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Activity of flavone acetic acid (NSC-347512) against solid tumors of mice
Abstract:
Flavone acetic acid (FAA) is a new antitumor agent that has recently entered Phase I clinical trials. In preclinical studies, we have found that FAA was broadly active against a variety of transplantable solid tumors of mice (colon #51, #07, #10, #26; pancreatic ductal adenocarcinomas #02 and #03; mammary adenocarcinoma #16/C/Adr; M5076 reticulum cell sarcoma and Glasgow's osteosarcoma). FAA was curative for colon adenocarcinoma #10 and pancreatic ductal adenocarcinoma #03. Thus, for the first time an agent has been identified with very broad, perhaps nearly universal solid tumor activity. FAA was also found to be orally active and stable in solution at 37 degrees C for 48 h. FAA was selectively cytotoxic in vitro for solid tumors over leukemias L1210 and P388 (in a soft-agar colony formation assay), thus correlating cellular selectivity in vitro with in vivo antitumor activity. The finding that FAA was active in vitro, established that the agent did not need metabolism (activation) outside the tumor cell. The main drawback of FAA was an unusual 'threshold' behavior in which only a narrow range of doses were active and splitting the dose markedly decreased activity.
Insights
Flavone acetic acid (FAA) demonstrates broad antitumor activity against various solid tumors in preclinical models. This novel agent shows promise but exhibits dose-dependent efficacy with a narrow active range.
Area of Science:
- Oncology
- Pharmacology
Background:
- Flavone acetic acid (FAA) is an emerging antitumor agent.
- FAA has advanced to Phase I clinical trials for cancer treatment.
Purpose of the Study:
- To evaluate the preclinical antitumor activity of Flavone acetic acid (FAA).
- To assess the in vitro and in vivo efficacy and characteristics of FAA.
Main Methods:
- Preclinical testing of FAA against a panel of transplantable solid tumors in mice.
- In vitro cytotoxicity assays using soft-agar colony formation to assess selectivity against leukemias L1210 and P388.
Main Results:
- FAA exhibited broad activity against multiple solid tumors, including curative effects on colon adenocarcinoma #10 and pancreatic ductal adenocarcinoma #03.
- The agent demonstrated oral activity and stability in solution.
- FAA showed selective cytotoxicity for solid tumors over leukemias in vitro, correlating with in vivo findings.
- A significant 'threshold' effect was observed, with a narrow dose range showing activity and reduced efficacy upon dose splitting.
Conclusions:
- FAA represents a novel agent with potentially universal solid tumor activity.
- The in vitro activity suggests FAA does not require external metabolic activation.
- The narrow therapeutic window and dose sensitivity are key limitations for FAA's clinical application.