O6-(4-bromothenyl)guanine improves the therapeutic index of temozolomide against A375M melanoma xenografts

Middleton, Mark R.; Kelly, Jane; Thatcher, Nicholas; Donnelly, Dervilla M. X.; Mcelhinney, R. S.; McMurry, T. Brian H.; McCormick, Joan E.; Margison, Geoffrey P.

doi:10.1002/(sici)1097-0215(20000115)85:2%3c248::aid-ijc16%3e3.0.co;2-v

Cited by 62 publications

(42 citation statements)

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“…Thus, the therapeutic index of temozolomide is increased by PaTrin-2 in this animal model. We have previously shown that human melanoma xenografts expressing moderate levels of MGMT do respond to growth inhibition by temozolomide, but this is considerably enhanced by pretreatment with PaTrin-2 (Middleton et al, 2000(Middleton et al, , 2002. Current phase I studies are investigating the dose of PaTrin-2 that is necessary for complete inactivation of MGMT in patients with a variety of cancer types, prior to phase II studies.…”

Section: Discussionmentioning

confidence: 99%

O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts

et al. 2005

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Tumour resistance to chemotherapy involving methylating agents such as DTIC (dacarbazine) and temozolomide is linked to expression of the DNA repair protein O 6 -alkylguanine-DNA alkyltransferase (MGMT). There is considerable interest in improving the efficacy of such O 6 -alkylating chemotherapy by the prior inactivation of MGMT. We have examined the effect of the modified guanine base, O 6 -(4-bromothenyl)guanine (PaTrin-2, Patrint, Lomeguatrib) on MGMT activity and cell or xenograft tumour growth inhibition by temozolomide in the human breast carcinosarcoma cell line, MCF-7. PaTrin-2 effectively inactivated MGMT in MCF-7 cells (IC 50 B6 nM) and in xenografts there was complete inactivation of MGMT within 2 h of dosing (20 mg kg À1 i.p.) and only slight recovery by 24 h. MGMT inactivation in a range of murine host tissues varied between complete and B60%, with extensive recovery by 24 h. PaTrin-2 (10 mM) substantially increased the growth inhibitory effects of temozolomide in MCF-7 cells (D 60 ¼ 10 mM with PaTrin-2 vs 400 mM without). In MCF-7 xenografts, neither temozolomide (100 mg kg À1 day À1 for 5 days) nor PaTrin-2 (20 mg kg À1 day À1 for 5 days) had any significant effect on tumour growth. In contrast, the PaTrin-2 -temozolomide combination produced a substantial tumour growth delay: median tumour quintupling time was increase by 22 days (Po0.005) without any significant increase in toxicity as assessed from animal weight. A PaTrin-2 -temozolomide combination may therefore be beneficial in the treatment of human breast cancers.

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Section: Discussionmentioning

confidence: 99%

O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts

et al. 2005

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“…Even more effective than O6BG, on a molar basis, are 8ABG and O6BTG. 40 The IC 50 values for inhibition of MGMT in vivo (in cultivated cells) of these drugs are 60, 23 and 4 nM, respectively (Table I). Thus, O6BTG is about 15 times as effective as O6BG.…”

Section: Discussionmentioning

confidence: 99%

“…However, they do not exhibit organ or tumor specificity, and therefore, their application in combination with an O 6 -alkylguanine-generating drug might cause serious side effects due to systemic toxicity of non-tumor tissue. 17,40,41 Clearly, any method to target the MGMT inhibitor to the tumor tissue would provide the advantage of minimizing toxic side effects. To target MGMT inhibitors to the tumor tissue, and thus abolish general MGMT depletion, we coupled various MGMT inhibitors with D-glucose.…”

Section: Discussionmentioning

confidence: 99%

Inactivation ofO6-methylguanine-DNA methyltransferase by glucose-conjugated inhibitors

