Methods and compositions for use in treating cancer

This application is a continuation of, and claims priority from, U.S. patent application Ser. No. 10/687,526, filed Oct. 16, 2003, which is a continuation of U.S. patent application Ser. No. 10/272,167, filed Oct. 16, 2002 (now U.S. Pat. No. 6,653,341), which is a continuation-in-part of U.S. patent application Ser. No. 09/843,617, filed Apr. 26, 2001 (now U.S. Pat. No. 6,469,182), which is a continuation of U.S. patent application Ser. No. 09/677,485, filed Oct. 2, 2000 (now U.S. Pat. No. 6,365,759), which is a continuation of U.S. patent application Ser. No. 09/334,488, filed Jun. 16, 1999 (now U.S. Pat. No. 6,214,865), which claims benefit of U.S. Provisional Patent Application Ser. No. 60/089,682, filed Jun. 17, 1998 (now abandoned). The contents of the earlier filed applications are incorporated by reference herein in their entirety.

This invention relates to methods and compositions for use in treating cancer.

Cancer is a term used to describe a wide variety of diseases that are each characterized by the uncontrolled growth of a particular type of cell. It begins in a tissue containing such a cell and, if the cancer has not spread to any additional tissues at the time of diagnosis, may be treated by, for example, surgery, radiation, or another type of localized therapy. However, when there is evidence that cancer has metastasized from its tissue of origin, different approaches to treatment are typically used. Indeed, because it is not possible to determine the extent of metastasis, systemic approaches to therapy are usually undertaken when any evidence of spread is detected. These approaches involve the administration of chemotherapeutic drugs that interfere with the growth of rapidly dividing cells, such as cancer cells.

Halichondrin B is a structurally complex, macrocyclic compound that was originally isolated from the marine sponge Halichondria okadai, and subsequently was found in Axinella sp., Phakellia carteri, and Lissondendryx sp. A total synthesis of halichondrin B was published in 1992 (Aicher et al., J. Am. Chem. Soc. 114:3162-3164, 1992). Halichondrin B has been shown to inhibit tubulin polymerization, microtubule assembly, betas-tubulin crosslinking, GTP and vinblastine binding to tubulin, and tubulin-dependent GTP hydrolysis in vitro. This molecule has also been shown to have anti-cancer properties in vitro and in vivo. Halichondrin B analogs having anti-cancer activities are described in U.S. Pat. No. 6,214,865 B1.

The invention provides methods of treating cancer in a patient, involving administration of a compound having the formula:

or a pharmaceutically acceptable salt thereof, which is carried out in combination with a second approach to treatment.

The second approach to treatment can involve administration of a chemotherapeutic drug to the patient. Examples of types of such drugs include antimetabolites, antibiotics, alkylating agents, plant alkaloids, and hormonal agents.

An antimetabolite, such as gemcitabine, can be used in the invention in the treatment of, for example, non-small cell lung carcinoma, pancreatic cancer, or metastatic breast cancer. An antimetabolite, such as capecitabine, can also be used in the invention in the treatment of, for example, breast cancer or colorectal cancer.

An example of a type of antibiotic that can be used in the invention is anthracyclines (e.g., doxorubicin), which can be used in the invention, for example, in the treatment of breast cancer.

Alkylating agents, such as, for example, carboplatinum or cisplatinum, can be used in the invention to treat, for example, non-small cell lung cancer or ovarian cancer.

Plant alkaloids, such as irinotecan and topotecan, can be used in the invention to treat, for example, colorectal cancer, ovarian cancer, or non-small cell lung carcinoma.

The second approach to treatment can also involve administration of an anticoagulant or antithrombotic agent (e.g., heparin) to the patient.

The invention also provides compositions that include a compound having the formula: