Comparison of hypoxia-activated prodrug evofosfamide (TH-302) and ifosfamide in preclinical non-small cell lung cancer models

Abstract

Evofosfamide (TH-302) is a hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide. In hypoxic conditions Br-IPM is released and alkylates DNA. Ifosfamide is a chloro-isophosphoramide prodrug activated by hepatic Cytochrome P450 enzymes. Both compounds are used for the treatment of cancer. Ifosfamide has been approved by the FDA while evofosfamide is currently in the late stage of clinical development. The purpose of this study is to compare efficacy and safety profile of evofosfamide and ifosfamide in preclinical non-small cell lung cancer H460 xenograft models. Immunocompetent CD-1 mice and H460 tumor-bearing immunocompromised nude mice were used to investigate the safety profile. The efficacy of evofosfamide or ifosfamide, alone, and in combination with docetaxel or sunitinib was compared in ectopic and intrapleural othortopic H460 xenograft models in animals exposed to ambient air or different oxygen concentration breathing conditions. At an equal body weight loss level, evofosfamide showed greater or comparable efficacy in both ectopic and orthotopic H460 xenograft models. Evofosfamide, but not ifosfamide, exhibited controlled oxygen concentration breathing condition-dependent antitumor activity. However, at an equal body weight loss level, ifosfamide yielded severe hematologic toxicity when compared to evofosfamide, both in monotherapy and in combination with docetaxel. At an equal hematoxicity level, evofosfamide showed superior antitumor activity. These results indicate that evofosfamide shows superior or comparable efficacy and a favorable safety profile when compared to ifosfamide in preclinical human lung carcinoma models. This finding is consistent with multiple clinical trials of evofosfamide as a single agent, or in combination therapy, which demonstrated both anti-tumor activity and safety profile without severe myelosuppression.Abbreviations: BW, body weight; Br-IPM, a brominated analog of isophosphoramide mustard; CAA, chloroacetalde-

Blackboard to Bedside: A Mathematical Modeling Bottom-Up Approach Toward Personalized Cancer Treatments

“…48,56,58 It is difficult to study these effects independently of direct effects, and, moreover, mediators and targets for bystander signals are poorly understood even after several experimental studies. 49,57,[59][60][61][62][63][64] Recently, several modeling attempts have been made to study and understand radiation bystander effects. 65,66 In one of these attempts, Powathil et al 66 used a multiscale mathematical modeling framework (Fig 2) to study the impact of radiation and radiation-induced bystander effects on both normal and tumor cells.…”

“…52 HAPs comprise bioreductive prodrugs that reduce to active cytotoxins upon reaching hypoxic regions. 64,71,72 Because tumors, as a rule, express levels of hypoxia of higher severity than do other relevant tissues in the host system, tumors can be targeted. HAPs may thus operate as trojan horses, which are essentially harmless until they are converted in targets-in other words, hypoxic tumors regions.…”

Combining hypoxia-activated prodrugs and radiotherapy in silico: Impact of treatment scheduling and the intra-tumoural oxygen landscape

“…Anticancer prodrugs constitute relatively harmless compounds in their inactivated form with the potential to bioreduce, or transform, into cytotoxic species [21]. Specifically for HAPs, this bioreduction occurs in hypoxic conditions and thus HAPs are able to selectively target hypoxic tumour regions [21]. The oxygen dependent bioreduction is here modelled by the function…”

“…HAPs transform into activated drugs (AHAPs) via reductive metabolism [15,3] in sufficiently hypoxic environments, and the AHAPs can achieve cytotoxic effects in cells [21]. Freely available molecular oxygen may inhibit this bioreduction, and thus HAPs remain (for the most part) more intact, and by extension less toxic, in well-oxygenated environments [14].…”

“…TH-302 bioreduces to its activated form, bromo-isophosphoramide mustard (Br-IPM), in hypoxic tumour regions, and Br-IPM is a DNA-crosslinking agent [22]. Multiple in vitro and in vivo studies have validated this drug's preclincal success and, by extension, its clinical feasibility [13,24,25,26,6,7,18,27,9,21,10,28]. Multimodality treatment strategies combining HAPs, particularly Class II HAPs, with ionising radiation (IR) may be particularly promising [29,8,9,27,28] as the two therapies conceptually complement each other: HAPs target hypoxic tumour regions whilst radiotherapy is most effective against well oxygenated tumour regions.…”