Disease relevance of SR 2508

• Addition of misonidazole, etanidazole, or hyperthermia to treatment with fluosol-DA/carbogen/radiation [1].
• Complete pharmacological data from 71 patients treated on the phase I trial of SR 2508 were analyzed to see if the dose-limiting toxicity of peripheral neuropathy is related to the individual patient's pharmacokinetic profile [2].
• Somewhat unexpectedly, reversible grade 4 granulocytopenia was the dose-limiting toxicity occurring in four of five evaluable first combination courses at level 6 (SR-2508, 11.3 g/m2; CP, 1.0 g/m2), the initial maximum tolerated dose [3].
• Fluorinated derivatives of etanidazole are being explored as probes for tumor hypoxia [4].
• METHODS AND MATERIALS: Eighteen patients with brainstem glioma were treated with etanidazole and HRT on a dose escalation protocol (Phase I trial) between 1990 and 1996 [5].

High impact information on SR 2508

• Clinical pharmacokinetics of cyclophosphamide and metabolites with and without SR-2508 [6].
• A pentafluorinated derivative [EF5; 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetam ide] of etanidazole was synthesized with the expectation of lessening some of the non-oxygen-dependent variability in adduct formation observed previously with other nitroaromatic compounds [7].
• A phase I trial was carried out to assess toxicity and possible pharmacological interactions of the combination of short infusions of SR-2508 and cyclophosphamide (CP) [3].
• A phase I study of SR-2508 and cyclophosphamide administered by intravenous injection [3].
• Only four treatments were more toxic to dim cells: mitomycin C (3.5-fold), misonidazole (1.5-fold), etanidazole (3.5-fold), and 43 degrees C, 30 min local hyperthermia (2.6-fold) [8].

Chemical compound and disease context of SR 2508

• Four patients experienced the expected acute syndrome related to Ro 03-8799, but the incidence was not increased by escalating doses of SR-2508, and no peripheral neuropathy was seen [9].
• As predicted from the low partition coefficient, lower drug levels in neural tissue and more rapid serum elimination of RP-170 and etanidazole produced lower acute toxicity than lipophilic sensitizers (e.g., misonidazole) [10].
• The two current second generation radiosensitizers SR-2508 (etanidazole) and Ro 03-8799 (pimonidazole) have different dose-limiting toxicities in humans [11].
• The acute toxicity measured as the LD50/7 in 8-week-old female C3H/HeJ mice was found to be 2.4 g/kg (intravenously), 2.1 g/kg (intraperitonealy), and 4.25 g/kg (orally) for KU-2285, whereas it was 4.75 g/kg (intravenously) for etanidazole [12].
• CONCLUSIONS: This extremely high ratio of RP-343 could explain its lower toxicity than RP-170 or etanidazole [13].

Biological context of SR 2508

• SR-2508 exhibited linear pharmacokinetics over the dose range studied [3].
• Drug exposure [area under the curve (AUC)] for a single treatment was calculated by the integral over time of the serum concentration of SR 2508 [2].
• The maximum tolerated dose of the combination was determined by dose escalation of SR-2508 while the dose of CP remained fixed, initially 1.0 g/m2, and then a second maximum tolerated dose was determined with CP at 1.6 g/m2 [3].
• RESULTS: Etanidazole (10 mM) induced apoptosis in EL4 cells [14].
• When both drugs were given together in equitoxic proportions, the LD50/2 was 0.45 mg of Ro 03-8799 plus 2.9 mg of SR-2508/gbw [15].

Anatomical context of SR 2508

• However, MISO, SR-2508 and Ro-03-8799 were less effective in this cell line than in V79 cells, presumably due to higher GSH content of the A549 cells [16].
• Vitamin E succinate also protected spinal cord cultures from etanidazole-induced neuronal loss [14].
• Sensitizer enhancement ratios (SER) for a range of SR-2508 concentrations were determined for human tumor cell lines varying in inherent GSH levels [17].
• In CHO cells exposed to SR-2508 under hypoxic conditions, this unstable GSH conjugate has been detected and suggests the possibility of GSH functioning as a carrier of a toxic metabolite of 2-nitroimidazoles under certain conditions [18].
• Ro 03-8799 produces an acute, transient central nervous system syndrome, whereas SR 2508 causes cumulative, peripheral neurotoxicity; both effects are dose-limiting [19].

Associations of SR 2508 with other chemical compounds

• Dose escalation of the hypoxic cell sensitizer etanidazole combined with ifosfamide, carboplatin, etoposide, and autologous hematopoietic stem cell support [20].
• Radiosensitization by the combination of etanidazole (SR-2508) and pimonidazole (Ro 03-8799) in human tumor xenografts [11].
• RESULTS: In the cytokinesis-block micronucleus assay, the sensitizer enhancement ratio (SER) for KU-2285 and SR-2508 was 1.43 and 1.17 at 0.05 mM, 1.75 and 1.27 at 0.10 mM, and 2.14 and 1.69 at 0.25 mM, respectively [21].
• In contrast to etanidazole, in which the administration route is limited to intravenous injection, with RP-170 oral administration also exhibited effective distribution to tumors, sensitizing radiation activity to solid EMT6 and SCC VII tumors [10].
• Incubation of Chinese hamster ovary cells with etanidazole under hypoxic conditions increases cell killing by subsequent treatment with melphalan under aerobic conditions [22].

Gene context of SR 2508

• PEG modulated release of etanidazole from implantable PLGA/PDLA discs [23].
• BSO increased the maximum SER for SR 2508 (3 mM/fraction) from 1.2 to 1.4 in the RIF tumor, and from 1.4 to 1.8 in the MCA tumor [24].
• However, the combination of BSO and SR-2508 in hypoxic cells resulted in SSB and DSB comparable to oxic irradiation [25].
• SR2508 (etanidazole) pharmacokinetics and biochemical effects in tumor and normal tissues of scid mice bearing HT-29 human colon adenocarcinoma [26].
• Planned doses of etanidazole were 1.8 g/m(2) x 17 doses (30.6 g/m(2)) at Step 1 to a maximum of 2.4 g/m(2) x 21 doses (50.4 g/m(2)) at Step 8 [5].

Analytical, diagnostic and therapeutic context of SR 2508

• An interim analysis showed that 27% of the patients assigned to radiotherapy plus etanidazole are receiving less than 14 doses of the drug [27].
• METHODS AND MATERIALS: Thirty-two previously untreated patients with locally advanced esophageal cancer were entered on a Phase I study of etanidazole combined with radiation therapy and chemotherapy [28].
• Seventy-eight patients have been treated on a Phase I trial using continuous infusion etanidazole while undergoing brachytherapy for locally advanced tumors [29].
• Etanidazole was given via intravenous infusion over 15 minutes, followed within 20 to 30 minutes by intraoperative radiation therapy [30].
• The 2-year actuarial loco-regional control rates were 53% in the Etanidazole group and 53% in the control group (p = 0.93), and the overall 2-year survival rates were 54% in each group (p = 0.99) [31].

References