Targeted treatment of folate receptor-positive platinum-resistant ovarian cancer and companion diagnostics, with specific focus on vintafolide and etarfolatide

Among the gynecological malignancies, ovarian cancer is the leading cause of mortality in developed countries. Treatment of ovarian cancer is based on surgery integrated with chemotherapy. Platinum-based drugs (cisplatin and carboplatin) comprise the core of first-line chemotherapy for patients with advanced ovarian cancer. Platinum-resistant ovarian cancer can be treated with cytotoxic chemotherapeutics such as paclitaxel, topotecan, PEGylated liposomal doxorubicin, or gemcitabine, but many patients eventually relapse on treatment. Targeted therapies based on agents specifically directed to overexpressed receptors, or to selected molecular targets, may be the future of clinical treatment. In this regard, overexpression of folate receptor-α on the surface of almost all epithelial ovarian cancers makes this receptor an excellent “tumor-associated antigen”. With appropriate use of spacers/linkers, folate-targeted drugs can be distributed within the body, where they preferentially bind to ovarian cancer cells and are released inside their target cells. Here they can exert their desired cytotoxic function. Based on this strategy, 12 years after it was first described, a folate-targeted vinblastine derivative has now reached Phase III clinical trials in ovarian cancer. This review examines the importance of folate targeting, the state of the art of a vinblastine folate-targeted agent (vintafolide) for treating platinum-resistant ovarian cancer, and its diagnostic companion (etarfolatide) as a prognostic agent. Etarfolatide is a valuable noninvasive diagnostic imaging agent with which to select ovarian cancer patient populations that may benefit from this specific targeted therapy

Effects of anti-inflammatory [1, 2, 4]triazolo[4, 3-a] [1, 8]naphthyridine derivatives on human stimulated PMN and endothelial cells: an in vitro study

BACKGROUND: [1,2,4] triazolo [4, 3-a][1,8]naphthyridine derivatives (including NF161 and NF177) were tested for anti-inflammatory, analgesic and antipyretic properties and for their effects on spontaneous locomotor activity in mice and acute gastrolesivity in rats. Both NF161 and NF177 appeared to be anti-inflammatory and analgesic agents without toxic effects or acute gastrolesivity, but NF161 showed stronger anti-inflammatory activity, whereas NF177 was more active as analgesic. METHODS: An EIA kit was used to investigate the ability of NF161 and NF177 to affect prostaglandin E(2 )(PGE(2)) and prostacyclin (PGI(2)) production by human umbilical vascular endothelial cells (HUVEC). The compounds' effects on the production of reactive oxygen species (ROS) by human polymorphonuclear cells (PMNs) were studied in an in vitro cell model, evaluating inhibition of superoxide anion (O(2)(-.)) production induced by N-formylmethionyl-leucyl-phenylalanine (FMLP). Their effects on PMN adhesion to HUVEC were also investigated; they were incubated with PMNs and endothelial cells (EC) and challenged by stimuli including Platelet Activating Factor (PAF), FMLP, Phorbol Myristate Acetate (PMA), Tumor Necrosis Factor-α (TNF-α) and Interleukin-1β (IL-1β). Adhesion was quantitated by computerized micro-imaging fluorescence analysis. RESULTS: Neither compounds modified PGE(2 )or PGI(2 )production induced by IL-1α. O(2)(-. )production and myeloperoxidase release from PMNs stimulated by FMLP was inhibited in a dose- but not time-dependent manner by both [1,8]naphthyridine derivatives, NF161 being statistically more active than NF177 (P < 0.01). The compounds inhibited adhesion evoked by the pro-inflammatory stimuli PAF, FMLP, TNF-α and IL-1β in a concentration-dependent manner in the 10(-6)–10(-4)M range, being more active when PAF was used as stimulus and inactive when cells were challenged by PMA. Both compounds acted both on PMN and HUVEC. CONCLUSION: Considering the interesting anti-inflammatory effects of these compounds in in vivo models and the absence of acute gastrolesivity, the study improved knowledge of anti-inflammatory properties of NF161 and NF177, also demonstrating their potential in vitro, through inhibition of O(2)(-. )production, myeloperoxidase release and PMN adhesion to HUVEC. Negative results on PG production suggest a cyclooxygenase (COX)-independent mechanism