title: Pharmacological activities of spirogermanium and other structurally related azaspiranes: effects on tumor cell and macrophage functions.
abstract: Spirogermanium is a germanium containing azaspirane which has been shown to have activity in experimental models of cancer and immune dysfunction. A series of analogs of the parent compound were synthesized and evaluated in a number of in vitro and in vivo biological assays to define the structure-activity relationships of this class of compounds relative to their potential therapeutic activities. In a colony-forming assay using HT-29 human colon carcinoma cells various analogs in which carbon replaced germanium (e.g. carbon) retained the potent cytotoxic activity in vitro seen with spirogermanium. Increased cytotoxic potency within the group of carbon containing analogs was directly related to increase in the length of the alkyl group(s) attached to the carbon atom opposite the azaspirane ring structure. DNA and protein synthesis by HT-29 cells was inhibited by these compounds. However, inhibition occurred only at supralethal concentrations or after long exposure times with the drug. None of the azaspiranes demonstrated in vivo anti-tumor activity against P388 leukemia or ADJ-PC6 plasmacytoma. The effect of these compounds on macrophage cell function was evaluated in vitro by their ability to modulate superoxide (O2-) production by macrophages. Spirogermanium inhibited the production of O2- by activated macrophages with an IC50 of 5 microM. Although macrophage viability did not appear to be decreased at the respective IC50 concentrations, the rank order potency for the analogs in the O2- production assay was directly proportional to that measured for their cytotoxic potency in the HT-29 colony formation assay. The results demonstrate that, within this class of compounds, (1) potent biological activity does not require the presence of germanium in the structure; (2) in vitro cytotoxic activity does not appear to be a direct result of the inhibition of macromolecular synthesis, and (3) macrophage function can be modulated in vitro at non-cytotoxic concentrations. These results are discussed in context with the reported anti-tumor activity of spirogermanium and the potential anti-arthritic and immunomodulatory activity of this class of compounds.
authors.affiliation: Department of Molecular Pharmacology, Smith Kline & French Laboratories, King of Prussia, PA 19406-0939.
authors.forename: C K
authors.initials: CK
authors.lastname: Mirabelli
authors.forename: A M
authors.initials: AM
authors.lastname: Badger
authors.forename: C P
authors.initials: CP
authors.lastname: Sung
authors.forename: L
authors.initials: L
authors.lastname: Hillegass
authors.forename: C M
authors.initials: CM
authors.lastname: Sung
authors.forename: R K
authors.initials: RK
authors.lastname: Johnson
authors.forename: D
authors.initials: D
authors.lastname: Picker
authors.forename: D
authors.initials: D
authors.lastname: Schwartz
authors.forename: J
authors.initials: J
authors.lastname: Dorman
authors.forename: S
authors.initials: S
authors.lastname: Martellucci
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D002277:Carcinoma / Q000188:drug therapy; D003110:Colonic Neoplasms / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009942:Organometallic Compounds / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D010954:Plasmacytoma / Q000188:drug therapy; D013141:Spiro Compounds / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D013141:Spiro Compounds; C026818:spirogermanium