trying to predict which conventional cytotoxic drugs will be synergistic w Lapatinib

[Lani]

One of the two best combinations is herceptin plus lapatinib plus 5FU

Anticancer Drugs. 2006 Sep;17(8):921-928. Links
Identification of potentially useful combinations of epidermal growth factor receptor tyrosine kinase antagonists with conventional cytotoxic agents using median effect analysis.

Budman DR,
Soong R,
Calabro A,
Tai J,
Diasio R.
aExperimental Therapeutics Section, Don Monti Division of Oncology and bDepartment of Biostatistics of the Feinstein Institute, North Shore University Hospital, New York University, Manhasset, New York cDepartment of Pharmacology and Toxicology and Division of Hematology/Oncology, University of Alabama Cancer Center, Birmingham, Alabama, USA dOncology Research Institute, National University of Singapore, Singapore, Republic of Singapore.
Targeted therapy for breast carcinoma has achieved a major advance with the use of trastuzumab in Her2/neu-positive tumors. The epidermal growth factor receptor superfamily thus becomes an attractive target for therapeutic agents. As the epidermal growth factor receptor tyrosine kinase family has a conformational binding site, which allows small molecules to interfere with its function, we have explored the effects of a dual kinase (epidermal growth factor receptor-1 and epidermal growth factor receptor-2) inhibitor (GW282974X) with a variety of cytotoxic agents looking for synergistic effects in vitro. Using a median effect model in four breast cancer cell lines in vitro, cytotoxic agents commonly used in treatment of human malignant disease were combined with trastuzumab or one of two epidermal growth factor receptor tyrosine kinase inhibitors in a 72-h culture and then analyzed for cytotoxic effect by 3-[26]-2,5-diphenyl-tetrazolium bromide assay. Combination index values within one standard deviation of unity were considered additive, less than unity as synergistic and more than unity as antagonistic. Synergistic results were confirmed by curve shift analysis and by an enzyme-linked immunosorbent assay measuring apoptosis by cytoplasmic histone-associated DNA fragments. Quantitative real-time polymerase chain reaction analysis was used to measure the expression of three of the critical enzymes in 5'-deoxy-5-fluorouridine metabolism and activity: thymidine phosphorylase, dihydropyrimidine dehydrogenase and thymidine synthase. 5'-Deoxy-5-fluorouridine with GW282974X demonstrated global synergy, both in high and low expressing epidermal growth factor receptor breast cancer cell lines. These results were confirmed by apoptosis assay and cell counts. RNA quantification following treatment with the dual kinase inhibitor suggested reduction in thymidine synthase levels to be a potential mechanism of synergy. The triplet of trastuzumab, GW282974X and 5'-deoxy-5-fluorouridine, and the triplet of GW282974X, epirubicin and 5'-deoxy-5-fluorouridine were highly synergistic in low expression cells (MCF7/wt) and high expression cells (MCF7/adr). These experiments suggest further studies of the dual kinase inhibitor with selected cytotoxics such as 5'-deoxy-5-fluorouridine are warranted.
PMID: 16940802 [PubMed - as supplied by publisher]