<i>In vivo</i> administration of liposomal vincristine sensitizes drug‐resistant human solid tumors

Leonetti, Carlo; Scarsella, Marco; Semple, Sean C.; Molinari, Agnese; D’Angelo, Carmen; Stoppacciaro, Antonella; Biroccio, Annamaria; Zupi, Gabriella

doi:10.1002/ijc.20174

Cited by 24 publications

(8 citation statements)

References 22 publications

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“…Transformed BJ fibroblasts expressing hTERT and SV40 early region (BJ-EHLT) were maintained as previously described (20). Human M14 melanoma, CG5 breast carcinoma, and HT29 colon carcinoma lines were previously described (45)(46)(47). Human non-small cell lung carcinoma and PC3 prostate cancer cells were obtained from ATCC and maintained in RPMI-1640 supplemented with 10% FCS, 2 mM l-glutamine and antibiotics (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect

Salvati¹,

Leonetti²,

et al. 2007

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Functional telomeres are required for the replicability of cancer cells. The G-rich strand of telomeric DNA can fold into a 4-stranded structure known as the G-quadruplex (G4), whose stabilization alters telomere function limiting cancer cell growth. Therefore, the G4 ligand RHPS4 may possess antitumor activity. Here, we show that RHPS4 triggers a rapid and potent DNA damage response at telomeres in human transformed fibroblasts and melanoma cells, characterized by the formation of several telomeric foci containing phosphorylated DNA damage response factors γ-H2AX, RAD17, and 53BP1. This was dependent on DNA repair enzyme ATR, correlated with delocalization of the protective telomeric DNA-binding protein POT1, and was antagonized by overexpression of POT1 or TRF2. In mice, RHPS4 exerted its antitumor effect on xenografts of human tumor cells of different histotype by telomere injury and tumor cell apoptosis. Tumor inhibition was accompanied by a strong DNA damage response, and tumors overexpressing POT1 or TRF2 were resistant to RHPS4 treatment. These data provide evidence that RHPS4 is a telomere damage inducer and that telomere disruption selectively triggered in malignant cells results in a high therapeutic index in mice. They also define a functional link between telomere damage and antitumor activity and reveal the key role of telomere-protective factors TRF2 and POT1 in response to this anti-telomere strategy.

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Section: Methodsmentioning

confidence: 99%

Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect

Salvati¹,

Leonetti²,

et al. 2007

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“…Combined with prolonged and sustained delivery to ALL target tissues, these increased doses were likely instrumental in overcoming any relative VCR resistance and inducing remissions. 20 Based on landmark investigations, primarily in lymphoma patients, VCR dose (ie, individual dose, cumulative dose, and dose density), clinical efficacy, and neurotoxicity have been inextricably linked. [21][22][23][24][25][26][27] Doses of standard VCR comparable to the doses of VSLI achieved in this study have been associated with almost universal grade 3 or greater neurotoxicity.…”

mentioning

confidence: 99%

High-Dose Vincristine Sulfate Liposome Injection for Advanced, Relapsed, and Refractory Adult Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia

O’Brien

Schiller

Lister

et al. 2013

JCO

170

132

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A B S T R A C T PurposeRelapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated highdose VSLI monotherapy in adults with Philadelphia chromosome (Ph) -negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT). Patients and MethodsSixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m 2 , without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete response (CR) or CR with incomplete hematologic recovery (CRi). ResultsThe CR/CRi rate was 20% and overall response rate was 35%. VSLI monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single-and multiagent reinduction therapies. Median CR/CRi duration was 23 weeks (range, 5 to 66 weeks); 12 patients bridged to a post-VSLI HCT, and five patients were long-term survivors. VSLI was generally well tolerated and associated with a low 30-day mortality rate (12%). ConclusionHigh-dose VSLI monotherapy resulted in meaningful clinical outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of VSLI was predictable, manageable, and comparable to standard VCR despite the delivery of large, normally unachievable, individual and cumulative doses of VCR.

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“…70 In a murine model with human breast cancer xenografts, sphingomyelin/cholesterol liposomeencapsulated vincristine resulted in targeted delivery of the drug, with a four-fold increase in concentration of drug in tumor tissue and a three-fold increase in bone marrow, with maintenance of significant tissue drug concentrations for several days compared with free vincristine, and without increased toxicity. 73 The antitumor efficacy of sphingomyelin/ cholesterol liposome-encapsulated vincristine has also been confirmed in several preclinical murine and human tumor xenograft models, representing several cancer types, 54,70,[73][74][75][76] including human ALL. 24 The aggregate of the above studies supports the utility of encapsulating vincristine in sphingomyelin/cholesterol liposomes to increase drug delivery while limiting release in the central blood compartment to decrease drug toxicity.…”

Section: Preclinical Development Of Liposomeencapsulated Formulationsmentioning

confidence: 99%

Treating relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia: liposome-encapsulated vincristine

Davis¹,

Farag

2013

IJN

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In vivo administration of liposomal vincristine sensitizes drug‐resistant human solid tumors

Cited by 24 publications

References 22 publications

Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect

Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect

High-Dose Vincristine Sulfate Liposome Injection for Advanced, Relapsed, and Refractory Adult Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia

Treating relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia: liposome-encapsulated vincristine

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