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Am J Transl Res 2013;5(2):139-154

Original Article
An intravenous (i.v.) route-compatible formulation of FL118, a survivin,
Mcl-1, XIAP, and cIAP2 selective inhibitor, improves FL118 antitumor
efficacy and therapeutic index (TI)

Xiang Ling, Fengzhi Li

Departments of Pharmacology & Therapeutics, NCI CCSG-supported Experimental Therapeutics (ET) Program,
Roswell Park Cancer Institute (RPCI), Buffalo, New York 14263, USA

Received February 1, 2013; Accepted February 28, 2013; Epub March 28, 2013; Published April 8, 2013

Abstract: We recently reported a novel anticancer small molecule, designated FL118, which was discovered via
high throughput screening (HTS), and followed by hit-lead in vitro and in vivo analysis. FL118 selectively inhibits
the expression of four major cancer survival-associated gene products (survivin, Mcl-1, XIAP, and cIAP2) and
shows promising antitumor activity in animal models of human cancers when administered using a weekly x 4
schedule (Ling et al., PLOS ONE. 2012, 7: e45571). Here, we compared the antitumor efficacy and therapeutic
index (TI) of FL118 in a newly developed Tween 80-free formulation that can be delivered intravenously (i.v.) and
intraperitoneally (i.p.) against the previous Tween 80-containing formulation that can only be delivered via an i.p.
route. We found that the maximum tolerated dose (MTD) for FL118 in the i.v. formulation increases 3-7 fold in
comparison with the MTD of FL118 in the i.p. formulation. FL118 in the i.v. recipe was able to eliminate human
tumor xenografts in all three major schedules tested (daily x 5, q2 x 5 and weekly x 5). In contrast, FL118 was able
to eliminate human tumor xenografts in the i.p. formulation only with the weekly x 4 schedule previously reported.
The TI of FL118 in the i.v. formulation reached 5-6 in the most effective schedule, while the TI of FL118 in the i.p.
formulation was only 1.3 - 2. These findings overcome several clinical challenges including FL118 formulation to
realize clinically compatible drug administration routes, and expanding effective treatment schedules. The striking
improvement of the TI makes FL118 a much safer drug for further development toward clinical trials

Keywords: FL118, maximum tolerated doses (MTD), antitumor activity, human tumor animal model, intravenous
(i.v.), intraperitoneal (i.p.)

Address correspondence to: Dr. Fengzhi Li, Department of Pharmacology and Therapeutics, Roswell Park
Cancer Institute, Elm and Carlton Streets, CGP L4-301, Buffalo, New York 14263. Phone: 716-845-4398; Fax:
716-845-8857; E-mail: fengzhi.li@roswellpark.org