<i>In vitro</i> cytotoxicity of nelarabine, clofarabine and flavopiridol in paediatric acute lymphoblastic leukaemia

Beesley, Alex H.; Palmer, Misty-Lee; Ford, Jette; Weller, Renae E.; Cummings, Aaron J; Freitas, Joseph R; Firth, Martin J; Perera, Kanchana U.; Klerk, Nicholas de; Kees, Ursula R.

doi:10.1111/j.1365-2141.2007.06527.x

Cited by 26 publications

(18 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The cell line panel has been previously described (Kees et al, 2003;Beesley et al, 2006Beesley et al, , 2007 and comprised nine T-ALL lines derived in our own laboratory (PER cell lines), plus six additional T-ALL cell lines obtained from external sources (HSB2, CEM, JURKAT, ALL-SIL, MOLT4, DU.528). PER cell lines were derived from paediatric ALL bone marrow specimens according to the method previously described (Kees et al, 1987).…”

Section: Cell Linesmentioning

confidence: 99%

Glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia is associated with a proliferative metabolism

et al. 2009

View full text Add to dashboard Cite

Glucocorticoids (GCs) are among the most important drugs for acute lymphoblastic leukaemia (ALL), yet despite their clinical importance, the exact mechanisms involved in GC cytotoxicity and the development of resistance remain uncertain. We examined the baseline profile of a panel of T-ALL cell lines to determine factors that contribute to GC resistance without prior drug selection. Transcriptional profiling indicated GC resistance in T-ALL is associated with a proliferative phenotype involving upregulation of glycolysis, oxidative phosphorylation, cholesterol biosynthesis and glutamate metabolism, increased growth rates and activation of PI3K/AKT/mTOR and MYC signalling pathways. Importantly, the presence of these transcriptional signatures in primary ALL specimens significantly predicted patient outcome. We conclude that in lymphocytes the activation of bioenergetic pathways required for proliferation may suppress the apoptotic potential and offset the metabolic crisis initiated by GC signalling. It is likely that the link between GC resistance and proliferation in T-ALL has not been fully appreciated to date because such effects would be masked in the context of current multiagent therapies. The data also provide the first evidence that altered expression of wild-type MLL may contribute to GC-resistant phenotypes. Our findings warrant the continued development of selective metabolic inhibitors for the treatment of ALL.

show abstract

Section: Cell Linesmentioning

confidence: 99%

Glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia is associated with a proliferative metabolism

et al. 2009

View full text Add to dashboard Cite

show abstract

“…The in vitro efficacy of clofarabine was compared to those of nelarabine and AraC in a panel of acute lymphoblastic leukemia (ALL) cells [43]. This investigation could prove the combination of clofarabine nucleotidases inhibitors useful for cancer treatment [50].…”

Section: In Vitro Investigationsmentioning

confidence: 99%

Mechanisms of anti-cancer action and pharmacology of clofarabine

Zhenchuk

Lotfi

Juliusson

et al. 2009

Biochemical Pharmacology

101

114

View full text Add to dashboard Cite

“…106 FP was more potent in vitro than glucocorticoids and thiopurines and at doses that recent phase I experience predicts will translate into clinical efficacy. 109 FP should be widely effective in ALL if sufficient plasma levels can be achieved clinically.…”

Section: Gengmentioning

confidence: 99%

Current and Emerging Therapies in T-cell Acute Lymphoblastic Leukemia

Chuan-dong Geng

2012

Clinical Medicine Reviews in Oncology

View full text Add to dashboard Cite

Current studies of T-cell acute lymphoblastic leukemia (T-ALL) show promise for improving the treatment for this previously difficult to cure neoplasm. This has been facilitated by the increased understanding of the molecular basis of leukemogenesis in T-cells as well as advanced analytical technologies in modern molecular biology. Combined with intensive conventional therapies, novel drugs as well as improved diagnostic protocols have been developed for the rational therapy of T-ALL, resulting in a cure rate up to 80%. An understanding of the detailed molecular mechanism of action for T-ALL specific alterations in gene expression has led to the design and development of targeted molecular therapies of this aggressive cancer. Several novel, target-specific drugs are now available, including mitotic inhibitors with more specificity and potency for growth inhibition, γ-secretase inhibitors (GSIs) for leukemic NOTCHI signaling blockage in T-ALL as well as growth inhibition, tyrosine kinase inhibitors for correction of uncontrolled proliferation caused by certain genetic lesions, and inhibitors of BCL2 proteins leading to sensitization of leukemic cells to apoptosis induction. Some of these drugs are under development in the different phase of clinic trials, but others are currently included in successful therapeutic protocols, and, as hoped, they cause the remission of patients that suffered from certain types of T-ALLs, and who previously were poor responders using conventional treatment protocols. However, these new approaches still often need to be combined with highly toxic conventional treatment to obtain satisfactory overall outcome. The encouraging achievements in targeted molecular therapy challenge researchers to achieve no-event complete remission in T-ALL patient by developing novel therapies with even more specific targeting and efficacy to minimize complications. Finally, with the development of targeted molecular therapy, rational approaches for individually tailored treatment of T-ALL patients in the near future now may be an achievable goal.

show abstract

In vitro cytotoxicity of nelarabine, clofarabine and flavopiridol in paediatric acute lymphoblastic leukaemia

Cited by 26 publications

References 39 publications

Glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia is associated with a proliferative metabolism

Glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia is associated with a proliferative metabolism

Mechanisms of anti-cancer action and pharmacology of clofarabine

Current and Emerging Therapies in T-cell Acute Lymphoblastic Leukemia

Contact Info

Product

Resources

About