A Molecular Profile of Tumours Responsive to New Imidazotetrazine (Temozolomide Analogue) Prodrugs


Y.P. Ramirez,(a) A.C. Mladek,(b) C.L. Moody,(c) R.M. Phillips,(d) A.H. Ross,(a), J.N. Sarkaria,(b) R.T. Wheelhouse,(c)

(a)University of Massachusetts Medical School, Department of Biochemistry and Molecular Pharmacology, 364 Plantation St., Worcester, MA 01605, USA. (b)Department of Radiation Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA. (c)School of Pharmacy and (d)Institute of Cancer Therapeutics, University of Bradford, Bradford, BD7 1DP, UK.

Temozolomide (Temodal®, TMZ) is licensed in Europe and the USA as first line treatment for the aggressive brain tumour glioma. After twenty years in the clinic, TMZ remains the only drug in its class. The main reason for this is that range of tumours able to respond to TMZ is constrained by its dependence on DNA mismatch repair (MMR) for activity and the ready development of resistance mediated by O6-methylguanine-DNA methyltransferase (MGMT). Moreover, acquired drug-induced mutations of these two determinants of tumour susceptibility account for the occurrence of aggressive, drug-resistant tumour regrowth after “successful” initial therapy.

New imidazotetrazines have been designed and synthesised that deliver alternative chemosensitising electrophiles to DNA in cells. Representative examples are our agents DP68 and DP86. In the NCI60 screen the new agents show a >2 log range in GI50 and are COMPARE negative, indicating some selectivity of action and a distinctive pharmacology.

The response of monolayers and neurospheres to the new agents has been characterised using a range of in vitro tissue culture models and molecular biochemical methods. Response is independent of MGMT, MMR, and p53. The ATM/ATR/FANC pathway is involved in DNA damage recognition and repair. Deficiencies in this pathway make tumours hypersensitive to the new agents (e.g. BRCA2 deficiency conferred a 3-fold hypersensitivity). This pathway also provides an “escape” route for healthy cells.

Tumour regrowth has been modelled in a neurosphere recovery assay and cells treated with the new agents show a reduced propensity for re-growth compared with TMZ-treated controls.

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