RSU 1069, a nitroimidazole containing an aziridine group

Stratford, Ian J.; O’Neill, Peter; Sheldon, P.W.; Silver, Andrew; Walling, Jacqueline M.; Adams, G. E.

doi:10.1016/0006-2952(86)90566-6

Cited by 97 publications

(4 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An example is RSU1069 (34, Fig. 10), [163][164][165] which contains an aziridine moiety on the N1 side chain of the nitroimidazole core and acts as weak monofunctional alkylating agent. In light of the promising in vitro and in vivo results obtained in combination with RT, 166 compound 34 was evaluated clinically in 1985.…”

Section: Nitroaromatic Subunits As Integral Components Of Hypoxia-actmentioning

confidence: 99%

Hypoxia-targeted drug delivery

Sharma¹,

Arambula

Koo³

et al. 2019

Chem. Soc. Rev.

414

287

View full text Add to dashboard Cite

show abstract

Section: Nitroaromatic Subunits As Integral Components Of Hypoxia-actmentioning

confidence: 99%

Hypoxia-targeted drug delivery

Sharma¹,

Arambula

Koo³

et al. 2019

Chem. Soc. Rev.

414

287

View full text Add to dashboard Cite

show abstract

“…However, these nitroaromatic hypoxic cell radiosensitizers were only weakly cytotoxic, having only moderate (about ten-fold) selective toxicity for hypoxic cells over oxygenated cells (Sutherland et al, 1982). Subsequent drug development around the nitroimidazole platform led to the first agent, RSU1069, with marked enhancement in hypoxia selectivity (Stratford et al, 1986). Two other promising nitro compounds are the bioreductive prodrugs PR-104 and TH-302.…”

Section: 0 the Tumor Microenvironment As A Double Edged Swordmentioning

confidence: 99%

Modulation of the tumor vasculature and oxygenation to improve therapy

Siemann

Horsman

2015

Pharmacology & Therapeutics

126

107

View full text Add to dashboard Cite

The tumor microenvironment is increasingly recognized as a major factor influencing the success of therapeutic treatments and has become a key focus for cancer research. The progressive growth of a tumor results in an inability of normal tissue blood vessels to oxygenate and provide sufficient nutritional support to tumor cells. As a consequence the expanding neoplastic cell population initiates its own vascular network which is both structurally and functionally abnormal. This aberrant vasculature impacts all aspects of the tumor microenvironment including the cells, extracellular matrix, and extracellular molecules which together are essential for the initiation, progression and spread of tumor cells. The physical conditions that arise are imposing and manifold, and include elevated interstitial pressure, localized extracellular acidity, and regions of oxygen and nutrient deprivation. No less important are the functional consequences experienced by the tumor cells residing in such environments: adaptation to hypoxia, cell quiescence, modulation of transporters and critical signaling molecules, immune escape, and enhanced metastatic potential. Together these factors lead to therapeutic barriers that create a significant hindrance to the control of cancers by conventional anticancer therapies. However, the aberrant nature of the tumor microenvironments also offers unique therapeutic opportunities. Particularly interventions that seek to improve tumor physiology and alleviate tumor hypoxia will selectively impair the neoplastic cell populations residing in these environments. Ultimately, by combining such therapeutic strategies with conventional anticancer treatments it may be possible to bring cancer growth, invasion, and metastasis to a halt.

show abstract

“…Subsequent drug development around the nitroimidazole platform led to the first agent, RSU1069, which had the classic 2-nitroimidazole radiosensitising properties, but also an aziridine ring at the terminal end of the chain to give the molecule substantial potency as a hypoxic cell cytotoxin. Despite substantial activity against hypoxic cells in vitro and anti-tumour activity in vivo [166], the early clinical studies indicated doselimiting gastrointestinal toxicity. The less toxic pro-drug, RB 6145, which was reduced to RSU1069 in vivo, was developed.…”

Section: Hypoxia-activated Prodrugsmentioning

confidence: 99%

Therapeutic Modification of Hypoxia

et al. 2021

View full text Add to dashboard Cite

Regions of reduced oxygenation (hypoxia) are a characteristic feature of virtually all animal and human solid tumours. Numerous preclinical studies, both in vitro and in vivo, have shown that decreasing oxygen concentration induces resistance to radiation. Importantly, hypoxia in human tumours is a negative indicator of radiotherapy outcome. Hypoxia also contributes to resistance to other cancer therapeutics, including immunotherapy, and increases malignant progression as well as cancer cell dissemination. Consequently, substantial effort has been made to detect hypoxia in human tumours and identify realistic approaches to overcome hypoxia and improve cancer therapy outcomes. Hypoxia-targeting strategies include improving oxygen availability, sensitising hypoxic cells to radiation, preferentially killing these cells, locating the hypoxic regions in tumours and increasing the radiation dose to those areas, or applying high energy transfer radiation, which is less affected by hypoxia. Despite numerous clinical studies with each of these hypoxia-modifying approaches, many of which improved both local tumour control and overall survival, hypoxic modification has not been established in routine clinical practice. Here we review the background and significance of hypoxia, how it can be imaged clinically and focus on the various hypoxia-modifying techniques that have undergone, or are currently in, clinical evaluation.

show abstract

RSU 1069, a nitroimidazole containing an aziridine group

Cited by 97 publications

References 18 publications

Hypoxia-targeted drug delivery

Hypoxia-targeted drug delivery

Modulation of the tumor vasculature and oxygenation to improve therapy

Therapeutic Modification of Hypoxia

Contact Info

Product

Resources

About