Semisynthetic Vinca Alkaloid Research Articles

Vinorelbine as First-Line Treatment in Stage IV Canine Primary Pulmonary Carcinoma.

Vinorelbine (VRL), a semi-synthetic vinca alkaloid commonly used in humans with advanced lung cancer, reaches high concentrations in the lung tissue, has proven antineoplastic activity and a low toxicity profile in dogs. Treatment-naïve, client-owned dogs with a cyto/histological diagnosis of advanced pulmonary carcinoma, selected from a laboratory database and previously subjected to imaging, were enrolled in the study. Vinorelbine (15 mg/m2) was administered weekly for 4 weeks and then fortnightly until progressive disease was documented. Staging work-up was repeated by means of diagnostic imaging after the fourth VRL (i.e., 28 days) and monthly thereafter; response to treatment was evaluated according to the RECIST. Toxicity was graded following the VCOGC group. Ten dogs met the inclusion criteria. Partial response was documented in eight dogs. Median time to progression was 88 days (range: 7-112) and median survival time for all dogs was 100 days (range 7-635). The most common side effect was neutropenia. The main limitations of the study were the absence of histological diagnosis in eight cases and the limited number of treated dogs. VRL is well tolerated with an adequate toxicity profile and may be useful in the management of advanced lung tumours if used as a first-line treatment strategy.

Vinorelbine-related tetraplegia due to severe peripheral neuropathy.

Vinorelbine, a semi-synthetic vinca alkaloid with anticancer activity by binding to tubulin, has shown to be successful in the treatment of cancer types including advanced non-small cell lung cancer, uterine cancer, and metastatic breast cancer. Myelosuppression, hematological effects, nausea, vomiting, exhaustion, and neuropathy are some of the most typical side effects of vinorelbine. We discuss the unusual presentation of vinorelbine-induced tetraplegia in a breast cancer patient. A 66-year-old patient with breast cancer, who was followed up with adjuvant aromatase inhibitor therapy after mastectomy, presented with lung and bone metastases. She progressed in the follow-ups after receiving platinum and taxane chemotherapy, vinorelbine treatment was then started. The patient complained of weakness, weariness, and trouble walking after receiving a total dose of 180 mg. Tetraplegia was found after a neurological assessment. It was thought that vinorelbine was responsible for the recent acute weakness. The patient's vinorelbine treatment was stopped. During follow-up, upper extremity paresis regressed, while lower extremities muscle strength remained unchanged. Vinorelbine, frequently used in oncology practice, causes some side effects. Although very rare in the literature, in this case severe peripheral neuropathy has been reported in the follow-up of post-vinorelbine quadriparesis.

Alveolar rhabdomyosarcoma has superior response rates to vinorelbine compared to embryonal rhabdomyosarcoma in patients with relapsed/refractory disease: A meta-analysis.

Patients with alveolar rhabdomyosarcoma (ARMS) have inferior outcomes compared to patients with embryonal rhabdomyosarcoma (ERMS) and more effective chemotherapy options are needed for these patients. Vinorelbine is a semisynthetic vinca alkaloid that has clinical activity in relapsed rhabdomyosarcoma (RMS) when used alone or in combination with cyclophosphamide. The goal of our study was to evaluate whether RMS histology subtype influences response rate to vinorelbine alone or in combination. Five Phase 2 trials that enrolled RMS patients were included in the meta-analysis. Two studies evaluated vinorelbine alone, two studies evaluated vinorelbine in combination with low dose oral cyclophosphamide, and one study evaluated vinorelbine and intravenous cyclophosphamide in combination with temsirolimus or bevacizumab. All RMS patients had relapsed or refractory disease and had received at least one prior therapy. Response was reported according to RECIST1.1 and was defined as a complete or partial response. Response data was obtained from published results or from trial principal investigator. RMS NOS patients were grouped with ERMS patients for this analysis. Summary estimates comparing differences between ARMS and ERMS response rates were generated using a random-effects model to account for heterogeneity among the studies. One hundred fifty-six enrolled patients evaluable for response were included in the meta-analysis, 85 ARMS, 64 ERMS and 7 RMS-NOS. The combined effect generated from the random-effects model demonstrated a 41% increase (p = 0.001, 95% CI; 0.21-0.60) in response to vinorelbine as a single agent or in combination in patients with ARMS compared to patients with ERMS. There was no significant difference in the rate of progressive disease between patients with ARMS compared to ERMS (p = 0.1, 95%CI; -0.26-0.02). Vinorelbine is an active agent for the treatment of relapsed or refractory RMS and a meta-analysis of Phase 2 studies shows that radiographic responses in patients with ARMS were significantly higher than ERMS or RMS-NOS. These data support further investigation of vinorelbine in newly diagnosed patients with RMS particularly those with alveolar histology.

LINC-26. ORAL VINORELBINE IN PROGRESSIVE UNRESECTABLE LOW-GRADE GLIOMA

BACKGROUNDThe management of progressive unresectable low-grade glioma (PULGG) remains controversial. Some series suggests that chemotherapy may delay or even avoid radiotherapy and/or surgery in a group of patients. Within this context, we performed at IOP/GRAACC/UNIFESP an institutional protocol with IV vinorelbine, a semi-synthetic vinca alkaloid that showed activity against PULGG. The objective of this study was to evaluate the response as long as the tolerability of oral vinorelbine in PULGG.PATIENTS AND METHODSFrom April 2013 to Aug 2017, 17 patients with recurrent (n=5) and newly-diagnosed (n=12) optic-pathway glioma (OPG) were treated with oral vinorelbine in a dose of 90 mg/m² days 0, 8 and 22 for 18 cycles. Response criteria used a combination of magnetic resonance imaging, physical and visual evaluation.RESULTSMean age 8.6 years (4.8–17.9y). Three children with neurofibromatosis type 1. Eleven patients had neurosurgical intervention revealing grade I (n=8) and grade II astrocytoma (n=3). Twelve patients were assessable after 8 cycles of vinorelbine with 2 objective response (OR), 8 stable disease (SD) and 2 progressive disease (PD), one died after surgery and 1 alive in different protocol. After 18 cycles, eight patients were assessable to date for response with 1 OR, 7 SD. The most important toxicity was gastrointestinal observed in 12 patients- six of them switched to IV vinorelbine (3OR, 3SD). None of the patients showed neurotoxicity.CONCLUSIONThese results suggest that oral vinorelbine, as the IV formulation, may show some activity in OPG. However, gastrointestinal toxicity should be considered.

Determining critical parameters that influence in vitro performance characteristics of a thermosensitive liposome formulation of vinorelbine

Studies have demonstrated the advantages associated with heat-triggered drug delivery via thermosensitive liposomes for the treatment of localized cancer. Challenges that traditional liposomal systems face such as limited drug release and homogeneous distribution throughout the region of interest can potentially be overcome when triggering intravascular drug release. The most prominent example is a thermosensitive liposome formulation of doxorubicin known as ThermoDox®. Many other drugs may benefit from the same targeted and localized delivery approach using thermosensitive liposomes as it can result in a significant improvement in the therapeutic index. Vinorelbine is a semi-synthetic vinca alkaloid which has shown to be active in a broad range of cancers. Several liposome formulations encapsulating vinorelbine have been developed as a means to reduce systemic drug exposure. The present study takes a systematic approach in exploring formulation and drug loading parameters and their influence on performance characteristics of a rapidly releasing thermosensitive liposome formulation of vinorelbine. More broadly, this study shows that trends observed for non-thermosensitive liposome formulations of specific drugs (i.e. vinorelbine) can not be easily translated to their thermosensitive counterparts. The profound impact of the presence of albumin on stability and in vitro release is also highlighted. This is of significance given that a number of recent reports examine drug release in the absence of biologically relevant components. As a result, a strong recommendation emanating from this is a thorough challenge of the liposome formulation in vitro in order to gain a better understanding of its likely behaviour in vivo as well as potential for future clinical translation.

Efficacy of Vinorelbine Monotherapy as Third- or Further-Line Therapy in Patients with Advanced Non-Small-Cell Lung Cancer

