We describe the discovery of a novel series of anticancer adamantane derivatives which induce G1 arrest in Colo 205 and HT 29 colon cancer cells. Seven adamantane derivatives were screened for their activity in vitro against 60 human cancer cell lines in the National Cancer Institute (NCI)'s Anticancer Drug Screen system. The relationships between structure and in vitro anticancer activity are discussed. 1,3-Bis(4-(4-amino-3-hydroxyphenoxy)phenyl)adamantane (1,3-DPA/OH/NH2) and 2,2-bis(4-(4-amino-3-hydroxyphenoxy)phenyl)adamantane (DPA) exhibited strong growth inhibitory on anticancer activities in vitro. The IC50s of 1,3-DPA/OH/NH2 (NSC-706835) and DPA (NSC-706832) were found to be < 3 microM against 45 (85%) and 48 (91%) cell lines, respectively. 2,2-Substituted adamantane derivatives exhibited stronger growth inhibition on anticancer activities in vitro than the corresponding 1,3-substituted analogs. Very strong growth inhibition of 2,2-bis(4-aminophenyl)adamantane (NSC-711117) was observed against two colon cancer lines (HT-29 and KM-12), one CNS cancer line (SF-295) and one breast cancer line (NCI/ADR-RES) with IC50 < 1.0 microM, i.e. 0.1, 0.01, 0.059 and 0.079 microM, respectively. In addition, we also examined the in vitro and in vivo effects of DPA on three human colon cancer cells. DPA-treated Colo 205 and HT-29 cells were arrested at G0/G1 as analyzed by flow cytometric analysis. The DPA-induced cell growth inhibition was irreversible after removal of DPA. The in vivo effect of tumor growth suppression by DPA was also observed on colon Colo 205 xenografts. No acute toxicity was observed after an i.p. challenge of DPA in ICR nude mice weekly. These results suggest that DPA appears to be a new potentially less toxic modality of cancer therapy.