title: Synergistic enhancement of the efficacy of the bioreductively activated alkylating agent RSU-1164 in the treatment of prostatic cancer by photodynamic therapy.
abstract: Bioreductively activated alkylating agents (BAA) require metabolic reduction to become cytotoxic. Hypoxia induces a massive increase in reductive metabolism activating BAA to their cytotoxic form. One of these BAA agents is cis-2,3-dimethyl 1-(2-nitro-1-imidazolyl)-3-(1-aziridinyl)-2-propanol referred to as RSU-1164. In a hypoxic environment, RSU-1164 is activated to a highly reactive bifunctional alkylating agent capable of crosslinking macromolecules which results in cell death. Photodynamic therapy (PDT) is a treatment modality which consists of the initial accumulation of hematoporphyrin derivative (HPD) within a tumor followed by the activation of the HPD by 630 nm. light to induce a cytotoxic response. The precise mechanism of PDT is not known, however, two actions of the activated HPD have been documented. The first is a direct cytotoxic effect, secondary to singlet oxygen production. The second is through vascular collapse and subsequent hypoxia. The combination of a chemotherapeutic agent like RSU-1164, which is activated by hypoxia, with PDT to produce such hypoxia, therefore, should greatly increase the efficiency and utility of RSU-1164. To test this hypothesis, Copenhagen rats bearing established Dunning R-3327 AT-2 prostate cancers were treated with PDT treatment alone (HPD 20 mg./kg. injected IP and then 24 hr. later, the tumor exposed to 630 nm. light at 400 mW/cm.2 for 30 min. [total dose 720 J/cm.2]), RSU-1164 alone (injected IP at a dose of 200 mg./kg.) or with the combination of this PDT treatment plus RSU-1164 given 30 min. before light exposure. These results demonstrated that this combinational treatment synergistically produces a greater retardation in the growth of the AT-2 tumor than either of the monotherapies of RSU-1164 or PDT alone.
authors.affiliation: Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: J M
authors.initials: JM
authors.lastname: Henry
authors.forename: J T
authors.initials: JT
authors.lastname: Isaacs
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D004305:Dose-Response Relationship, Drug; D008297:Male; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010778:Photochemotherapy; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D051381:Rats; D014410:Tumor Stem Cell Assay
chemical_list: C049944:1-(2-nitro-1-imidazoly)-3-(2,3-dimethylaziridino)-2-propanol; D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D008920:Misonidazole