Spirohydantoin mustard (SHM) has reported activity against the murine intracerebral ependymoblastoma and is currently in Phase I clinical trials. SHM is metabolized in vitro by mouse liver mixed function oxidases (MFO) to monodechloroethyl-SHM and spirohydantoin aziridine (SHAZ). Both metabolites possess alkylating and mutagenic activity and may, therefore act as mediators of SHM antitumor activity. Consequently, the objective of the proposed research is to investigate the significance of the metabolites of SHM to the mechanism of action of the drug against the murine intracerebral ependymoblastoma. The following studies are proposed using the murine intracerebral ependymoblastoma tumor model and established methodologies: (1) chemical synthesis of SHM, monodechloroethyl-SHM, and SHAZ (H3-labeled and unlabeled); (2) the effect of pretreatment with phenobarbital, an MFO inducer, or SKF 525A, and MFO inhibitor, on the antitumor activity of SHM; (3) correlation of the antitumor effect of the above pretreatments with the disposition of SHM and metabolites in serum, brain, and tumor (TLC, radioassay), and also with the macromolecular binding (protein, RNA DNA) of the H3-label in brain and tumor, as a function of dose of H3-SHM; (4) a comparison of the antitumor activity of monodechloreothyl-SHM and SHAZ with that of SHM as a means of assessing the relative contribution of each metabolite to the antitumor activity of SHM; (5) a comparison of the disposition of monodechloroethyl-SHM and SHAZ with that of SHM in serum, brain, and tumor, and also macromolecular binding (protein, RNA, DNA) in brain and tumor, as a function of dose of H3-SHM, H3-monodechloreothyl-SHM, or H3-SHAZ. The objective of the latter study is to correlate tumor versus brain tissue specificity of the three drugs with therapeutic specificity. The proposed studies address basic pharmacologic and biochemical questions which are important in gaining a better understanding of the mechanism of action of SHM and the design of second generation agents with improved activity.
| Struck, R F; Kirk, M C; Rice, L S et al. (1986) Isolation, synthesis, and antitumor evaluation of spirohydantoin aziridine, a mutagenic metabolite of spirohydantoin mustard. J Med Chem 29:1319-21 |
