Application of ProTide Technology to Gemcitabine: A Successful Approach to Overcome the Key Cancer Resistance Mechanisms Leads to a New Agent (NUC-1031) in Clinical Development

Ślusarczyk, Magdalena; Lopez, Monica Huerta; Balzarini, Jan; Mason, Malcolm David; Jiang, Wen Guo; Blagden, Sarah P.; Thompson, Emely; Ghazaly, Essam; McGuigan, Christopher

doi:10.1021/jm401853a

Cited by 138 publications

(218 citation statements)

References 40 publications

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“…However it results in only very modest increases in median life expectancy due to the onset of chemo-resistance. A number of variants on the use of gemcitabine have been explored, including pro-drug approaches and combinations with paclitaxel789. However to date none have shown major improvements in late-stage clinical trials, which contrasts with the advances in treatment seen with a number of other cancer types.…”

mentioning

confidence: 99%

A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer

Ohnmacht

Marchetti

Gunaratnam

et al. 2015

Sci Rep

110

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We report here that a tetra-substituted naphthalene-diimide derivative (MM41) has significant in vivo anti-tumour activity against the MIA PaCa-2 pancreatic cancer xenograft model. IV administration with a twice-weekly 15 mg/kg dose produces ca 80% tumour growth decrease in a group of tumour-bearing animals. Two animals survived tumour-free after 279 days. High levels of MM41 are rapidly transported into cell nuclei and were found to accumulate in the tumour. MM41 is a quadruplex-interactive compound which binds strongly to the quadruplexes encoded in the promoter sequences of the BCL-2 and k-RAS genes, both of which are dis-regulated in many human pancreatic cancers. Levels of BCL-2 were reduced by ca 40% in tumours from MM41-treated animals relative to controls, consistent with BCL-2 being a target for MM41. Molecular modelling suggests that MM41 binds to a BCL-2 quadruplex in a manner resembling that previously observed in co-crystal structures with human telomeric quadruplexes. This supports the concept that MM41 (and by implication other quadruplex-targeting small molecules) can bind to quadruplex-forming promoter regions in a number of genes and down-regulate their transcription. We suggest that quadruplexes within those master genes that are up-regulated drivers for particular cancers, may be selective targets for compounds such as MM41.

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mentioning

confidence: 99%

A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer

Ohnmacht

Marchetti

Gunaratnam

et al. 2015

Sci Rep

110

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“…A recent strategy to improve the treatment efficiency of gemcitabine have been developed by using the phosphoramidate ProTide approach [217] Slusarczyk et al [217] developed Acelarin (NUC-1031) by addition of a phophoramidate ProTide moiety to gemcitabine which enables: a) passive entry into the cell; b) by-passing of the reliance on transporters; c) reduced reliance on kinases for phosphorylation, and, d) reduced susceptibility to deamination. Acelarin generates high intracellular levels of the active agents and has been well tolerated by the patients [217,218].…”

Section: Emerging Chemotherapeutic Treatmentsmentioning

confidence: 99%

“…Acelarin generates high intracellular levels of the active agents and has been well tolerated by the patients [217,218]. Results from the Phase I/II study showed that Acelarin achieved a remarkable disease control rate of 78% in patients with advanced, rapidly progressing solid tumours, relapsed/refractory on prior chemotherapy, including gemcitabine [218].…”

Section: Emerging Chemotherapeutic Treatmentsmentioning

confidence: 99%

Scientific rationale for integrative and personalised strategies for pancreatic ductal adenocarcinoma management

Korhan¹,

Verkerk²,

Critchley³

2017

Integr Mol Med

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Pancreatic ductal adenocarcinoma (PDAC) arises from epithelia of pancreas. Despite its low incidence, it is the most lethal cancer type. Although the poor outcome is largely secondary to the high proportion of patients who are diagnosed with advanced disease, the prognosis of PDAC is also influenced by the inherent biological aggressiveness and the high metastatic potential of this malignancy. Treatment options remain limited with little progress over the last decades. Some improvements in surgical outcome occur in patients who also receive chemotherapy and/or radiotherapy, however, the impact on long-term survival has been minimal owing to the intense resistance of PDAC to all extent treatments regimen. Hence, there is an urgent need to 1) gain better understanding of the biology of PDAC; 2) to develop early detection and prevention programs; 3) to identify new therapeutic strategies to improve quality of life and survivorship. In this review, first, we will summarise the state of knowledge of PDAC pathogenesis with a particular the focus on the molecular characteristics causing therapeutic resistance. Then, we will briefly review current and emerging approaches in the PDAC care. Lastly, we will highlight the integrative approaches in the light of new experimental and clinical research conducted with the aim of moving towards personalised therapy in patients with PDAC.

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“…N-Acyl-phosphoramidates derivatives of gemcitabine can overcome acquired resistance to gemcitabine caused by deoxycytidine kinase deficiency [186]. Similarly, Mcguigan et al have disclosed NUC-1031, a gemcitabine phosphoramidate prodrug that has shown significant reduction in viability of tumor cells [187]. Zhao et al demonstrated the efficacy of cell penetrable dendrimer as a potential antitumor drug carrier by 5-FU and lysine dendrimer conjugates [188].…”

Section: Prodrug Approach: Analog / Chemical Conjugation For Cancementioning

confidence: 99%

Novel delivery approaches for cancer therapeutics

Mitra

Agrahari

Mandal

et al. 2015

Journal of Controlled Release

138

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Currently, a majority of cancer treatment strategies are based on the removal of tumor mass mainly by surgery. Chemical and physical treatments such as chemo- and radiotherapies have also made a major contribution in inhibiting rapid growth of malignant cells. Furthermore, these approaches are often combined to enhance therapeutic indices. It is widely known that surgery, chemo- and radiotherapy also inhibit normal cells growth. In addition, these treatment modalities are associated with severe side effects and high toxicity which in turn lead to low quality of life. This review encompasses novel strategies for more effective chemotherapeutic delivery aiming to generate better prognosis. Currently, cancer treatment is a highly dynamic field and significant advances are being made in the development of novel cancer treatment strategies. In contrast to conventional cancer therapeutics, novel approaches such as ligand or receptor based targeting, triggered release, intracellular drug targeting, gene delivery, cancer stem cell therapy, magnetic drug targeting and ultrasound-mediated drug delivery, have added new modalities for cancer treatment. These approaches have led to selective detection of malignant cells leading to their eradication with minimal side effects. Lowering, multi-drug resistance and involving influx transportation in targeted drug delivery to cancer cells can also contribute significantly in the therapeutic interventions in cancer.

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Application of ProTide Technology to Gemcitabine: A Successful Approach to Overcome the Key Cancer Resistance Mechanisms Leads to a New Agent (NUC-1031) in Clinical Development

Cited by 138 publications

References 40 publications

A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer

A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer

Scientific rationale for integrative and personalised strategies for pancreatic ductal adenocarcinoma management

Novel delivery approaches for cancer therapeutics

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