Small cell
lung cancers (SCLCs), many non-SCLCs, and other
cancers have neuroendocrine features, including paracrineand autocrine growth stimulation by various
neuropeptides. Interference with this pathway is an attractive target for novel
therapies. We developed a novel
bradykinin antagonist dimer,
CU201 (
B9870), that acts as a "biased agonist" for
neuropeptides by blocking G(alphaq) signaling and activating G(alpha12,13) signaling.
CU201 induced apoptosis and complete growth inhibition in various
lung cancer and other
cancer cell lines.
CU201 was 10-fold more potent than
substance P derivatives and was stable in serum for >7 days. In this study, we evaluated the ability of
CU201 to produce additive or synergistic growth inhibition in combination with various
antitumor agents used in
lung cancer therapy. We found that
CU201 produced additive or synergistic growth inhibition when combined with
doxorubicin,
etoposide,
cisplatin,
vinorelbine, and
paclitaxel for SCLC lines and with
paclitaxel and
ZD1839, an
epidermal growth factor receptor tyrosine kinase inhibitor, for non-SCLC cell lines. Pharmacokinetic parameters associated with the i.v. administration of
CU201 were evaluated in normal mice, and the effects of
CU201 on the growth of human
lung cancer xenografts were evaluated in athymic nude mice. In CD2F1 mice given an i.v. bolus infusion of 5 mg/kg, the c(max) was 5773 ng/ml (5 microM), and the decay was biexponential. When fitted to a two-compartment model, the t(1/2alpha) was 14.4 min, and the t(1/2beta) was 44.3 h, indicating a long terminal half-life consistent with the prolonged in vitro effects.
CU201 inhibited the growth of human
lung cancers in athymic nude mice by the intratumoral, s.c., and i.p. routes at a dose of 5 mg/kg/day. This dose is >10-fold less than the dose of
substance P derivatives used to inhibit SCLC xenografts in nude mice. We conclude that
CU201 should undergo further preclinical toxicology studies in its development as a novel targeted
therapy for the treatment of
lung cancers with neuroendocrine features. These studies are in progress through the NCI RAID mechanism.