DNA damaging agents in combination with tyrosine kinase inhibitors

• US 7,838,512 B2
• Filed: 05/02/2006
• Issued: 11/23/2010
• Est. Priority Date: 02/04/1994
• Status: Expired due to Term

• Current Assignee: Dana-Farber Cancer Institute, ARCH Development Corporation (University of Chicago)
• Original Assignee: Dana-Farber Cancer Institute, ARCH Development Corporation (University of Chicago)
• Inventors: Kufe, Donald, Weichselbaum, Ralph R.
• Primary Examiner(s): Lankford; Leon B
• Assistant Examiner(s): Ariani; Kade
• Application Number:
  US11/381,311
• Publication Number:
  US 20060251734A1
• Time in Patent Office: 1,666 Days
• Field of Search: None
• US Class Current: 514/107
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/38 having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 41/0023 Agression treatment or altering
• CPC Class Codes: A61K 41/17 by ultraviolet [UV] or infrared [IR] light, X-rays or gamma rays
• CPC Class Codes: A61N 5/10 X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy A61N5/01 takes precedence

Abstract

Methods and compositions for enhancing cancer cell death using therapeutically effective amounts of DNA damaging agent(s) that act in combination to enhance cancer cell death, e.g., nucleic acid precursors, and protein tyrosine kinase inhibitors, e.g., that inhibit EGFR activity. The agents and inhibitors are administered in an amount effective to kill cancer cells, that is, the combined effect is sufficient so that cancer cell death is enhanced. If not administered at the same time, the DNA damaging agent(s) and tyrosine kinase inhibitors are administered close enough in time so they are still able to enhance cancer cell death. The methods and compositions are useful to treat neoplastic disease, e.g., pancreatic cancer.

Claims

1. A method of improving chemotherapeutic intervention in a patient, the method comprising:

(a) administering a DNA damaging agent to the patient;

(b) administering a therapeutically effective amount of a low molecular weight tyrosine kinase inhibitor to the patient, wherein the low molecular weight inhibitor binds intracellularly to inhibit the activity of more than one tyrosine kinase protein, and wherein the agent and the inhibitor act in combination by effecting a series of intracellular events to enhance cell death, thereby improving chemotherapeutic intervention.

2. A method of improving chemotherapeutic intervention in a patient, the method comprising:

(a) administering a DNA damaging agent to the patient; and

(b) administering a therapeutically effective amount of a low molecular weight tyrosine kinase inhibitor to the patient, wherein the low molecular weight inhibitor binds intracellularly to inhibit the activity of more than one tyrosine kinase protein and intracellularly inhibits phosphorylation of downstream effector molecules, and wherein the agent and the inhibitor act in combination to enhance cell death, thereby improving chemotherapeutic intervention.

3. A method of improving chemotherapeutic intervention in a patient, the method comprising:

(a) administering a DNA damaging agent to the patient;

(b) administering a therapeutically effective amount of a low molecular weight tyrosine kinase inhibitor to the patient, wherein the low molecular weight inhibitor binds intracellularly to inhibit the activity of EGFR and at least one other tyrosine kinase protein by intracellularly inhibiting phosphorylation of downstream effector molecules, and wherein the agent and the inhibitor act in combination to enhance cell death, thereby improving chemotherapeutic intervention.

4. A method of improving chemotherapeutic intervention in a patient, the method comprising:

(a) administering a DNA damaging agent to the patient;

(b) administering a therapeutically effective amount of a low molecular weight tyrosine kinase inhibitor to the patient, wherein the low molecular weight inhibitor binds intracellularly to inhibit the activity of EGFR and at least one other tyrosine kinase protein by intracellularly inhibiting the phosphorylation of downstream effector molecules to prevent DNA repair during G2 arrest, and wherein the agent and the inhibitor act in combination to enhance cell death, thereby improving chemotherapeutic intervention.

5. A method of enhancing apoptosis of cancer cells in a patient comprising chemotherapeutic intervention in a patient, the method comprising:

(a) administering a DNA damaging agent to the patient;

(b) administering a therapeutically effective amount of a low molecular weight tyrosine kinase inhibitor to the patient, wherein the low molecular weight inhibitor binds intracellularly to inhibit the activity of more than one tyrosine kinase protein and intracellularly inhibits phosphorylation of downstream effector molecules, and wherein the agent and the inhibitor act in combination to enhance apoptosis.

6. A method of improving chemotherapeutic intervention in a patient, the method comprising:

(a) administering a DNA damaging agent to the patient;

(b) administering a therapeutically effective amount of a low molecular weight tyrosine kinase inhibitor to the patient, wherein the low molecular weight inhibitor binds intracellularly to alter substrate function by inhibiting substrate phosphorylation, and wherein the agent and the inhibitor act in combination to alter the cell'"'"'s response to the agent, thereby improving chemotherapeutic intervention.

7. A method of improving chemotherapeutic intervention in a patient, the method comprising:

(a) administering a DNA damaging agent to the patient;

(b) administering a therapeutically effective amount of a low molecular weight tyrosine kinase inhibitor to the patient, wherein the low molecular weight inhibitor binds intracellularly to inhibit the activity of more than one tyrosine kinase protein to prevent DNA repair during G2 arrest, and wherein the agent and the inhibitor act in combination to enhance cell death, thereby improving chemotherapeutic intervention.