Vincristine: Can its therapeutic index be enhanced?

Moore, Andrew S.; Pinkerton, Ross

doi:10.1002/pbc.22161

Cited by 75 publications

(76 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Vincristine also has significant dose-limiting toxicities. The peripheral neuropathies resulting from its use can be debilitating and permanent, often halting use of the drug (7,8).…”

mentioning

confidence: 99%

Repurposing Mebendazole as a Replacement for Vincristine for the Treatment of Brain Tumors

Witt

Gamble

Hanson

et al. 2017

Mol Med

View full text Add to dashboard Cite

The microtubule inhibitor vincristine is currently used to treat a variety of brain tumors, including low-grade glioma and anaplastic oligodendroglioma. Vincristine, however, does not penetrate well into brain tumor tissue, and moreover, it displays dose-limiting toxicities, including peripheral neuropathy. Mebendazole, a Food and Drug Administration-approved anthelmintic drug with a favorable safety profile, has recently been shown to display strong therapeutic efficacy in animal models of both glioma and medulloblastoma. Importantly, appropriate formulations of mebendazole yield therapeutically effective concentrations in the brain. Mebendazole has been shown to inhibit microtubule formation, but it is not known whether its potency against tumor cells is mediated by this inhibitory effect. To investigate this, we examined the effects of mebendazole on GL261 glioblastoma cell viability, microtubule polymerization and metaphase arrest, and found that the effective concentrations to inhibit these functions are very similar. In addition, using mebendazole as a seed for the National Cancer Institute (NCI) COMPARE program revealed that the top-scoring drugs were highly enriched in microtubule-targeting drugs. Taken together, these results indicate that the cell toxicity of mebendazole is indeed caused by inhibiting microtubule formation. We also compared the therapeutic efficacy of mebendazole and vincristine against GL261 orthotopic tumors. We found that mebendazole showed a significant increase in animal survival time, whereas vincristine, even at a dose close to its maximum tolerated dose, failed to show any efficacy. In conclusion, our results strongly support the clinical use of mebendazole as a replacement for vincristine for the treatment of brain tumors.

show abstract

“…Vincristine also has significant dose-limiting toxicities. The peripheral neuropathies resulting from its use can be debilitating and permanent, often halting use of the drug (7,8).…”

mentioning

confidence: 99%

Repurposing Mebendazole as a Replacement for Vincristine for the Treatment of Brain Tumors

Witt

Gamble

Hanson

et al. 2017

Mol Med

View full text Add to dashboard Cite

show abstract

“…This may be clinically important due to the expression of CYP3A5 polymorphisms, with subsequent inter-racial differences in expression and potential effects on VCR efficacy and toxicity. 22 There are no specific interactions reported with the liposomal formulation of VCR, but other known interactions with free VCR would still apply to the use of VSLI, including drugs known to inhibit these CYP3A enzymes or P-glycoprotein and induce CYP3A enzymes (Table 1). 22 …”

Section: Drug-drug Interactionsmentioning

confidence: 99%

“…22 There are no specific interactions reported with the liposomal formulation of VCR, but other known interactions with free VCR would still apply to the use of VSLI, including drugs known to inhibit these CYP3A enzymes or P-glycoprotein and induce CYP3A enzymes (Table 1). 22 …”

Section: Drug-drug Interactionsmentioning

confidence: 99%

“…35 In human VCR studies, as for most anticancer drugs, intrapatient and interpatient PK profiles vary markedly. 22 For example, in a recent study of children, the median clearance, AUC, and Cmax of VCR were 482 mL/min/m 2 (range 132-698 mL/min/m 2 ), 49.7 mcg/L ⋅ h (16.5-143.1 mcg/L ⋅ h), and 3.5 mcg/L (1.0-31.2 mcg/L), respectively. 37 It is important to highlight that comparison between VSLI and VCR PK studies is difficult due to dose capping resulting from the neurotoxicities associated with free VCR compound.…”

Section: Liposomal Vincristine Sulfate Injectionmentioning

confidence: 99%

“…19 However, it is the perturbance of these biochemical pathways that is predicted to mediate VCR-induced autonomic and peripheral sensory-motor polyneuropathy, a dose-limiting side effect of VCR. 22 The neurotoxic effects of VCR, mediated by impaired microtubule function leading to blockade of axon transport and subsequent axonal degradation, have significantly impaired the use of high-dose VCR in the treatment of neoplastic disease. 22 As a result, VCR doses are generally capped at 2 mg. 22 Therefore, there has been a recent impetus to enhance the therapeutic activity of VCR with liposomal encapsulation systems to increase the VCR dose whilst limiting free-drug-associated toxicity.…”

Section: Vincristinementioning

confidence: 99%

See 2 more Smart Citations

Vincristine sulfate liposomal injection for acute lymphoblastic leukemia

Raj

Smith²,

Moore

2013

IJN

Self Cite

View full text Add to dashboard Cite

Vincristine (VCR) is one of the most extensively used cytotoxic compounds in hemato-oncology. VCR is particularly important for the treatment of acute lymphoblastic leukemia (ALL), a disease that accounts for approximately one-third of all childhood cancer diagnoses. VCR’s full therapeutic potential has been limited by dose-limiting neurotoxicity, classically resulting in autonomic and peripheral sensory–motor neuropathy. In the last decade, however, the discovery that liposomal encapsulation of chemotherapeutics can modulate the pharmacokinetic characteristics of a compound has stimulated much interest in liposomal VCR (vincristine sulfate liposomal injection [VSLI]) formulations for the treatment of ALL and other hematological malignancies. Promising data from recent clinical trials investigating VSLI in adults with ALL resulted in US Food and Drug Administration approval for use in patients with Philadelphia chromosome (t[9;22]/ BCR–ABL1 ) (Ph)-negative (Ph−) disease. Additional clinical trials of VSLI in adults and children with both Ph-positive (Ph+) and Ph− ALL are ongoing. Here we review the preclinical and clinical experience to date with VSLI for ALL.

show abstract

The two faces of FBW7 in cancer drug resistance

et al. 2011

View full text Add to dashboard Cite

Chemotherapy is an important therapeutic approach for cancer treatment. However, drug resistance is an obstacle that often impairs the successful use of chemo-therapies. Therefore, overcoming drug resistance would lead to better therapeutic outcomes for cancer patients. Recently, studies by our own and other groups have demonstrated that there is an intimate correlation between the loss of the F-box and WD repeat domain-containing 7 (FBW7) tumor suppressor and the incurring drug resistance. While loss of FBW7 sensitizes cancer cells to certain drugs, FBW7-/- cells are more resistant to other types of chemotherapies. FBW7 exerts its tumor suppressor function by promoting the degradation of various oncoproteins that regulate many cellular processes, including cell cycle progression, cellular metabolism, differentiation, and apoptosis. Since loss of the FBW7 tumor suppressor is linked to drug resistance, FBW7 may represent a novel therapeutic target to increase drug sensitivity of cancer cells to conventional chemotherapeutics. This paper thus focuses on the new functional aspects of FBW7 in drug resistance.

show abstract

Vincristine: Can its therapeutic index be enhanced?

Cited by 75 publications

References 89 publications

Repurposing Mebendazole as a Replacement for Vincristine for the Treatment of Brain Tumors

Repurposing Mebendazole as a Replacement for Vincristine for the Treatment of Brain Tumors

Vincristine sulfate liposomal injection for acute lymphoblastic leukemia

The two faces of FBW7 in cancer drug resistance

Contact Info

Product

Resources

About