Use of CHK1 inhibitors to control cell proliferation
A technology of cell proliferation and inhibitors, which is applied in anti-inflammatory agents, non-central analgesics, medical preparations containing active ingredients, etc., and can solve the problems of selective sensitization or enhanced effects, such as ineffectiveness and effectiveness
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Embodiment 1
[0888] Exposure of abnormally proliferating cells to a Chk1 inhibitor following substantial cell cycle synchronization with a Chk1 activator in an animal model of small cell lung cancer exhibits better antiproliferative activity than coadministration
[0889] The methods of the invention provide superior anti-proliferative effects of concurrent administration in in vitro tumor models known in the art. In this experiment, gemcitabine was used as a Chk1 activator, and a diaryl urea compound according to Keegan et al., PCT / US02 / 06452, was used as a selective Chk1 inhibitor (the same Chk1 inhibitor used in Examples 2-11 ). The target phase of gemcitabine is the S phase of the cell cycle. Non-small cell lung tumor xenograft tumor model H460 is a well-known in vitro tumor model.
[0890] Nude mice were implanted with H460 tumor cells and allowed to grow to an average of 75 mm3. Tumor-bearing mice were then treated with vehicle, gemcitabine, or gemcitabine + 400 mg / kg selective Ch...
Embodiment 2
[0893] Exposure of abnormally proliferating cells to Chk1 inhibitors reduces the required exposure time to Chk1 inhibitors following substantial cell cycle synchronization with Chk1 activators in the mitotic index assay
[0894] Chkl inhibitors are tested in cell-based proliferation assays conferring the ability to increase the sensitivity of tumor cells to ionizing radiation or chemotherapeutic agents. Chk1 inhibitors were compared with 5-FU, gemcitabine, ionizing radiation, camptothecin, etoposide, hydroxyurea, cisplatin, fludarabine, Ara-C, and aphidicolin. Union is used for testing. For each experiment, serial dilutions of each compound were included in combination with ten-point dilutions of each chemotherapeutic agent to determine the chemotherapeutic agent required to inhibit cell growth by 90% (GI90) in the presence and absence of a Chk1 inhibitor concentration. The ratio of GI90 in the presence of the Chk1 inhibitor to the GI90 in the absence of the Chk1 inhibitor i...
Embodiment 3
[0899] Exposure of abnormally proliferating cells to a Chk1 inhibitor following substantial cell cycle synchronization with a Chk1 activator in an animal model of colon cancer exhibits better antiproliferative activity than coadministration
[0900] Transplant HT29 colon cancer cells into nude mice, and let the tumor grow to 200mm within 10 days 3 . Mice bearing HT-29 tumors were then treated with vehicle, 600 mg / kg Chk1 inhibitor (p.o.), 160 mg / kg gemcitabine (i.p.), or concurrent administration of gemcitabine and Chk1 inhibitor. Alternatively, mice were pretreated with gemcitabine for 24 hours, given the Chk1 inhibitor on the second day, and rested on the third day. This treatment protocol was repeated four times. This dosing regimen combines the MTD administration of gemcitabine (160 mg / kg q3d×4, that is, 4 doses are given, one dose per day, given at intervals of 3 days) and the gemcitabine pretreatment regimen.
[0901] Tumors were measured every 2-3 days until reaching...
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