Reinhard

Eichhorn²,

Wießler

et al. 2001

Int. J. Cancer

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Methylating and chloroethylating agents have been used in the therapy of various kinds of cancer for a decade. 1 Methylating drugs (e.g., procarbazine, dacarbazine, streptozotocin and temozolomide) and chloroethylating agents (e.g., carmustine, lomustine, semustine and fotemustine) alkylate DNA at various sites, among them the O 6 position of guanine. The resulting DNA lesions, i.e., O 6 -methylguanine and O 6 -chloroethylguanine, are highly pro-mutagenic 2 and pro-carcinogenic 3,4 and act as a trigger of cytotoxicity 5,6 and apoptosis. 7,8 Cytotoxicity and apoptosis caused by O 6 -methylguanine are mediated by mismatch repair, 9,10 whereas when caused by O 6 -chloroethylguanine the result is chemical re-arrangement of the chloroethyl group forming cross-links between N1 of guanine and N3 of cytosine. 11 These cross-links are supposed to block DNA replication and trigger the cytotoxic response.The primary cytotoxic lesions O 6 -methylguanine and O 6 -chloroethylguanine are subject to repair by the DNA-repair protein O 6 -methylguanine-DNA methyltransferase (MGMT; also designated alkyltransferase), which transfers the alkyl group from the O 6 position of guanine onto an internal cysteine residue in its active site, leading to an alkylthioether that cannot be re-activated. Thus, guanine in the DNA is restored and the MGMT molecule inactivated. Due to the suicide mechanism of action, the repair reaction is stoichiometric, depending on the initial number of MGMT molecules per cell and the rate of resynthesis upon alkylation. 12,13 The MGMT-repair protein plays a key role in the resistance of tumor cells to methylating and chloroethylating drugs. This has been demonstrated by comparison of naturally occurring tumor cell variants, 14 by transfection experiments in which MGMT was over-expressed, 6 by MGMT knockout strategies 15 and by MGMTdepletion experiments with anti-sense oligonucleotides 16 or specific inhibitors. 17,18 In isogenic cell lines transfected with MGMT cDNA, the level of resistance was a linear function of cellular MGMT activity up to a maximal saturation level, where nonspecific effects of the drugs come into play. A significant protective effect of MGMT can be achieved with quite low expression levels. 6

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“…The development of nontoxic MGMT pseudosubstrates has enabled this strategy to be revisited. O 6 -meG itself was shown to be very inefficient (Gerson et al, 1992) but its analogues, O 6 -benzylguanine (Dolan et al, 1992) and lomeguatrib (LM;methoxypurin-2-amine) (Middleton et al, 2000a;Ranson et al, 2006), are considerably more potent MGMT inactivators and currently in clinical trials.…”

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confidence: 99%

O6-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib

et al. 2009

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We evaluated the pharmacodynamic effects of the O 6 -methylguanine-DNA methyltransferase (MGMT) inactivator lomeguatrib (LM) on patients with melanoma in two clinical trials. Patients received temozolomide (TMZ) for 5 days either alone or with LM for 5, 10 or 14 days. Peripheral blood mononuclear cells (PBMCs) were isolated before treatment and during cycle 1. Where available, tumour biopsies were obtained after the last drug dose in cycle 1. Samples were assayed for MGMT activity, total MGMT protein, and O 6 -methylguanine (O 6 -meG) and N7-methylguanine levels in DNA. MGMT was completely inactivated in PBMC from patients receiving LM, but detectable in those on TMZ alone. Tumours biopsied on the last day of treatment showed complete inactivation of MGMT but there was recovery of activity in tumours sampled later. Significantly more O 6 -meG was present in the PBMC DNA of LM/TMZ patients than those on TMZ alone. LM/TMZ leads to greater MGMT inactivation, and higher levels of O 6 -meG than TMZ alone. Early recovery of MGMT activity in tumours suggested that more protracted dosing with LM is required. Extended dosing of LM completely inactivated PBMC MGMT, and resulted in persistent levels of O 6 -meG in PBMC DNA during treatment.

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O6-(4-bromothenyl)guanine improves the therapeutic index of temozolomide against A375M melanoma xenografts

Cited by 62 publications

References 0 publications

O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts

O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts

Inactivation ofO6-methylguanine-DNA methyltransferase by glucose-conjugated inhibitors

O6-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib

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