US5646185A
Expired / Lapsed
US
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Tumor treatment method
Assignee: Leland Stanford Junior University
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Filing: 1993-10-14
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Granted: 1997-07-08
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Expires: 2013-10-14
Abstract
Abstract Disclosed is a method of treating a solid tumor, where the tumor contains regions of hypoxic cells, either because of poor vascularization in the tumor or because of vasoconstrictive or vaso-occlusive measures brought to bear on the tumor. The method includes administering to a subject, a compound effective to activate protein kinase C activity in the cells of the tumor, via a route effective to direct the compound to such regions of hypoxia in the tumor. Preferred compounds include phorbol esters, diacylglycerols, and thapsigargin. Also disclosed is a vaso-occlusive composition containing a protein kinase C activator, for use in the treatment method.
Inventors
- 👤 Amato J. Giaccia
- 👤 Albert C. Koong
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-10 01:48
CPC Classifications
C; C07; C07K; C07K14/00; C07K14/435; C07K14/52; C07K14/525; A; A61; A61K; A61K31/00; A61K31/21; A61K31/215; A61K31/22; A61K31/23; A61K31/33; A61K31/335; A61K31/34; A61K38/00; A61K38/16; A61K38/17; A61K38/19; A61K38/191; A61K38/39; A61K48/00; C07K14/46; C07K14/47; C07K14/4701; C07K14/4702; C07K14/4703; A61K2300/00
Claims Analysis
Total Claims: 21
Claim 1
Independent Claim
93 words
A method of selectively killing cells in a solid tumor in a subject comprising administering to the subject, a compound effective to activate protein kinase C activity in the cells of the tumor, via a route effective to direct the compound to hypoxic cells in the tumor, where said compound is selected from the group consisting of a phorbol ester protein kinase C activator, a diacylglycerol activator of protein kinase C, and thapsigargin, and by said administering, achieving a substantially higher degree of cytotoxicity in such hypoxic cells than in normally oxygenated cells.
Claim 2
Independent Claim
93 words
A method of selectively killing cells in a solid tumor in a subject comprising administering to the subject, a compound effective to activate protein kinase C activity in the cells of the tumor, via a route effective to direct the compound to hypoxic cells in the tumor, where said compound is selected from the group consisting of a phorbol ester protein kinase C activator, a diacylglycerol activator of protein kinase C, and thapsigargin, and by said administering, achieving a substantially higher degree of cytotoxicity in such hypoxic cells than in normally oxygenated cells.
Claim 3
Dependent Claim
14 words
The method of claim 1, wherein said administering is by intravenous delivery of compound.
Claim 4
Dependent Claim
46 words
The method of claim 1, wherein the tumor contains hypoxic cells by virtue of poor vascularization of the tumor, said method further comprising identifying regions within the tumor containing said hypoxic cells, and where said administering includes introducing said compound directly into said hypoxic cell regions.
Claim 5
Dependent Claim
18 words
The method of claim 3, wherein said introducing is by hypodermic injection directly into said hypoxic cell regions.
Claim 6
Dependent Claim
19 words
The method of claim 3, wherein said introducing is by catheter delivery into vessels supplying said hypoxic cell regions.
Claim 7
Dependent Claim
25 words
The method of claim 1, which further comprises occluding vessels supplying blood to the tumor, to induce a hypoxic state in cells of the tumor.
Claim 8
Dependent Claim
26 words
The method of claim 6, wherein said occluding includes delivering a vasoconstrictive agent to the tumor site, prior to or at the time of said administering.
Claim 9
Dependent Claim
29 words
The method of claim 6, wherein said occluding includes delivering a vaso-occlusive agent to the tumor site, via catheter administration, prior to or at the time of said administering.
Claim 10
Dependent Claim
15 words
The method of claim 8, wherein said vaso-occlusive agent contains said compound in releasable form.
Claim 11
Dependent Claim
13 words
The method of claim 1, wherein said compound is 12-O-tetradecanoylphorbol-13-acetate or phorbol 12,13-dibutyrate.
Claim 12
Dependent Claim
10 words
The method of claim 1, wherein said compound is 2-acetyl-1-oleylglycerol.
Claim 13
Dependent Claim
10 words
The method of claim 1, wherein said compound is thapsigargin.
Claim 14
Dependent Claim
95 words
A vaso-occlusion composition for use in treating a solid tumor, by catheter delivery of the composition to vessels feeding the tumor, comprising a vaso-occlusion agent effective to form a stable vaso-occlusive mass when injected from a catheter into a vessel, to occlude blood flow in the vessel, and contained in said agent, in a releasable form, a compound effective to activate protein kinase C activity in mammalian tumor cells, where said compound is selected from the group consisting of a phorbol ester protein kinase C activator, a diacylglycerol activator of protein kinase C, and thapsigargin.
Claim 15
Dependent Claim
95 words
A vaso-occlusion composition for use in treating a solid tumor, by catheter delivery of the composition to vessels feeding the tumor, comprising a vaso-occlusion agent effective to form a stable vaso-occlusive mass when injected from a catheter into a vessel, to occlude blood flow in the vessel, and contained in said agent, in a releasable form, a compound effective to activate protein kinase C activity in mammalian tumor cells, where said compound is selected from the group consisting of a phorbol ester protein kinase C activator, a diacylglycerol activator of protein kinase C, and thapsigargin.
Claim 16
Dependent Claim
13 words
The composition of claim 13, wherein said vaso-occlusive agent is composed of collagen.
Claim 17
Dependent Claim
13 words
The composition of claim 13, wherein said compound is 12-O-tetradecanoylphorbol-13-acetate or phorbol 12,13-dibutyrate.
Claim 18
Dependent Claim
10 words
The composition of claim 13, wherein said compound is 2-acetyl-1-oleylglycerol.
Claim 19
Independent Claim
125 words
A method of selectively killing cells in a solid tumor in a subject comprising: administering to the subject, a compound effective to activate protein kinase C activity in the cells of the tumor, via a route effective to direct the compound to hypoxic cells in the tumor; transforming cells in the tumor with a vector containing (i) a gene encoding a yeast oxygen-dependent repressor protein, a promoter upstream of the gene effective to ensure high levels of transcription of the gene, and (ii) an oxygen-dependent repressor sequence, and under the control of this sequence, a minimal promoter and a gene encoding tumor necrosis factor protein, and by said administering, achieving a substantially higher degree of cytotoxicity in such hypoxic cells than in normally oxygenated cells.
Claim 20
Independent Claim
125 words
A method of selectively killing cells in a solid tumor in a subject comprising: administering to the subject, a compound effective to activate protein kinase C activity in the cells of the tumor, via a route effective to direct the compound to hypoxic cells in the tumor; transforming cells in the tumor with a vector containing (i) a gene encoding a yeast oxygen-dependent repressor protein, a promoter upstream of the gene effective to ensure high levels of transcription of the gene, and (ii) an oxygen-dependent repressor sequence, and under the control of this sequence, a minimal promoter and a gene encoding tumor necrosis factor protein, and by said administering, achieving a substantially higher degree of cytotoxicity in such hypoxic cells than in normally oxygenated cells.
Claim 21
Dependent Claim
21 words
The method of claim 17, wherein said vector further includes a protein kinase C responsive element upstream of said oxygen-dependent repressor.
References Cited (Backward Citations)
JPS63250323A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 2000-07-07 | 2001-01-06 | 2001-07-08 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2004-07-07 | 2005-01-06 | 2005-07-08 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2008-07-07 | 2009-01-06 | 2009-07-08 | $7700.00 | Window Closed / Lapsed |