Background: The survival rate of patients with lung cancer has increased significantly over the years, but there has been no further progress in third- or fourth-line therapy. We investigated the efficacy and tolerability of monotherapy with weekly vinorelbine, a semi-synthetic vinca alkaloid, in advanced non-small-cell lung cancer (NSCLC) patients who had previously been treated several times. Methods: In all, 159 NSCLC patients who received vinorelbine monotherapy as third- or further-line therapy between January 2008 and July 2017 were included in this study. Patients received vinorelbine intravenously at a dose of 25–30 mg/m²/week. Results: Their mean age was 62.4 years. The histologic types of tumor were adenocarcinoma (50.9%), squamous cell carcinoma (42.8%), and others (6.2%). The overall response rate was 19.5% (31/159). The median progression-free survival (PFS) was 3.0 months (95% confidence interval [CI] 2.5–3.5 months), and the median overall survival (OS) after vinorelbine use was 7.6 months (95% CI 6.2–9.0 months). Vinorelbine therapy showed significantly higher efficacy in patients with adenocarcinoma, and these patients had a longer PFS than patients with other types of cancer. Patients who received vinorelbine as fifth- or further-line treatment had a higher response rate and longer PFS and OS than those who received vinorelbine as third- or fourth-line treatment. Conclusions: Weekly vinorelbine monotherapy may be a feasible therapeutic option for patients with heavily treated, advanced NSCLC, particularly lung adenocarcinoma.

Gemcitabine, vinorelbine and cyclooxygenase inhibitors in the treatment of glioblastoma. Ultrastructural analyses in C6 glioma in vitro

ObjectivesTo define ultrastructural features accompanying to antitumor effects of gemcitabine, vinorelbine and cyclooxygenase inhibitors in C6 glioma cells in vitro. Vinorelbine is a semisynthetic vinca alkaloid and recent studies showed its antitumor activity in pediatric optic and pontine gliomas. Vinorelbine infusion induces a severe tumor site-pain in systemic cancers, but it is unknown whether algesia and inflammation contribute to its antitumor effects. Gemcitabine is a nucleoside-chemotherapeutic which was recently shown to act as a radiosensitizer in high-grade glioma. Some studies showed synergism of anti-inflammatory cyclooxygenase-inhibitors with microtubule inhibitors and gemcitabine. DMSO is a solvent and blocks both cylooxygenase and ribonucleotide reductase, another target of gemcitabine. Rofecoxib is withdrawn from the market, yet we used it for investigational purposes, since it blocks cylooxygenase-2 1000-times more potently than cylooxygenase -1 and is also a selective inhibitor of crinophagy. MethodsPlating efficacy, 3D-spheroid S-phase analysis with BrdU labelling and transmission electron microscopical analyses were performed. ResultsVinorelbine induced frequent mitotic slippage/apoptosis and autophagy. Despite both DMSO and rofecoxib induced autophagy alone and in synergy, they reduced mitotic catastrophe and autophagy triggered by vinorelbine, which was also reflected by reduced inhibition of spheroid S-phase. Gemcitabine induced karyolysis and margination of coarse chromatin towards the nuclear membrane, abundant autophagy, gutta adipis formation and decrease in mitochondria, which were enhanced by DMSO and rofecoxib. ConclusionsDetailed ultrastructural analysis of the effects of chemotherapeutic drugs may provide a broader insight about their actions and pave to develop better strategies in treatment of glioblastoma.

Vitamin E TPGS Emulsified Vinorelbine Bitartrate Loaded Solid Lipid Nanoparticles (SLN): Formulation Development, Optimization and In vitro Characterization.

Vinorelbine bitartrate (VRL), a semi synthetic vinca alkaloid approved for breast cancer, has been proven to be beneficial as first line and subsequent therapies. However, its hydrophilic and thermo labile nature provides hindrance to oral clinical translation. The current work focused on the application of DOE a modern statistical optimization tool for the development and optimization of a solid lipid nanoparticle (SLN) formulation that can encapsulate hydrophilic and thermolabile Vinorelbine bitartrate (VRL) to a maximum extent without compromising integrity and anticancer activity of the drug. SLNs were prepared by solvent diffusion technique employing Taguchi orthogonal array design with optimized formulation and process variables. The emulsifying nature and low melting point of glyceryl mono-oleate (GMO) were exploited to enhance entrapment and minimizing temperature associated degradation, respectively. Moreover, two types of surfactants, Vitamin E TPGS (TPGS) and Poloxamer-188 were utilized to obtain TPGS-VRL-SLNs and PL-VRL-SLNs, respectively. The SLNs were characterized for various physicochemical properties, in-vitro drug release kinetics and anticancer activity by MTT assay on MCF-7 cancer cell lines. The SLNs were found to be spherical in shape with entrapment efficiency (EE) up to 58 %. Invitro release studies showed biphasic release pattern following Korsemeyer peppas model with fickian release kinetics. Results of MTT assay revealed that TPGS-VRL-SLNs and PL-VRL-SLNs were 39.5 and 18.5 fold more effective, respectively, compared to the pristine VRL. DOE approach was successfully applied for the development of VRL-SLNs. Enhanced entrapment and anticancer efficacy of TPGS-VRL-SLN can be attributed to emulsifying nature of GMO and inherent cytotoxic nature of TPGS, respectively, which synergizes with VRL. Therefore, TPGS associated SLNs may be potential carrier in cancer chemotherapeutics.

