Summary
Flavone acetic acid (FAA; LM 975; NSC 347512) is a new anticancer agent with unprecedented, broad antitumor activity in murine models. Although FAA is very effective in vivo against solid tumors, including colon 38 adenocarcinoma, it was not cytotoxic in vitro against colon 38 cells and human colon adenocarcinoma cells HCT116 at pharmacologically achievable concentrations and exposure times. For example, a concentration of 300 μg/ml for a 10-day exposure time was required to obtain <1log cell kill. After the administration of an effective FAA dose (180 mg/kg, i.v.) to mice, plasma cytotoxicity against HCT116 cells attained a 2 log cell kill between 0.5 and 2 h, which decreased to 1 log cell kill at 4 h. No cytotoxicity was observed 6, 12 or 21 h after drug administration. The controls used comprised mouse plasma containing FAA concentrations similar to those assayed in the above plasma samples from in-vivo-dosed mice. These apiked plasma were not cytotoxic, indicating that other cytotoxic species, formed in vivo, were responsible for the increased cytotoxicity. Mouse hepatocytes co-cultured with HCT116 cells increased FAA cytotoxicity to 1 log cell kill at 30–100 μg/ml. The addition of phenobarbital-induced mouse liver supernatant S-9000xg also markedly increased FAA cytotoxicity to a 2 log cell kill at 300 μg/ml. We conclude that FAA can be activated both in vivo and in vitro to cytotoxic species that are more active than the parent compound.
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Atassi G, Briet P, Berthelon JJ, Collonges F (1985) Synthesis and antitumor activity of some 8-substituted-4-oxo-4H-1-benzopyrans. Eur J Med Chem-Chim Ther 20:393
Bibby MC, Double JA, Phillips RM, Loadman PM (1987) Factors involved in the anti-cancer activity of the investigational agents LM985 (flavone acetic acid ester) and LM975 (flavone acetic acid). Br J Cancer 55:159
Bissery MC, Valeriote FA, Chabot GG, Crissman JD, Yost C, Corbett TH (1988) Flavone acetic acid (NSC-347512)-induced DNA damage in Glasgow osteogenic sarcoma in vivo. Cancer Res 48:1279
Brattain MG, Fine WD, Khaled FM, Thompson J, Brattain DE (1981) Heterogeneity of malignant cells from a human colonic carcinoma. Cancer Res 41:1751
Capolongo LS, Balconi G, Ubezio P, Giavazzi R, Taraboletti G, Regonesi A, Yoder OC, D'Incalci M (1987) Antiproliferative properties of flavone acetic acid (NSC 347512; LM 975), a new anticancer agent. Eur J Cancer Clin Oncol 23: 1529
Chabot GG, Rutkowski K (1988) Activation of flavone-8-acetic acid to cytotoxic metabolites in vitro. Proc Am Assoc Cancer Res 29:484
Chabot GG, Bissery MC, Corbett TH, Rutkowski K, Baker L (1989) Pharmacodynamics and causes of dose-dependent pharmacokinetics of flavone-8-acetic acid (LM-975; NSC-347512) in mice. Cancer Chemother Pharmacol 24:15–22
Ching LM, Baguley BC (1987) Induction of natural killer cell activity by the antitumour compound flavone acetic acid (NSC 347512). Eur J Cancer Clin Oncol 23:1047
Corbett TH, Griswold DP Jr, Roberts BJ, Peckham JC, Schabel FM Jr (1975) Tumor induction relationships in development of transplantable cancers of the colon in mice for chemotherapy assays, with a note on carcinogen structure. Cancer Res 35:2434
Corbett TH, Bissery MC, Wozniak A, Plowman J, Polin L, Tapazoglou E, Dieckman J, Valeriote F (1986) Activity of flavone acetic acid (NSC-347512) against solid tumors of mice. Invest New Drugs 4:207
Davis HP, Newlands ES, Allain T, Hegde U (1988) Immune thrombocytopenia caused by flavone-8-acetic acid. Lancet 1: 412
