Potency of new duplex drugs linking 3'-C-ethynylcytidine and 5-fluoro-2'-deoxyuridine against human melanoma in vitro and in vivo.

Abstract

8570 Background: Melanoma is increasingly common and currently no cure exists for patients with stage IV disease. There is an urgent need for noval drugs in order to effectively treat this potentially fatal malignancy. 2’-Deoxy-5-fluorouridylyl-(3’-5’)-3’-C-ethynylcytidine [5-FdU(3’-5’)ECyd] and 3’-C-ethynylcytidinylyl-(5’->1-O)-2-O-octadecyl-sn-glycerylyl-(3-Oà5’)-2’-deoxy-5-fluorouridine [ECyd-lipid-5-FdU] are so called duplex drugs that chemically link two antimetabolites into one molecule. They act as cytostatics by metabolisation into a mixture of active antimetabolites with different properties. This concept could use the advantage of a combination therapy avoiding its inconveniences Methods: The duplex drugs were evaluated along the National Cancer Institute (NCI) Developmental Therapeutic Program up to xenograft models. We assessed the cytotoxicity and mechanism of these heterodinucleoside phosphate analogues and their corresponding monomers ECyd and 5-FdU on six metastatic melanoma cell lines and six ex-vivo patient-derived melanoma cells in comparison to current standard cytostatic agents and combinations thereof. Further, in vitro (real-time)-proliferation assays were performed. The embryotoxixity was also evaluated in the chick embryo model. Results: Cell proliferation assays demonstrated that 5-FdU(3’-5’)ECyd and ECyd-lipid-5-FdU had a high cytostatic efficacy causing 75% melanoma cell death at concentrations ranging between nano- and micromolar. Cytotoxicity was conducted by induction of DNA cleavage/apoptosis, and via senescence in cells not undergoing apoptosis. Embryotoxicity demonstrated that the duplex drugs were less toxic than their parental monomers. In vivo results of the NCI showed that the duplex drug 5-FdU(3’-5’)ECyd was efficacious in the LOX IMVI solid tumor xenograph model when 11.2mg/kg/injection were administered every fourth day. Conclusions: Both duplex drugs represent potential new chemotherapeutic drug combinations for malignant melanoma which are more potent than available standard monocytostatica and mixture thereof and thus further development is justified and desirable.