Development of difluoromethylornithine as a chemoprevention agent for the management of colon cancer

Abstract

D,L-␣-difluoromethylornithine (DFMO) was synthesized over 20 years ago. It was hoped that this enzymeactivated, irreversible inhibitor of ornithine decarboxylase, the first enzyme in polyamine synthesis, would be effective as a chemotherapy for hyperproliferative diseases, including cancer and/or infectious processes. DFMO was generally found to exert cytostatic effects on mammalian cells and tissues, and its effectiveness as a therapeutic agent has been modest. DFMO was also found to cause treatment-limiting (but reversible) ototoxicity at high doses. This side effect, along with its minimal therapeutic activity, contributed to the loss of interest by many clinicians in further developing DFMO as a cancer therapeutic agent. However, DFMO was subsequently shown to inhibit carcinogen-induced cancer development in a number of rodent models, and interest in developing this compound as a preventive agent has increased. The rationale for the inhibition of ornithine decarboxylase as a cancer chemopreventive agent has been strengthened in recent years because this enzyme has been shown to be transactivated by the c-myc oncogene in certain cell/tissue types and to cooperate with the ras oncogene in malignant transformation of epithelial tissues. Recent clinical cancer chemoprevention trials, using dose de-escalation designs, indicate that DFMO can be given over long periods of time at low doses that suppress polyamine contents in gastrointestinal and other epithelial tissues but cause no detectable hearing loss or other side effects. Current clinical chemoprevention trials are investigating the efficacy of DFMO to suppress surrogate end point biomarkers (e.g., colon polyp recurrence) of carcinogenesis in patient populations at elevated risk for the development of specific epithelial cancers, including colon, esophageal, breast, cutaneous, and prostate malignancies. Early Rationale for the Development of Inhibitors of Polyamine MetabolismStudies on the diamine putrescine and its polyamine products spermidine and spermine date to the 17 th century with the observation by Leeuwenhoek of spermine phosphate crystals in human semen (1). The strong association between high levels of the polyamines and rapid proliferation in prokaryotes and eukaryotes was recognized more than 25 years ago (2-4). These investigations led scientists at the Merrell Research Institute in Strasbourg to synthesize specific inhibitors of ODC 3 (5), the first enzyme in mammalian polyamine synthesis, and of other enzymes involved in polyamine metabolism (6 -7). It was hoped that the inhibition of polyamine metabolism would be a successful strategy for chemotherapy for cancer and/or other hyperproliferative diseases or infectious diseases such as protozoal parasiticism (8).Subsequent studies by the Merrell group and others, using specific ODC inhibitors (9 -14) or genetic approaches (15, 16) to manipulate levels of endogenous polyamines, confirmed that amines derived from ornithine are essential for mammalian cell viability, and high levels are n...

Polyamines and cancer: old molecules, new understanding

“…DFMO inhibits intestinal polyp formation in Apc Min/+ mice 32 . APC mutations are found in almost all sporadic (nonhereditary) forms of colon cancer, and ODC levels are increased in colon polyps in humans 18 . Our group has therefore carried out chemoprevention trials with DFMO in patients with FAP and sporadic colon polyps.…”

“…The mechanism of this effect is thought to involve inhibition of the increased cell proliferation that is associated with the promotion phase. Subsequent studies indicated that DFMO was a potent inhibitor of epithelial carcinogenesis in a range of models, including those for skin, breast and colon 18 . …”

“…In addition to these links between ODC activity and cancer risk factors, the use of pharmacological inhibitors of polyamine metabolism has implicated polyamines in a range of cancers. Difluoromethylornithine (DFMO), which irreversibly inactivates ODC, is the most widely studied example of a polyamine-metabolism inhibitor that suppresses cancer development in animal models 18 and has been evaluated in clinical trials. Agents that target other polyamine metabolic enzymes (FIG.…”

Pharmaceutical properties of supramolecular assembly of co-loaded cardanol/triazole-halloysite systems

“…Over 80% of liver cancer patients are diagnosed with hepatocellular carcinoma, which is resistant to most conventional chemotherapeutic agents (Wilson et al, 2012). Moreover, the use of chemoprevention agents is typically associated with side effects that lead to the destruction of normal tissues, such as those of the digestive, hematopoietic and nervous systems (Meyskens and Gerner, 1999;Suzuki et al, 2008;Florea and Büsselberg, 2011). The development of drugs that specifically target tumor cells, but not normal cells, represents a common goal.…”

Evaluation of Difluoromethylornithine for the Chemoprevention of Barrett's Esophagus and Mucosal Dysplasia

“…Accordingly, patients with BE and mucosal dysplasia are prime candidates for secondary prevention approaches, including chemoprevention, given their increased risk for developing esophageal adenocarcinoma. Difluoromethylornithine (DMFO) is a chemopreventive agent that irreversibly inhibits ornithine decarboxylase (ODC) that has been shown to decrease tissue polyamine levels and tumorigenesis (5,6). Polyamines are produced during cellular metabolism and act as signaling molecules for cell growth and differentiation (5).…”