LGG-54. ORAL VINORELBINE IN PROGRESSIVE UNRESECTABLE LOW-GRADE GLIOMA: EXPERIENCE OF A SINGLE INSTITUTION

The management of progressive unresectable low-grade glioma (PULGG) remains controversial. Some series suggests that chemotherapy may delay or even avoid radiotherapy and/or surgery in a proportion of children. Within this context we performed initially an institutional protocol with .8IV vinorelbine, a semi-synthetic vinca alkaloid that shown activity against PULGG. The objective of this study is to evaluate the response as long as the tolerability of oral vinorelbine in patients with diagnosis of optic pathway glioma (OPG). PATIENTS AND Since 2013, 16 patients with recurrent (n=4) and newly-diagnosed (n=12) OPG have been treat with oral vinorelbine in a dose of 90 mg/m2 days 0, 8 and 22 for 18 cycles. Response criteria used a combination of magnetic resonance imaging, physical and visual evaluation. Mean age 8.6 years (4.8-17.9). Three children with neurofibromatosis type 1. Eleven patients had neurosurgical intervention revealing grade I (n=9) and grade II astrocytoma (n=2). Eleven patients were assessable after 4/8 cycles of vinorelbine with 2 objective response (OR), 7 stable disease (SD) and 2 progressive disease (PD), one died after surgery and 1 alive in different protocol. After 18 cycles, seven patients were assessable to date for response with 2 OR, 5 SD. The most important toxicity was gastrointestinal observed in 12 patients- six of them withdraw treatment. None of the patients showed neurotoxicity. The preliminary results suggest that oral vinorelbine may show some activity in PULGG. However, gastrointestinal toxicity should be considered.

DT-13 synergistically enhanced vinorelbine-mediated mitotic arrest through inhibition of FOXM1-BICD2 axis in non-small-cell lung cancer cells

Non-small-cell lung cancer (NSCLC) is the most commonly diagnosed malignant disease with the leading cause of cancer-related death. Combination treatment remains the major strategy in the clinical therapy of NSCLC. Vinorelbine (NVB), a semi-synthetic vinca alkaloid, is used for advanced and metastatic NSCLC by destabilizing microtubule formation to induce mitotic arrest and cell death. However, the side effect of NVB heavily affected its effectiveness in clinical therapy. Hence, it is of great significance to develop new agents to synergize with NVB and decrease the adverse effect. In our study, we found that the saponin monomer 13 of the dwarf lilyturf tuber, DT-13, exhibiting anti-angiogenesis and anti-metastasis effect, synergized with NVB to inhibit cell proliferation in NSCLC cells. The synergistic interaction of DT-13 and NVB was confirmed by combination Index values. Also, DT-13 and NVB act in concert to inhibit the long-term colony formation. Furthermore, DT-13/NVB co-treatment cooperated to induce mitotic arrest and subsequent apoptosis. Mechanistically, we found that nuclear expression of transcription factors forkhead box M1 (FOXM1) and levels of motor adaptor bicaudal D2 (BICD2) were dramatically reduced by combination treatment. Importantly, oncogene FOXM1 was identified as the crucial regulator of BICD2, which played critical roles in NVB-induced mitotic spindle defects. Moreover, overexpression of FOXM1 and BICD2 significantly reversed mitotic arrest induced by DT-13/NVB co-treatment, and siRNAs against both genes greatly increased the combinational effects. In addition, in vivo study revealed that DT-13 combined with NVB significantly suppressed tumor growth in nude mice xenograft model, and downregulated the expression of FOXM1 and BICD2 in tumor tissues, which was consistent with in vitro study. In conclusion, DT-13 might provide a novel strategy for the chemosensitization of NVB in NSCLC therapy.

DT-13, a saponin monomer 13 of the Dwarf lilyturf tuber, synergized with vinorelbine to induce mitotic arrest via activation of ERK signaling pathway in NCI-H1299 cells.

