A phase II trial of lomeguatrib and temozolomide in metastatic colorectal cancer

Khan, Omar; Ranson, Malcolm R; Michael, M; Olver, Ian; Levitt, N C; Mortimer, Peter G.; Watson, Amanda J.; Margison, Geoffrey P.; Midgley, Rachel; Middleton, Mark R.

doi:10.1038/sj.bjc.6604366

Cited by 52 publications

(37 citation statements)

References 27 publications

(27 reference statements)

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“…60,61 At therapeutic levels, O 6 -benzylguanine renders the tumor cells more sensitive to the alkylating agent and establishes its potential therapeutic effect as an enhancer of drug effect. In gliomas, it has been used with negative results.…”

Section: Future Directionsmentioning

confidence: 99%

Treatment of pituitary neoplasms with temozolomide

Syro

Ortíz

Scheithauer

et al. 2010

Cancer

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Temozolomide, an orally administered alkylating agent, is used to treat malignant gliomas. Recent reports also have documented its efficacy in the treatment of pituitary adenomas and carcinomas. Temozolomide methylates DNA and thereby exhibits an antitumor effect. O 6 -methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, removes alkylating adducts induced by temozolomide, counteracting its effects. The authors of this review conducted a Medline database search regarding temozolomide in the treatment of pituitary tumors. Demographic characteristics, tumor types, and therapeutic responses were noted in all patients. Data regarding MGMT immunoexpression, which was documented in some studies, were correlated with information regarding clinical and radiologic responses. To date, there have been 19 reported cases of adenohypophyseal tumors treated with temozolomide, including 13 adenomas and 6 carcinomas. Ten of those 13 adenomas responded favorably, and 2 nonresponsive tumors had highlevel MGMT immunoexpression. All 6 carcinomas responded to therapy, but data regarding MGMT expression were available for only 3 patients, and each had low MGMT expression. In 2 adenomas, morphologic studies were performed both before and after the patients received temozolomide. The responsive tumor had necrosis, hemorrhage, fibrosis, and neuronal differentiation. The nonresponsive tumor had no changes. There have been no reported complications attributable to temozolomide. The current results indicated that temozolomide is efficacious in the treatment of aggressive pituitary adenomas and pituitary carcinomas. Evidence indicated that low-level MGMT immunoexpression is correlated with a favorable response. A significant proportion of pituitary adenomas and carcinomas had low MGMT immunoexpression. Cancer 2011;117:454-62.

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Section: Future Directionsmentioning

confidence: 99%

Treatment of pituitary neoplasms with temozolomide

Syro

Ortíz

Scheithauer

et al. 2010

Cancer

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“…Moreover, in elderly glioblastoma patients MGMT status predicts clinical response to temozolomide (13) Unfortunately, therapies combining MGMT inhibitors with temozolomide in melanoma or colorectal cancer patients have so far failed to improve outcome due to exacerbated treatment-related hematologic toxicity (14)(15)(16). More recently, several small-molecule inhibitors have been developed to target other DNA repair mechanisms, with the aim to use them as synthetically lethal single agents or in combination therapies with chemotherapeutic agents such as temozolomide.…”

Section: Introductionmentioning

confidence: 99%

MGMT Expression Predicts PARP-Mediated Resistance to Temozolomide

Erice

Smith

White

et al. 2015

Molecular Cancer Therapeutics

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Melanoma and other solid cancers are frequently resistant to chemotherapies based on DNA alkylating agents such as dacarbazine and temozolomide. As a consequence, clinical responses are generally poor. Such resistance is partly due to the ability of cancer cells to use a variety of DNA repair enzymes to maintain cell viability. Particularly, the expression of MGMT has been linked to temozolomide resistance, but cotargeting MGMT has proven difficult due to dose-limiting toxicities. Here, we show that the MGMT-mediated resistance of cancer cells is profoundly dependent on the DNA repair enzyme PARP. Both in vitro and in vivo, we observe that MGMT-positive cancer cells strongly respond to the combination of temozolomide and PARP inhibitors (PARPi), whereas MGMT-deficient cells do not. In melanoma cells, temozolomide induced an antiproliferative senescent response, which was greatly enhanced by PARPi in MGMTpositive cells. In summary, we provide compelling evidence to suggest that the stratification of patients with cancer upon the MGMT status would enhance the success of combination treatments using temozolomide and PARPi.

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“…Therefore, we hypothesized that MGMT inactivation by hypermethylation may confer sensitivity to these agents (17). However, discrepant data about the clinical activity of these drugs in mCRC are reported in the literature (18)(19)(20)(21). A response rate of 19%, including one complete response, was reported in 26 fluoropyrimidine-resistant patients receiving cisplatin and dacarbazine (19).…”

Section: Introductionmentioning

confidence: 99%

“…Temozolomide is an imidazotetrazine derivative of dacarbazine. The combination of lomeguatrib and temozolomide did not show activity in unselected mCRC (20). In a pilot study including patients selected by tumor molecular profiling, temozolomide was effective in 2 patients with mCRC exhibiting loss of MGMT expression (22).…”

Section: Introductionmentioning

confidence: 99%