There is considerable interest n the omega-3 fatty acid docosahexaenoic acid (DHA,22:6 DELTA 4,7,10,13,16,19) as a unique and natural adjunct therapy, one that may be combined with suboptimal doses of toxic drugs to achieve optimal therapeutic results. The challenge is to select a DHA/drug combination that is synergistic and may be efficiently delivered. This project proposes to combine the drug methotrexate (MTX), an effective but toxic treatment for cancer and rheumatoid arthritis, with DHA. The rationale for this choice is that MTX targets cells in S phase and DHA appears to prolong S phase. To ensure that cells receive both agents simultaneously, a novel therapeutic agent, phosphatidylcholine (PC) with DHA covalently linked in the sn-1 position and MTX in the sn-2 position, will be produced. The hypothesis to be tested is that DHA, MTX-PC can be synthesized and used to concurrently deliver DHA and MTX specifically to cells to inhibit cell growth and/or increase cell death without effects on bystander cells. This proposal is for an Exploratory/Developmental Research Grant (R21) having specific aims to 1) synthesize and partially characterize two novel phospholipids (18:0,MTX-PC and 22:6,MTX-PC): 2) monitor the cellular uptake of liposomes containing the novel phospholipids; 3) compare cytotoxic/cytostatic activity of 18:0,MTX-PC;22:6,MTX-PC, and free MTX and fatty acids on cultured cells and on bystander cells; 4) determine whether MTX and 22:6 synergize through concerted actions in the S phase of the cell cycle. If the hypothesis is supported, then DHA,MTX-PC containing liposomes may be useful clinically as non-leaky, fusogenic agents that deliver two potentially synergistic compounds acting through different mechanisms and whose release into the cell requires active phospholipases prominent in activated cells such as reactive leukocytes and cancer cells. Funding is requested through the R21 mechanism to provide funds sufficient to produce the novel phospholipid and perform a few critical tests, thereby generating the preliminary data necessary for application through the R01 mechanism and/or to attract industrial partners.
| Zerouga, Mustapha; Stillwell, William; Jenski, Laura J (2002) Synthesis of a novel phosphatidylcholine conjugated to docosahexaenoic acid and methotrexate that inhibits cell proliferation. Anticancer Drugs 13:301-11 |
| Siddiqui, R A; Jenski, L J; Wiesehan, J D et al. (2001) Prevention of docosahexaenoic acid-induced cytotoxicity by phosphatidic acid in Jurkat leukemic cells: the role of protein phosphatase-1. Biochim Biophys Acta 1541:188-200 |
