SK 655. Ardeemins and Ningalins as Multidrug Reversal Agents

Summary of Invention

Each year, more than 500,000 new patients in the United States are diagnosed with hematological and solid tumors that cannot be treated effectively due to multiple drug resistance (MDR). This invention provides compounds that are useful as MDR-reversal, collateral-sensitive, and quantitated synergistic agents to treat cancer and prevent emergence of the MDR phenotype.

N-acetyl ardeemin (NAA) is a natural product known to be an effective MDR agent. Researchers at MSKCC have developed a synthetic route to produce NAA and analogues. Many of these analogues have proven to be more active than the original compound. NAA is a better MDR agent than Verapomil and is substantially less toxic. NAA is also effective alone against MDR-resistant cells. Studies have demonstrated NAA and analogues act synergistically with Taxol, Adriamycin, and Vinblastine to kill MDR-resistant tumors and cell lines by reducing the IC50 of the chemotherapeutic agent and enhancing activity toward the resistant cells.

Further support for this synergistic quality of NAA and chemotherapeutic agents is found in studies that show that NAA, used in combination with Taxol, significantly reduces the IC50 of Taxol in nonresistant cell lines.

Advantages

• NAA acts synergistically with chemotherapeutic agents without toxicity problems. (For P388 and P388Dx leukemic cells, addition of NAA reduced the IC50 of Adriamycin 2.7- and 5.1-fold, respectively, and reduced the IC50 of Taxol by 4-fold).
• Exceptionally low toxicity observed for several NAA analogues in mice studies.
• A very potent MDR agent with very low toxicity (IC50=5-30 m). (Enhances Vinblastine intracellular accumulation 200 to 350 percent in MDR cell lines).
• NAA and analogues display collateral sensitivity in MDR cells. (MDR cell lines are 3- to 11-fold more sensitive to NAA than their non-MDR parent cell lines).
• Has been demonstrated to increase the therapeutic efficacy of Adriamycin and Doxorubicin in significantly reducing tumor size in mice.

Areas of Application

Therapeutic drugs.

Stage of Development

Animal studies in progress.

Lead Inventor

Dr. Samuel J. Danishefsky

Patent Information

• US issued patents 6,147,076 and 5,284,947 (to which Memorial Sloan-Kettering has exclusive rights) covering method of preparation, composition, and therapeutic uses of N-acetyl ardeemin and analogues.
• PCT application published as WO 97/18215.
• Patent prosecution ongoing in several major countries and issued in Australia (No. 729877) and in Mexico (No. 210289).

Related Inventions

• SK 1087. Ningalin B analogs employable for reversing multidrug resistance.
• SK 740. Use of reverse prenyl compounds for suppressing immune function.

Contact Information

Julia Calonge, PhD
Tel. 212-639-6181; Fax212-717-3439
E-mail: calongej@mskcc.org