Treatment of cancer using hypoxia activated prodrugs
a cancer and activated prodrug technology, applied in the field of medicine, pharmacology, medicinal chemistry, can solve the problems of adverse side effects of patients, difficult to kill cancer cells without damaging or killing normal cells, and difficult to cure cancer cells
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example 1
Pharmaceutical Formulations of TH-302
[0186]This example describes pharmaceutical formulations of TH-302 as well as the results of experimentation demonstrating the advantages of certain formulations. As discussed below, a formulation containing TH-302, ethanol and TWEEN 80 provided advantages over other formulations including higher solubility of TH-302, allowing for a more concentrated solution, greater stability on storage, and the absence of precipitation when the concentrated formulation is diluted into D5W or saline.
[0187]The experimentation was performed on the following systems (or equivalents): HP 1090 Series II, with Alltech, Alltima C18, 50×4.6, 3 μM or 5 μm HPLC column; HP1090 pump; Diode-Array Detector; and Chemstation version A.08.01 data acquisition system. The following reversed phase HPLC conditions were used for the experimental studies: column temperature was room temperature; there was no sample thermostat; the detector wavelength was 325 nm, 254 nm; the pump conf...
example 2
Treatment of Lung Cancer and Melanoma in Human Patients Using TH-302 Monotherapy
[0219]A Phase 1 clinical trial was conducted with TH-302. The starting dose was 7.5 mg / m2 IV over 30-60 min administered once weekly for 3 weeks of a 4 week cycle. A modified accelerated titration design was used. Two of five patients dosed at 670 mg / m2 exhibited dose limiting toxicity (DLT): herpes simplex perianal / rectal ulcers and dehydration due to mucositis. Six patients were enrolled at an intermediate dose of 575 mg / m2, and this dose was established as the MTD for this administration schedule, as five of the six patients did not exhibit a DLT at this dose.
[0220]There was evidence of anticancer activity even at the lowest dose, with one NSCLC patient exhibiting stable disease (SD) for 7.3 months. Two patients, one with SCLC treated at 480 mg / m2 and another with melanoma treated at 670 mg / m2, had unconfirmed partial responses, as described in more detail below; 16 patients had stable disease.
[0221]M...
example 3
Effect of Administration Schedule for HAP and Non-HAP Chemotherapeutic Agents in Combination Therapy
[0227]As demonstrated herein (also see Examples 4 and 5 below), combination therapy of cancer with HAP and non-HAP anticancer agents provide more efficacious treatment with fewer side effects. For this demonstration, ectopic models were employed in nude mice. Anti-tumor activity was evaluated by tumor growth delay (TGD) and tumor growth inhibition (TGI). Body weight change, gross and microscopic assessment of tissue changes, and hematologic assays served for toxicity assessment. Testing in these models was conducted generally as follows. 1×106 (H460 human non-small cell lung cancer or HT1080 human fibrosarcoma cells) or 3×106 (PC-3 human prostate cancer cells) were implanted in the subcutaneous space of the right flank to obtain ectopic xenograft models. Randomization and dosing was initiated when tumors reached a certain size (100-150 mm3). API grade of TH-302 was used in all experim...
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