Single Tricyclic Compounds with Cytostatic and Cytotoxic Activity

The formation of new blood vessels from existing vasculature (angiogenesis) plays a crucial role in the growth and metastasis of solid tumors. Angiogenesis is primarily a receptor process mediated by growth factors that cause signal transduction by receptor tyrosine kinases (RTKs). RTKs consist of families of growth factor receptors (like vascular endothelial growth factor receptor (VEGFr), epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr)). Aberrant expression of growth receptors has been implicated in the development, progression and aggressiveness of a variety of solid tumors. RTK inhibition of angiogenesis is primarily cytostatic limiting the ability of the tumor to grow; however, to kill tumor cells, cytotoxic agents are also necessary.

These cytotoxic agents can be existing cancer chemotherapeutic compounds.
Both dihydrofolate reductase (DHFR) and thymidylate synthase (TS) inhibitors are well established cytotoxic agents used in cancer chemotherapy. There is a need for new single compounds which combine anti-angiogenic and antitumor and inhibit the formation of new blood vessels as well as selectively kill tumor cells with a high degree of selectivity and low toxicity.

The compounds included in this invention eliminate the challenges of
transporting two or more drugs simultaneously to target tumor cells (pharmokinetic and pharmacological dynamics), the additive or synergistic toxicities of two or more different drugs, development of drug resistance in multidrug therapy, as well as the associated cost. This invention solves these challenges with multi-acting drugs which can provide both antiangiogenic and cytotoxic properties within single molecular entities. The efficacy of these compounds is supported by data from studies of the vascularity, metastasis and primary tumor growth of human colon cancer cells and lung tumors in mice.

Tricyclic heteroaromatic compounds with antimitotic action are novel candidates for chemotherapy against tumor cells. These compounds can reduce the multi- drug resistance considered to be one of factors responsible for chemotherapeutic failure. The compounds inhibit P-glycoprotein and do not require any solubilizing agents. .Efficacy of these compounds has been demonstrated by flow cytometry and microtubule depolymerization immunofluroscence assays using various human cell lines as well as in mice models of breast cancer and brain tumors.

Duquesne University holds pending patents on these families of tricyclic compounds and their therapeutic use in cancer treatment.

File Number: 5 

Web site: http://www.research.duq.edu/

Disease: Cancer