5-methylxanthen-9-one-4-acetic-acid and Adenocarcinoma

The antitumor agent flavone-8-acetic acid (FAA) is remarkable because it induces hemorrhagic necrosis, altered tumor blood flow, and cytokine synthesis. We show here that FAA and structurally related analogues increase plasma nitrite plus nitrate (NO2-/NO3-) levels in mice. Dose-dependent increases in plasma NO2-/NO3- concentrations, which reached maximum levels at 12 h, were found following administration of FAA. Furthermore, the presence of a palpable s.c. Colon 38 tumor significantly enhanced the response. Tumor-dependent increases were also observed with the active FAA analogues xanthenone-4-acetic acid, 5-methyl XAA, and 5,6-dimethyl XAA, while the inactive analogue 8-methyl XAA failed to increase plasma NO2-/NO3- concentrations substantially above basal levels. Increased plasma NO2-/NO3- levels were also observed in response to endotoxin (100 micrograms/mouse) and to recombinant human tumor necrosis factor alpha (4 to 16 micrograms/mouse). NO2-/NO3- levels may signify nitric oxide production as a result of stimulation of the L-arginine-dependent pathway in activated macrophages. The tumor dependence of the response may reflect the immunological stimulus imposed by tumor implantation. A clear relationship was found between increased plasma NO2-/NO3- levels and tumor growth delays induced by FAA and xanthenone-4-acetic acid analogues. It is suggested that nitric oxide may contribute to tumor cell death by two mechanisms, alteration of blood flow contributing to tumor ischemia and direct tumor cell killing. Plasma NO2-/NO3- concentrations may be a sensitive indication of the antitumor response to this class of compounds.

Topics: Adenocarcinoma; Animals; Colonic Neoplasms; Dose-Response Relationship, Drug; Flavonoids; Methylation; Mice; Mice, Inbred Strains; Nitrates; Nitrites; Xanthenes; Xanthones

9-Oxoxanthene-4-acetic acids are a class of antitumor agents effective against the mouse colon adenocarcinoma 38 in vivo. Within this class, 5-substituents on the xanthenone are known to enhance potency. To extend structure-activity relationships for the class, a series of derivatives bearing a wide variety of substituents at the 5-position have been prepared and evaluated. The results suggest that activity correlates better with the lipophilic properties of substituents rather than with their electronic properties. Generally, lipophilic substituents result in more active compounds, but there may be a size limitation on such substituents. The 5-methyl derivative is the most dose-potent of the analogues studied.

Topics: Acetates; Adenocarcinoma; Animals; Antineoplastic Agents; Chemical Phenomena; Chemistry; Colonic Neoplasms; Flavonoids; Mice; Structure-Activity Relationship; Xanthenes

In a search for compounds related to flavoneacetic acid with activity against solid tumors, a series of methyl-, methoxy-, chloro-, nitro-, and hydroxy-substituted xanthenone-4-acetic acids have been synthesized and evaluated against subcutaneously implanted colon adenocarcinoma 38 in vivo, using a short-term histology assay as a primary screening system. A major goal of this work was to identify compounds with similar profiles of activity to that of flavoneacetic acid but of higher potency. The level of activity of the compounds appeared to depend more on the nature of the substituent than its positioning, in the order Cl greater than Me, OMe greater than NO2, OH. However, the potency of the compounds was related much more to the position rather than the nature of the substitution, with 5-substituted compounds being clearly the most dose potent. 5-Methylxanthenone-4-acetic acid has a similar level of activity to that of flavoneacetic acid in the test systems employed but is more than 7-fold as dose potent.

Topics: Acetates; Adenocarcinoma; Animals; Chemical Phenomena; Chemistry; Chlorine; Colonic Neoplasms; Hydroxylation; Methylation; Mice; Nitro Compounds; Structure-Activity Relationship; Xanthenes