Treatment of metastasis

• US 4,751,224 A
• Filed: 01/21/1986
• Issued: 06/14/1988
• Est. Priority Date: 07/21/1983
• Status: Expired due to Fees

• Current Assignee: Brown University
• Original Assignee: Brown University
• Inventors: Agarwal, Kailash C., Parks, Robert E. Jr.
• Primary Examiner(s): Goldberg, Jerome D.
• Application Number:
  US06/820,923
• Time in Patent Office: 875 Days
• Field of Search: 514/455, 514/307, 514/218, 514/258, 514/264, 514/46, 514/573, 514/248
• US Class Current: 514/248
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom

Abstract

A method for reducing the incidence of metastasis in tumor victims without treating the primary tumor per se resides in the administration of forskolin or its analogs which are potent inhibitors of platelet aggregation. Forskolin compounds are generally defined as labdane diterpenoids having the general formula: ##STR1## These compounds may be administered alone or in combination with other inhibitors of platelet aggregation.

Claims

1. A method for preventing metastatic disease in a human or animal suffering from a tumor without treating the primary tumor, the method comprising:

administering a forskolin compound to said human or animal in amount effective to inhibit metastatic tumor cell-platelet interactions, the compound having the formula;

##STR4## where R₁ is hydrogen or a hydroxy or lower alkoxy, sulfonate or carbonate group;

where R₂ is a hydroxy, carbonate, acetyl, or acetoxy or lower alkanoyl group;

where R₃ is a hydroxy, carbonate, acetyl or acetoxy or lower alkanoyl or tosyl group;

where R₄ is hydrogen or a hydroxy or lower alkoxy, sulfonate or carbonate group;

where R₅ is either double-bonded oxygen or separately bound hydrogen and hydroxy groups; and

where R₆ is a lower alkene or oxygen.

2. The method of claim 1 wherein the forskolin compound has the formula:

##STR5##

3. The method of claim 1 wherein the method further includes administering to said human or animal suffering from a tumor in conjunction with said forskolin compound a nucleoside transport inhibitor selected from the group consisting of p-nitrobenzylthionosine, dilazep, dipyridamole, oxagrelate and papaverine in an amount effective to retard adenosine uptake by red blood cells.

4. The method of claim 1 wherein the method further includes administering to said human or animal suffering from a tumor in conjunction with said forskolin compound a cAMP-blocking agent selected from the group consisting of theophylline, dipyridamole, oxagrelate and papaverine in an amount effective to block the action of cAMP phosphodiesterase in converting cAMP to AMP.

5. The method of claim 1 wherein the method further includes administering to said human or animal suffering from a tumor in conjunction with said forskolin compound as adenylate cyclase stimulating agent selected from the group consisting of prostaglandin E, N⁶ -phenyladenosine and 2-fluoroadenosine in an amount effective to stimulate membrane adenylate cyclase.

6. A pharmaceutical composition for preventing metastatic disease in a human or animal suffering from a tumor without treating the primary tumor, the composition comprising an effective amount of forskolin compound having the formula ##STR6## where R₁ is hydrogen or a hydroxy or lower alkoxy, sulfonate or carbonate group;

where R₂ is a hydroxy, carbonate, acetyl, or acetoxy or lower alkanoyl group;

where R₃ is a hydroxy, carbonate, acetyl or acetoxy or lower alkanoyl or tosyl group;

where R₄ is hydrogen or a hydroxy or lower alkoxy, carbonate or carbonate group;

where R₅ is either double-bonded oxygen or separately bound hydrogen and hydroxy groups; and

where R₆ is a lower alkene or oxygen, and a nucleoside transport inhibitor selected from the group consisting of p-nitrobenzylthionosine, dilazep, dipyridamole, oxagrelate and papervine in an amount effective to retard adenosine uptake by red blood cells.

7. The composition of claim 6 wherein the forskolin compound has the following formula:

##STR7##

8. A pharmaceutical composition for preventing metastatic disease in a human or animal suffering from a tumor without treating the primary tumor the composition comprising an effective amount of a forskolin compound having the formula:

##STR8## where R₁ is hydrogen or a hydroxy or lower alkoxy, sulfonate or carbonate group;

where R₂ is a hydroxy, carbonate, acetyl, or acetoxy or lower alkanoyl group;

where R₃ is a hydroxy, carbonate, acetyl or acetoxy or lower alkanoyl or tosyl group;

where R₄ is hydrogen or a hydroxy or lower alkoxy, sulfonate or carbonate group;

where R₅ is either double-bonded oxygen or separately bound hydrogen and hydroxy groups; and

where R₆ is a lower alkene or oxygen, and a cAMP-blocking agent selected from the group consisting of theophylline, dipyridamole, oxagrelate and papaverine in an amount effective to block the action of cAMP phosphodiesterase in converting cAMP to AMP.

9. The composition of claim 8 wherein the cAMP-blocking agent is oxagrelate.

10. The composition of claim 8 wherein the forskolin compound has the following formula:

##STR9##