To evaluate the anti-
tumor characteristics of
ONO-4007, a synthetic analog of
lipid A, the authors examined its acute toxicity and anti-
tumor activity in a mouse MM46 mammary
tumor system in comparison with LA-15-PP, an E. coli-type synthetic
lipid A and LPS. Systemic and local (
tumor site) induction of
tumor necrosis factor (TNF) by a single i.v. shot of
ONO-4007 and LA-15-PP correlated with manifestation of their toxicity, showing that
ONO-4007 is 100-fold less effective than LA-15-PP. However, a protocol of repeated administration (3 shots twice a week) exhibited about 10 times more therapeutic potency of
ONO-4007 for
cancer therapy than expected in the above experiments. In a dose inducing submaximal systemic and intratumoral TNF production, repeated
injections (twice a week) of
ONO-4007 (10 mg/kg), LA-15-PP (0.1 mg/kg) and LPS (0.1 mg/kg) commonly generated a tolerant state in the systemic response (serum and liver) to subsequent stimulation. The intratumoral response was retained with this repeated administration of
ONO-4007, but was not with LA-15-PP or LPS. TIM (
tumor-infiltrating macrophages) isolated from mice pre-injected with
ONO-4007 and LA-15-PP were found to lose their response to both substances, but the response was rapidly recovered until 72 h after injection and virtually no difference was observed in their response to either
drug. The in vitro treatment of naive TIM with
ONO-4007 or LA-15-PP for 2 h depressed the response to both substances and the depression continued for 72 h even in culture with fresh medium. The relatively high efficacy of
ONO-4007 in
cancer therapy likely depends on the retraction of the tolerant state, especially at the
tumor site where the response to
ONO-4007 is recovered much more efficiently than that to
lipid A. While constant recruitment of macrophages to
tumor tissue might be involved in the difference of tolerance recovery between this region and others, selective response to
ONO-4007 may not be explained simply by the sensitivity of recruited TIM. Pharmacokinetical experiments revealed that repeated
injections of LA-15-PP enhanced its clearance from blood circulation, while the clearance of
ONO-4007 was stable after repeated
injections. Thus, pharmacokinetical properties of
ONO-4007 may also possibly be implicated in this event.