Influence of bone marrow stromal microenvironment on forodesine-induced responses in CLL primary cells

Balakrishnan, Kumudha; Burger, Jan A.; Quiroga, Maite P.; Henneberg, Marina; Ayres, Mary; Wierda, William G.; Gandhi, Varsha

doi:10.1182/blood-2009-10-246199

Cited by 59 publications

(63 citation statements)

References 50 publications

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“…6 A recent study provided an alternative mechanism of forodesine resistance as marrow stromal cells were shown to antagonize forodesine-enforced apoptosis in CLL cells. 44 The combination cytotoxicity assays revealed no antagonistic or synergistic effect of forodesine/dGuo combined with prednisone, vincristine, or asparaginase. For daunorubicin, we observed an antagonistic effect, but only at a single concentration combined with the LC10, but not with the concentration of LC30 forodesine/ dGuo.…”

Section: Discussionmentioning

confidence: 91%

In vitro efficacy of forodesine and nelarabine (ara-G) in pediatric leukemia

Homminga

Zwaan

Manz

et al. 2011

Blood

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Forodesine and nelarabine (the pro-drug of ara-G) are 2 nucleoside analogues with promising anti-leukemic activity. To better understand which pediatric patients might benefit from forodesine or nelarabine (ara-G) therapy, we investigated the in vitro sensitivity to these drugs in 96 diagnostic pediatric leukemia patient samples and the mRNA expression levels of different enzymes involved in nucleoside metabolism. Forodesine and ara-G cytotoxicities were higher in T-cell acute lymphoblastic leukemia (T-ALL) samples than in B-cell precursor (BCP)-ALL and acute myeloid leukemia (AML) samples. Resistance to forodesine did not preclude ara-G sensitivity and vice versa, indicating that both drugs rely on different resistance mechanisms. Differences in sensitivity could be partly explained by significantly higher accumulation of intracellular dGTP in forodesine-sensitive samples compared with resistant samples, and higher mRNA levels of dGK but not dCK. The mRNA levels of the transporters ENT1 and ENT2 were higher in ara-Gsensitive than -resistant samples. We conclude that especially T-ALL, but also BCP-ALL, pediatric patients may benefit from forodesine or nelarabine (ara- G IntroductionLeukemia is the most common childhood malignancy, and the general incidence in both adults and children of acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) is approximately 1 per 100 000 and 2-3 per 100 000, respectively. Although overall cure rates have been improved over the last decades, approximately 20% of children with ALL and 40% of children with AML still eventually die from their disease. 1,2 In adults, the prognosis is worse with a survival below 60% in ALL 3 and 50% in AML, 4 indicating that there is still a great need for better therapy. Currently, purine nucleosides analogues are in clinical trials for different types of leukemia including clofarabine, forodesine (BCX-1777/Immucillin H), and nelarabine (506U78/Arranon/ Atriance) the latter being the pro-drug for 9-␤-D-arabinofuranosylguanine (ara-G).Forodesine is a noncleavable inosine analog developed to bind and inhibit the purine nucleoside phosphorylase (PNP) enzyme. 5 PNP normally degrades excess of intracellular deoxyguanosine (dGuo) into guanosine and deoxyribose-1-phosphate through phosphorylysis. dGuo is continuously produced in the body as the result of DNA degradation during cellular turnover. Inhibition of PNP by forodesine results in the intracellular accumulation of dGuo. DGuo is rapidly phosphorylated to dGTP in the purine salvage pathway leading to dGTP accumulation. 6,7 High intracellular levels of dGTP cause cell death through mechanisms that are still not fully understood, but which may likely involve imbalance in the deoxynucleotide pool and/or inhibition of ribonucleotide reductase 8 resulting in inhibition of DNA synthesis and/or by activation of a p53-induced cell-cycle arrest and apoptosis. 9 Whereas most nucleoside analogues depend on DNA incorporation to exert their toxic effect, this is not the case for forodesine. T cells seem...

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Section: Discussionmentioning

confidence: 91%

In vitro efficacy of forodesine and nelarabine (ara-G) in pediatric leukemia

Homminga

Zwaan

Manz

et al. 2011

Blood

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“…MSCs have also been shown to protect chronic myeloid leukemia (CML) cells from the imatinib therapy, conferring CML resistance to this medication by reducing caspase-3 activation and modulating anti-apoptotic Bcl-XL expression via the CXCL12/CXCR4 axis [13]. The inability of forodesine to decrease peripheral chronic lymphocytic leukemia (CLL) cells in clinical trials, despite very promising pre-clinical data, was found to be due to MSC protection preventing the forodesine-induced 2'-deoxyguanosine (dGuo) triphosphate accumulation and ATP depletion which would have led to CLL apoptosis [14].…”

Section: Drug Resistancementioning

confidence: 99%

Involvement of Mesenchymal Stem Cells in Cancer Progression and Metastases

Chang¹,

Schwertschkow²,

Nolta³

et al. 2015

CCDT

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Mesenchymal stem/stromal cells (MSCs) are known to be the helpers for the healing of tissue damage, often referred to as ambulatory cells. However, MSCs are also recruited by cancer cells to similarly aid in tumor growth and progression. In this review, some of the key steps in cancer progression and metastases are described including the various steps in which MSCs participate and may play important roles. MSCs aid in cancer cells' ability to evade immune attack, while promoting tumor angiogenesis, even being counter-acting against chemotherapeutics and other drugs used to fight various cancers. Furthermore, MSCs participate in many of the crucial steps in invasion and metastasis, including stimulating the epithelial-mesenchymal transition (EMT) and induction of stem-like properties that allow cancer stem cells to increase their survivability through the circulation. These steps are described in detail. Differences between circulating tumor cells (CTCs) and cancer stem cells (CSCs) are discussed, along with descriptions of the formation of a pre-metastatic niche, the role of exosomes from both cancer cells and MSCs in metastasis and tumor reseeding (self-seeding). More and more, MSCs are being proposed as a promising tumor targeting drug-delivery tool. In order to fulfill this promise, further understanding of the precise roles that MSCs play in the process of cancer metastases must be achieved, in attempting to create remedies that will improve the outcome of available therapeutics.

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“…This goes in line with our findings in which we recently demonstrated that CLL B cells cocultured in the presence of bone marrow stromal microenvironment exhibits reduced level of apoptosis with forodesine. 33 Thus, circulating CLL lymphocytes in the peripheral blood may be more susceptible to forodesine therapy, whereas those in lymph nodes and the bone marrow microenvironment may be resistant to this treatment.…”

Section: Discussionmentioning

confidence: 99%