Vinorelbine (NVB) is a semi-synthetic vinca alkaloid that is approved for the clinical therapy of lung cancer. However, the clinical application of NVB was limited because of the acquisition of resistance and inacceptable toxicity. Therefore, it is of great interest to develop low-cytotoxic drugs that can synergize with NVB. DT-13, a saponin monomer 13 of the Dwarf lilyturf tuber, showed inhibitory effects on tumor metastasis and angiogenesis in the previous studies. Here, we found that DT-13 combined with NVB exhibited synergistic effect to inhibit the cell proliferation in human lung cancer NCI-H1299 cells rather than human embryonic lung fibroblasts WI-38. The combination of DT-13 and NVB significantly inhibited the colony formation, induced cellular and nuclear morphological changes, and triggered cell cycle arrest at mitotic phase. Furthermore, MAPK signaling pathway was activated by the combination treatment, and the activation of ERK was required for the induction of mitotic arrest. Taken together, DT-13 combined with NVB exhibited synergistic anticancer effect in NCI-H1299 cells, and DT-13 may be a candidate agent for adjuvant chemotherapy of NVB in lung cancer.

Involvement of Toll-like receptor 4 in vinorelbine-induced vascular endothelial injury.

Vinorelbine (VIN) is a semi-synthetic vinca alkaloid and is one of the most active agents for the treatment of solid tumors. The drug is commonly administered through a peripheral vein. Although VIN is known to cause local venous toxicity, such as drug-induced phlebitis, the mechanism responsible for the toxicity remains unclear. To investigate the role of Toll-like receptor 4 (TLR4) in VIN-induced vascular endothelial injury, human umbilical vein endothelial cells (HUVECs) were prepared from umbilical cords recovered with the written informed consent of the parents and treated with VIN for 60 min. Following the washing away of the VIN, the cells were cultured for a further 6 and 12 h, and the changes in TLR4 expression in the HUVECs were detected by quantitative polymerase chain reaction and western blot analyses. Finally, the effects of VIN on the translocation of nuclear factor κB (NF-κB) were determined by immunofluorescence and confocal analysis. The VIN-treated cells were stretched, extended and irregular while the control cells exhibited normal morphology. The TLR4 mRNA and protein levels were significantly higher in the VIN-treated HUVECs than those in the control group (P<0.05). The rate of NF-κB p65 nuclear translocation in the VIN-treated HUVECs was significantly higher than that in the vehicle-treated group (P<0.05). These results indicated that TLR4 is involved in the development of VIN-induced vascular endothelial injury by affecting the translocation of NF-κB.

A new lipid-based nano formulation of vinorelbine.

Vinorelbine (VLB) is a semi-synthetic Vinca alkaloid which is currently used in treatment of different cancer types mainly advanced breast cancer (ABC) and advanced/metastatic non-small cell lung cancer (NSCLC). However, its marketed formulation has been reported to have serious side effects, such as granulocytopenia, which is the major dose-limiting toxicity. Other unwanted effects include venous discoloration and phlebitis proximal to the site of injection, as well as localized rashes and urticaria, blistering, and skin sloughing. Our long-term aim in synthesizing a novel nanomicellar vinorelbine formulation is to reduce or even eliminate these side effects and increase drug activity by formulating the drug in a lipid-based system as a nanomedicine targeted to the site of action. To this end, the purpose of this study was to prepare, characterize, and determine the in vitro efficacy of vinorelbine-loaded sterically stabilized, biocompatible, and biodegradable phospholipid nanomicelles (SSM; size, ∼15nm). Our results indicated that vinorelbine incorporate at high quantities and within the interface between the core and palisade sections of the micelles. Incorporation ratio of drug within sterically stabilized micelles increased as the total amount of drug in the system increased, and no drug particles were formed at the highest drug concentrations tested. The nanomicellar formulation of vinorelbine was ∼6.7-fold more potent than vinorelbine dissolved in DMSO on MCF-7 cell line. Collectively, these data indicate that vinorelbine-loaded SSM can be developed as a new, safe, stable, and effective nanomedicine for the treatment of breast and lung cancers.

