Squalamine is a novel anti-angiogenic aminosterol that is postulated to inhibit neovascularization by selectively inhibiting the
sodium-hydrogen antiporter exchanger. To determine how to most effectively use this agent in patients with
cancer, we examined the antitumor effects of
squalamine with or without
cytotoxic agents in human
lung cancer xenografts and correlated these observations with the degree of
tumor neovascularization. No direct cytotoxic effects of
squalamine against
tumor cells were observed in vitro with or without
cisplatin.
Squalamine was effective in inhibiting the establishment of H460 human
tumors in BALBc nude mice but was ineffective in inhibiting the growth of H460, CALU-6, or NL20T-A human
tumor xenografts when administered i.p. to mice bearing established
tumors. However, when combined with
cisplatin or
carboplatin,
squalamine increased
tumor growth delay by > or =1.5-fold in the three human lung
carcinoma cell lines compared with
cisplatin or
carboplatin alone. No enhancement of antitumor activity was observed when
squalamine was combined with
paclitaxel,
vinorelbine,
gemcitabine, or
docetaxel. Repeated cycles of
squalamine plus
cisplatin administration delayed H460
tumor growth >8.6-fold.
Squalamine plus
cisplatin reduced CD31 vessel formation by 25% compared with controls,
squalamine alone, or
cisplatin alone; however, no inhibition in CD31 vessel formation was observed when
squalamine was combined with
vinorelbine. These data demonstrate that the combination of
squalamine and a
platinum analog has significant preclinical antitumor activity against human
lung cancer that is related to the anti-angiogenic effects of
squalamine.