Methods for cytotoxic chemotherapy-based predictive assays
The invention relates to methods, systems and kits for determining therapeutic effectiveness or toxicity of cancer-treating compounds that incorporate into or bind to DNA. In particular, the invention is directed to methods, systems and kits for predicting a patient's treatment outcome after administration of a microdose of therapeutic composition to the patient. The methods provides physicians with a diagnostic tool to segregate cancer patients into differential populations that have a higher or lower chance of responding to a particular therapeutic treatment.
1. A method of screening a cancer patient for treatment with oxaliplatin, comprising:
administering a diagnostic reagent comprising a patient dose of a microdose formulation of a radiolabeled oxaliplatin to a patient, wherein said radiolabeled oxaliplatin binds to the DNA of said patient to form a DNA-oxaliplatin adduct;
obtaining a tumor tissue sample from said patient about 36-72 hours after said administration, wherein said sample comprises said DNA-oxaliplatin adduct;
measuring a frequency of said DNA-oxaliplatin in said sample; and
comparing said frequency with a first predetermined threshold.
2. The method of claim 1 , further comprising administering oxaliplatin to said patient based on said comparison of said DNA-drug adduct frequency with said first predetermined threshold.
3. The method of claim 1 , further comprising administering oxaliplatin to said patient if said DNA-drug adduct frequency is above said first predetermined threshold.
4. The method of claim 3 , further comprising administering oxaliplatin to said patient if said DNA-drug adduct frequency is below a second predetermined threshold, wherein said second predetermined threshold is indicative of drug toxicity.
5. The method of claim 1 , wherein said microdose formulation is administered to a patient at a dose of 10% or less, 1% or less, or 0.1% or less of a therapeutic dose of oxaliplatin.
6. The method of claim 1 , wherein said radiolabel is 14 C or 3 H.
7. The method of claim 1 , wherein said comparison provides a likelihood of responsiveness to a therapeutic dose of oxaliplatin based on said DNA-drug adduct frequency.
8. The method of claim 1 , wherein said DNA drug adduct comprises a monoadduct or a diadduct or both.
9. The method of claim 8 , wherein the patient dose of said microdose formulation comprises 1×10 6 to 10×10 6 DPM/kg body weight of [ 14 C]oxaliplatin, and wherein said DNA-drug adduct frequency is between 0.5 and 50 per 10 8 nucleotides.
10. A method of screening a cancer patient for combination chemotherapy treatment, comprising:
administering a diagnostic reagent comprising a microdose formulation of a plurality of chemotherapeutic drugs to a patient, wherein at least one of said plurality of chemotherapeutic drugs is radiolabeled oxaliplatin and binds to the DNA of said patient to form a DNA-oxaliplatin adduct;
obtaining a tumor tissue sample from said patient about 36-72 hours after said administration, wherein said sample comprises said DNA-oxaliplatin adduct;
measuring a frequency of said DNA-oxaliplatin adduct in said sample; and
comparing said frequency with a first predetermined threshold.
11. The method of claim 1 , wherein said tumor tissue sample is obtained from said patient about 48 hours after said administration of said microdose formulation to said patient.