Drewinko B, Yang LY (1986) The activity of flavone acetic acid (NSC-347512) on human colon cancer cells in vitro. Invest New Drugs 4:289
Evelhoch JL, Bissery MC, Chabot GG, Simpson NE, McCoy CL, Heilbrun LK, Corbett TH (1988) Flavone acetic acid (NSC 347512)-induced modulation of tumor physiology monitored by in vivo nuclear magnetic resonance spectroscopy. Cancer Res 48:4749
Finlay GJ, Smith GP, Fray LM, Baguley BC (1988) Effect of flavone acetic acid on Lewis lung carcinoma: evidence for an indirect effect. J Natl Cancer Inst 80:241
Giavazzi R, Garofalo A, Damia G, Garattini S, D'Incalci M (1988) Response to flavone acetic acid (NSC 347512) of primary and metastatic human colorectal carcinoma xenografts. Br J Cancer 57:277
Gouyette A, Kerr DJ, Kaye SB, Setanoians A, Cassidy J, Bradley C, Forrest G, Soukop M (1988) Flavone acetic acid: a nonlinear pharmacokinetic model. Cancer Chemother Pharmacol 22:114
Havsteen B (1983) Flavonoids a class of natural products of high pharmacological potency. Biochem Pharmacol 32:1141
Hornung RL, Young HA, Urba WJ, Wiltrout RH (1988) Immunomodulation of natural killer cell activity by flavone acetic acid: occurrence via induction of interferon alpha/beta. J Natl Cancer Inst 80:1226
Kerr DJ, Kaye SB, Cassidy J, Bradley C, Rankin EM, Adams L, Setanoians A, Young T, Forrest G, Soukop M, Clavel M (1987) Phase I and pharmacokinetic study of flavone acetic acid. Cancer Res 47:6776
Plowman J, Narayanan VL, Dykes D, Szarvasi E, Briet P, Yoder OC, Paull DK (1986) Flavone acetic acid (NSC-347512), a novel agent with preclinical antitumor activity against the colon adenocarcinoma 38 in mice. Cancer Treat Rep 70:631
Renton KW (1987) Cytochrome P-450-dependent monooxygenase systems in mouse hepatocytes. In: Rauckman EJ, Padilla GM (eds) The isolated hepatocyte, use in toxicology and xenobiotic biotransformations. Academic, Orlando, Florida, p 69
Rubin J, Ames MM, Schutt AJ, Nichols WL, Bowie EJW, Kovacs JS (1987) Flavone-8-acetic acid inhibits ristocetin-induced platelet agglutination and prolongs bleeding time. Lancet II:1081
Schroyens WA, Dodion PF, Sanders C, Loos M, Dethier NE, Delforge AR, Stryckmans PA, Kenis Y (1987) In vitro chemosensitivity testing of flavone acetic acid (LM 975; NSC 347512) and its diethylaminoethyl ester derivative (LM 985; NSC 293015). Eur J Cancer Clin Oncol 23:1135
Smith GP, Calveley SB, Smith MJ, Baguley BC (1987) Flavone acetic acid (NSC 347512) induces haemorrhagic necrosis of mouse colon 26 and 38 tumors. Eur J Cancer Clin Oncol 23:1209
Staubus AE, Lyon ME, Grever MR, Wilson HE Jr, Malspeis L (1987) Dose-dependent pharmacokinetics of flavone acetic acid (NSC 347512) in humans. Proc Am Assoc Cancer Res 28:227
Urba WJ, Longo DL, Lombardo FA, Weiss RB (1988) Enhancement of natural killer activity in human peripheral blood by flavone acetic acid. J Natl Cancer Inst 80:521
Wiltrout RH, Boyd MR, Back TC, Salup PR, Arthur JA, Hornung RL (1988) Flavone-8-acetic acid augments systemic natural killer cell activity and synergizes with IL-2 for treatment of murine renal cancer. J Immunol 9:3261
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Part of this work has been published in abstract form in: Proc Am Assoc Cancer Res 29: 484, 1988
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Chabot, G.G., Bissery, MC. & Gouyette, A. Flavone acetic acid (LM-975; NSC-347512) activation to cytotoxic species in vivo and in vitro. Cancer Chemother. Pharmacol. 24, 273–276 (1989). https://doi.org/10.1007/BF00304757
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DOI: https://doi.org/10.1007/BF00304757