In addition, exogenous reductive enzymes can be delivered to tumor cells through fusion with tumor-specific antibodies or overexpressed in tumor cells through gene delivery approaches. Many anticancer prodrugs have been designed to use both the endogenous and exogenous reductive enzymes for target-specific activation and these prodrugs often contain functional groups such as quinones, nitroaromatics, N-oxides, and metal complexes. Although no new agents have been approved for clinical use, several reductively activated prodrugs are in various stages of clinical trial. This review mainly focuses on the medicinal chemistry aspects of various classes of reductively activated prodrugs including design principles, structure-activity relationships, and mechanisms of activation and release of active drug molecules.

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A cytochrome P450 2B6 meditated gene therapy strategy to enhance the effects of radiation or cyclophosphamide when combined with the bioreductive drug AQ4N

Abstract: The results show the efficacy of a CYP2B6-mediated GDEPT strategy for bioreduction of AQ4N; this may offer an additional approach to target radiation- and chemo-resistant hypoxic tumours that should enhance overall tumour control.

Cited by 29 publications

References 16 publications

A Tumor Vascular‐Targeted Interlocking Trimodal Nanosystem That Induces and Exploits Hypoxia

A Tumor Vascular‐Targeted Interlocking Trimodal Nanosystem That Induces and Exploits Hypoxia

Tumor-selective drug activation: a GDEPT approach utilizing cytochrome P450 1A1 and AQ4N

Design of anticancer prodrugs for reductive activation

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