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Title: Optimising treatment with combinations of novel anti-kinase drugs and cytotoxic therapy
Author: Harrison, Luke Robert Edward
ISNI:       0000 0001 3539 2321
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2008
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Aim: To investigate the mechanism of potentiation of cytotoxic drugs by NU2058 (06-cyclohexylmethyl guanine), which had been synthesised as a cyclin-dependent kinase 2 (CDK2) inhibitor. One hundred and forty four structurally related compounds to NU2058 were screened for their ability to potentiate cisplatin cytotoxicity in SQ20b human cancer cells. Sixty six compounds> increased cisplatin cytotoxicity; however, no relationship between CDK2 enzyme inhibition (assessed by immunoblotting for phospho_Rb1 821 protein - a target of CDK2) and cisplatin potentiation was observed. Compound NU6242 was identified as being 10-fold more potent potentiator of cisplatin than NU2058. This was confirmed using LoVo tumour cells. . I They did not potentiate cisplatin despite inhibiting CDK2. A screen of purified' Compounds NU6230 and NU6094 were structural similar to NU2058 and NU6242. kinases identified AMP-activated protein kinase as a possible target ofNU6242. NU2058 (100 ~M) was non-toxic to SQ20b cells. NU2058 only increased cisplatin cytotoxicity (LCso dose modification factor (DMF) of 3.8), when present simultaneously with cisplatin. NU2058 increased cytotoxicity of carboplatin (DMF 2.7), oxaliplatin (DMF 1.8), and melphalan (DMF 2.2), but not temozolomide or ionising radiation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available