Optimizing the Dosing Schedule of TNP-470 [O-(Chloroacetyl-carbamoyl) Fumagillol] Enhances Its Antitumor and Antiangiogenic Efficacies

Abstract

Many drugs vary in potency and/or toxicity according to the time of day when they are administered. In this study, we investigated whether antitumor efficacy of angiogenesis inhibitor, fumagillol], could be improved by optimizing the dosing schedule. Tumor-bearing mice were housed under standardized light/dark cycle conditions (lights on at 7:00 AM, off at 7:00 PM) with food and water ad libitum. The antitumor effect of TNP-470 (30 mg/kg s.c.) was more potent in mice injected with the drug at the early light phase than it was when administered at the early dark phase. The diurnal change in the antitumor effect of TNP-470 was parallel to that in its antiangiogenic activity. The variation in the effects of TNP-470 was closely related to the diurnal variations in its inhibitory action on methionine aminopeptidase activity in tumor masses. There was a significant dosing time-dependent change in the concentration of TNP-470 in plasma. The higher concentration of TNP-470 in plasma was observed when its antitumor and antiangiogenic activities were increased. These results suggest that therapeutic efficacy of TNP-470 can be enhanced by choosing the most appropriate time of day to administer the drug.Angiogenesis, the formation of new vessels from pre-existing vessels, has been shown to be necessary for the progression and metastasis of malignant tumors (Folkman, 1971). Tumors require a supply of nutrients, oxygen, and various growth factors. In addition, they utilize the newly formed blood vessels as conduits to disseminate invasive tumor cells. Because the growth and metastasis of malignant tumors are dependent on angiogenesis, a novel anticancer treatment has been developed in which tumors are regressed by prolonged inhibition of angiogenesis. In comparison with conventional chemotherapy, antiangiogenic therapy has a number of clinical advantages, including low toxicity, lack of drug resistance, and easy access of the drugs to the targeted endothelial cells (Boehm et al., 1997). A variety of antiangiogenic agents are currently undergoing clinical trails for dormancy therapy of tumors.TNP-470 (AGM-1470), a synthetic analog of fumagillin, has been shown to prevent angiogenesis by arresting the endothelial cell cycle (Hori et al., 1994), and it potently inhibits tumor growth and metastasis in a wide range of in vivo tumor models (Ingber et al., 1990;O'Reilly et al., 1995). TNP-470 arrests the endothelial cell cycle by inhibiting the activities of type II methionine aminopeptidase (MetAP-2), which appears to play an important role in cell cycle initiation (Griffith et al., 1997;Sin et al., 1997). Although TNP-470 has significant clinical advantages as a therapeutic agent for cancer treatment, its short serum half-life and dose-limiting side effects diminish the potency of this drug (Logothetis et al., 2001).One approach to increase the efficacy of pharmacotherapy is to administer drugs at a time of day when they are most effective and/or best tolerated. Daily rhythmic variations in biological functions such as se...

24-Hour Oscillation of Mouse Methionine Aminopeptidase2, a Regulator of Tumor Progression, Is Regulated by Clock Gene Proteins

“…The rhythmic patterns of clock gene expression in tumor masses are similar to those reported in healthy tissues, such as liver and skeletal muscle (15, 26 -28). In addition, the 24-hour rhythm of mCRY1 protein expression was antiphase to that of mMetAP2 mRNA expression in the present study (9,24). Therefore, the transcription of mMetAP2 mRNA may be regulated by clock gene proteins in tumor masses.…”

“…MetAP2 has been examined as a physiologic target for the potent angiogenesis inhibitor TNP-470, a synthetic analogue of fumagillin, which acts by directly inhibiting endothelial cell proliferation (12). Recently, we clarified that the antitumor effect of TNP-470 is more potent in mice injected with the drug during the early light phase than in those injected with the drug during the early dark phase (9). In a nondrugged state, mouse methionine aminopeptidase (mMetAP) activity in tumor masses showed a significant 24-hour rhythm.…”

Mechanisms of cadmium-induced chronotoxicity in mice

“…For example, biological responses to various drugs used for antitumor, antiangiogenic, antiasthma or antihypertensive show 24-hr rhythmicity (Peters et al, 1987;Koyanagi et al, 2003;Hermida et al, 2005;Burioka et al, 2010). This diurnal variation may depend on alterations in drug metabolism activities, e.g.…”

Diurnal variation of cadmium-induced mortality in mice

“…GSH provides a first defense line against Cd toxicity before induction of MT synthesis occurs (Singhal et al, 1987). It is well known that biological responses to variety of drugs used to antitumor, antiangiogenic, antiasthma or antihypertensive show 24-hr rhythmicity (Peters et al, 1987;Koyanagi et al, 2003;Hermida et al, 2005;Burioka et al, 2010), investigating administration timing influences the effects of these drugs. This diurnal variation may depend on alterations in drug metabolism activities, e.g.…”