Disease relevance of RSU-1069

• Unfortunately, preliminary clinical studies have revealed a dose-limiting gastrointestinal toxicity for RSU 1069 [1].
• The ability of cellular systems to repair damage induced by RSU-1069 may play a significant role in determining its efficiency to act as a hypoxic cell radiosensitizer and a hypoxia selective cytotoxin [2].
• RSU-1069 is a highly effective hypoxic cell cytotoxin in KHT sarcomas treated in vivo [3].
• At the cellular level, the cytoxicity of RSU-1069 was determined for a series of repair deficient mutants of E. coli under both aerobic and hypoxic conditions [2].
• Administration of equitoxic doses of SR-2508 (3.0 g/kg) and RSU-1069 (0.1 g/kg) also promoted metastases formation [4].

High impact information on RSU-1069

• Hoechst-labelled cells sorted from these tumours were more sensitive to killing by hypoxic cell cytotoxins (tirapazamine, RSU-1069) and less sensitive to damage by ionizing radiation [5].
• Chinese hamster V79 spheroids, exposed for 1 h to RSU 1069, were disaggregated and individual cells were analysed for DNA damage [6].
• Detection of hypoxia by measurement of DNA damage in individual cells from spheroids and murine tumours exposed to bioreductive drugs. II. RSU 1069 [6].
• The ability of the dual-function bioreductive drug, RSU 1069, to identify hypoxic cells in multicell spheroids and murine SCCVII squamous cell carcinomas was examined using the alkaline comet method [6].
• Pharmacologic/pharmacokinetic evaluation of emesis induced by analogs of RSU 1069 and its control by antiemetic agents [7].

Chemical compound and disease context of RSU-1069

• Incubation with RSU-1069 induces DNA-SSB under both hypoxic and aerobic conditions, whereas incubation with misonidazole induces DNA-SSB only under hypoxia [8].
• The results obtained show that 5-HT at a dose of 5 mg kg-1, although not cytotoxic alone, can potentiate the cytotoxic effects of RSU-1069 in the Lewis lung carcinoma over the dose range 0.01-0.15 mg g-1 [9].
• It is our contention that in air, RSU 1069 functions as a typical monofunctional alkylating agent, presumably due to the presence of the aziridine group whereas, in hypoxia, reduction of the nitro group provides an additional alkylating species, converting the compound into a bifunctional agent [10].
• Hypobaric hypoxia has been used to induce tumor hypoxia for in vivo comparison of the anti-tumor effects of the bioreductive agents SR 4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide), RSU 1069 (1(2-nitro-1-imidazolyl)-3-aziridino-2-propanol), and Nitromin (methylbis(2-chloroethyl)amine N-oxide) [11].
• Potentiation of melphalan activity in the KHT sarcoma by the radiosensitizer RSU 1069 [12].

Biological context of RSU-1069

• For equivalent levels of DNA strand breakage following such treatment it is evident from the relative transformation frequencies that interactions with reduced RSU-1069 lead to DNA damage consistent with bifunctional action of a metabolite(s) [2].
• Experimental pharmacokinetics of RSU-1069 and its analogues: high tumor/plasma ratios [13].
• Cell survival in both tumours following combined RSU-1069 and radiation (1500 or 2000 cGy) treatment was similar when the drug was given 60 min before or immediately after irradiation suggesting that the effect observed was due to hypoxic cell cytotoxicity rather than radiosensitization [14].
• Strand breakage of plasmid DNA by parent and radiation-reduced RSU-1069 (2.0-8.0 mmol dm-3) has been measured in air over 4 hr at 310K [15].
• Whereas the relative order of DNA damage was RSU 1069 greater than CB 1954 greater than misonidazole the order in inducing SOS repair was RSU 1069 greater than misonidazole greater than CB 1954 [16].

Anatomical context of RSU-1069

• The effects of three bioreductive drugs (mitomycin C, RSU-1069 and SR4233) on cell lines selected for their sensitivity to mitomycin C or ionising radiation [17].
• Toxicity of RSU 1069 toward bone marrow stem cells was also less after po administration than after ip administration; 0.1 mmol/kg ip RSU 1069 and 0.38 mmol/kg po RSU 1069 both reduced the surviving fraction of clonogenic CFU-A cells by 50% [18].
• In contrast, differential toxicities of between 3 and 30 have been observed for all CHO cells treated with RSU-1069 and SR4233 [17].
• Results using the hypoxic cell cytotoxin RSU 1069 confirmed that the extent of hypoxia was not as severe in the testis as in the SCCVII murine tumour [19].
• In one set of experiments, the bioreductive drug RSU-1069 was injected once via the portal vein with or without degradable starch microspheres (DSM) 10 mins after tumour cell inoculation [20].

Associations of RSU-1069 with other chemical compounds

• Radiation sensitization and chemopotentiation: RSU 1069, a compound more efficient than misonidazole in vitro and in vivo [21].
• Maximum potentiation occurs when 5-HT is administered after RSU-1069 [9].
• We have examined the capacity of the nitroimidazole aziridine antitumour drug RSU 1069 to react with DNA in vitro in order to get a better understanding of its mechanism of action [22].
• We have studied the pharmacokinetics and metabolism in mice of CB 1954 and RSU 1069 [23].
• Enhancement of DNA damage in mammalian cells upon bioreduction of the nitroimidazole-aziridines RSU-1069 and RSU-1131 [24].

Gene context of RSU-1069

• Both parent and reduced RSU-1069 cause single strand breaks (ssbs) in pSV2 gpt plasmid DNA with the reduced compound causing a greater number of breaks [25].
• We conclude that the repair of cellular DNA damage induced by RSU-1069 involves activation of the gene products under the control of the recA gene and not those under the control of the ada gene [2].
• Drug-induced damage by RSU 1069 involves enhanced damage by endonuclease III suggesting drug-induced pyrimidine damage [16].

Analytical, diagnostic and therapeutic context of RSU-1069

• Direct measurement of tumours was used to record growth parameters, while the comet assay with the bioreductive drug RSU 1069 was used to assess tumour cell oxygenation [26].
• Oral administration of RSU 1069 resulted in lower spermatogenic toxicity [18].
• Subsequent irradiation of cells in vitro greatly improved the distinction between aerobic and hypoxic cells from spheroids or SCCVII murine tumours exposed to RSU 1069, especially after treatment with low drug doses [6].
• The concept of potentiating bioreductive drug activity by increasing tumor hypoxia is described and illustrated in particular by the use of photodynamic therapy (PDT) in combination with RSU-1069 [27].
• The pharmacokinetics following intraperitoneal injection of three members of this series, RSU-1069, RSU-1164, and RSU-1172 have been studied in C57BL mice bearing B16 melanoma [13].

References