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Methods for treating cancer

A cancer and application technology, applied in the direction of pharmaceutical formulations, medical preparations containing active ingredients, active ingredients of phosphorus compounds, etc., can solve the problems of increased efficacy of cancer

Active Publication Date: 2013-12-18
分子模板有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although clinical trials have made promising reports on the anticancer efficacy of TH-302, there is still a need to make use of TH-302 and other hypoxia-activated prodrugs to treat cancer in monotherapy and in combination with other anticancer agents. increased effectiveness of

Method used

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  • Methods for treating cancer
  • Methods for treating cancer
  • Methods for treating cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] Example 1: Effect of PARP Inhibitors on TH-302

[0096] The effect of the PARP inhibitor ABT-888 on TH-302 activity was investigated in three human cancer cell lines: human non-small cell lung cancer H460, human melanoma A375, and human colorectal cancer HCT116.

[0097] Cells were pretreated with ABT-888 for 1 h under normoxia, and then co-incubated with TH-302 for an additional 2 h under normoxia or hypoxia. After 3 days of incubation in the presence of ABT-888, cell viability was determined using alamar blue. For the temozolomide (TMZ) group, cells were co-treated with temozolomide and ABT-888 for 3 days after pretreatment with ABT-888 for 1 h. The results are listed in Tables 1-6 below.

[0098] The results indicated that TH-302 activity was not substantially affected by the presence of ABT-888 (see Tables 2, 4 and 6). In contrast, the activity of the monoalkylating agent temozolomide was enhanced by ABT-888 in these cancer cell lines (see Tables 1, 3 and 5). ...

Embodiment 2

[0114] Example 2: TH-302 is active in HDR impaired cells

[0115] Wild-type AA8 cells and HDR-impaired irs1SF and UV41 cells were treated with TH-302 for 2 h, washed, and then incubated for 3 days. At the end of the incubation, live cells were quantified using alamar blue. The hypoxia-selective anticancer activity of TH-302 was observed in homology-directed DNA repair (or homologous recombination DNA repair, HDR)-deficient cell lines UV41 and irs1SF. The results suggest that HDR may be related to the DNA repair process initiated by TH-302. The results indicate that the combination of TH-302 with agents that inhibit the repair of TH-302-induced DNA damage, especially HDR, is believed to result in enhanced efficacy of this clinical stage anticancer agent.

[0116] Table 8

[0117]

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PUM

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Abstract

Administration of TH-302 or another hypoxia activated prodrug in combination with a pharmacological agent that down-regulates or inhibits homology directed repair (HDR) is useful for treating cancer.

Description

[0001] Cross References to Related Applications [0002] This application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Application No. 61 / 470,921, filed April 1, 2011, the entire contents of which are incorporated herein by reference. technical field [0003] The present invention relates to the use of hypoxia-activated prodrugs in combination with homology-directed repair inhibitors to treat cancer. Background technique [0004] TH-302 is a hypoxia-activated prodrug in clinical development for the treatment of cancer. See PCT Publication Nos. 2007 / 002931; 2008 / 083101; 2010 / 048330; 2012 / 006032; and 2012 / 009288; and U.S. Patent Publication No. 61 / 475,844, filed April 15, 2011 No., each of which is incorporated herein by reference. TH-302 releases DNA-crosslinked bromoifosfamide (Br-IPM, bromoisophosphoramide) under hypoxic conditions. TH-302 is a hypoxia-activated prodrug (HAP) whose mechanism of action involves DNA alkylation, resulting in DNA cross-linking....

Claims

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Application Information

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IPC IPC(8): A61K31/4168A61K31/66A61P35/00
CPCA61K45/06A61K31/665A61K38/05A61K31/167A61K31/506A61K31/517A61K31/675A61P35/00A61P35/02A61P43/00A61K2300/00A61K31/66A61K31/4168
Inventor 查尔斯·哈特马克·马泰乌齐约翰·柯尔德
Owner 分子模板有限公司
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