Preclinical antitumor activity of penclomedine in mice: cross-resistance, schedule dependence, and oral activity against tumor xenografts in brain

Abstract

Penclomedine is 3,5-dichloro-2,4-dimethoxy-6-(trichloromethyl)pyridine (NSC 338720), an alpha-picoline derivative with p.o. antitumor activity in preclinical leukemia and solid tumor models. Described here are an in vivo cross-resistance profile of penclomedine, treatment schedule dependence studies, and studies exploring the effects of p.o. drug on human tumors xenografted into mouse brain. The latter studies exploited the apparent facile distribution of penclomedine to the central nervous system. Tumor models used included murine leukemia lines selected in vivo for acquired resistance to various antitumor drugs and the human mammary and lung tumor xenografts MX-1 and H82, respectively. The therapeutic effects of p.o. penclomedine against s.c. MX-1 and H82 xenografts were shown to be independent of treatment schedule. Therapeutic activity was comparable when p.o. and parenteral treatments were compared. Lines of P388 leukemia resistant to melphalan, cyclophosphamide, and carmustine were cross-resistant to penclomedine in vivo. Leukemia lines resistant to antimetabolites, DNA binders/intercalators, and vincristine were not cross-resistant to penclomedine. Intracerebrally implanted MX-1 xenografts retained their sensitivity to p.o. penclomedine, and therapeutic activity was at least comparable to that of carmustine, a drug known for its ability to cross the blood-brain barrier. These results demonstrate attributes of penclomedine that are relatively uncommon among currently available antitumor drugs and that are of interest for the anticipated clinical development of this drug.