Aspirin attenuates vinorelbine-induced endothelial inflammation via modulating SIRT1/AMPK axis

Vinorelbine (VNR), a semisynthetic vinca alkaloid acquired from vinblastine, is frequently used as the candidate for intervention of solid tumors. Nevertheless, VNR-caused endothelial injuries may lead a mitigative effect of clinical treatment efficiency. A growing body of evidence reveals that aspirin is a potent antioxidant and anti-inflammation drug. We investigated whether aspirin attenuate VNR-induced endothelial dysfunction. Human endothelial cells (EA.hy 926) were treated with VNR to cause endothelial inflammation. Western blotting, ROS assay, ELISA were used to confirm the anti-inflammatory effect of aspirin. We confirmed that VNR supresses SIRT1 expression, reduced LKB1 and AMPK phosphorylation as well as enriched PKC activation in treated endothelial cells. Furthermore, the membrane translocation assay displayed that the levels of NADPH oxidase subunits p47phox and Rac-1 in membrane fractions of endothelial cells were higher in cells that had been treated with VNR for than in untreated cells. We corroborated that treatment of Aspirin significantly diminishes VNR-repressed SIRT1, LKB1 and AMPK phosphorylation and VNR-promoted NADPH oxidase activation, however, those findings were vanished by SIRT1 and AMPK siRNAs. Our data also shown that Aspirin represses VNR-activated TGF-beta-activated kinase-1 (TAK1) activation, inhibited the interaction of TAK1/TAK-binding protein1 (TAB1), suppressed NF-kappa B activation and pro-inflammatory cytokine secretion. We demonstrated a novel connection between VNR-caused oxidative damages and endothelial dysfunction, and provide further insight into the protective effects of aspirin in VNR-caused endothelial dysfunction.

The Relative Contributions of CYP3A4 and CYP3A5 to the Metabolism of Vinorelbine

Vinorelbine is a semisynthetic vinca alkaloid used in the treatment of advanced breast and non-small cell lung cancers. Vincristine, a related vinca alkaloid, is 9-fold more efficiently metabolized by CYP3A5 than by CYP3A4 in vitro. This study quantified the relative contribution of CYP3A4 and CYP3A5 to the metabolism of vinorelbine in vitro using cDNA-expressed human cytochrome P450s (P450s) and human liver microsomes (HLMs). CYP3A4 and CYP3A5 were identified as the P450s capable of oxidizing vinorelbine using a panel of human enzymes and selective P450 inhibitors in HLMs. For CYP3A4 coexpressed with cytochrome b5 (CYP3A4+b5) and CYP3A5+b5, the Michaelis-Menten constants for vinorelbine were 2.6 and 3.6 μM, respectively, but the Vmax of 1.4 pmol/min/pmol was common to both enzymes. In HLMs, the intrinsic clearance of vinorelbine metabolism was highly correlated with CYP3A4 activity, and there was no significant difference in intrinsic clearance between CYP3A5 high and low expressers. When radiolabeled vinorelbine substrate was used, there were clear qualitative differences in metabolite formation fingerprints between CYP3A4+b5 and CYP3A5+b5 as determined by NMR and mass spectrometry analysis. One major metabolite (M2), a didehydro-vinorelbine, was present in both recombinant and microsomal systems but was more abundant in CYP3A4+b5 incubations. We conclude that despite the equivalent efficiency of recombinant CYP3A4 and CYP3A5 in vinorelbine metabolism the polymorphic expression of CYP3A5, as shown by the kinetics with HLMs, may have a minimal effect on systemic clearance of vinorelbine.

Phase II study of lapatinib in combination with vinorelbine, as first- or second-line therapy in women with HER2-overexpressing metastatic breast cancer.

621 Background: Lapatinib (L), an inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2) is approved in combination with capecitabine for second-line treatment of HER2+ metastatic breast cancer (MBC). Vinorelbine (V)is a semi-synthetic vinca alkaloid approved for use in patients (pts) with MBC. A previous phase I trial provided a maximum tolerated dose of L plus V. Methods: This was a multicenter, phase II study (LPT111110; NCT00709618) to evaluate the efficacy and safety of L plus V in women with histologically confirmed stage IV HER2+ MBC, ≤1 prior chemotherapeutic regimen (no prior L or V was allowed; prior trastuzumab was permitted) and a Zubrod performance status of 0-2. Pts received L (1500 mg daily) plus V (20 mg/m2IV on Days 1, 8, 15) in a 4-week treatment cycle until disease progression or study withdrawal. Primary endpoint: overall response rate (ORR). Secondary endpoints: progression-free survival (PFS), overall survival, time to response (TTR), duration of response (DOR), time to progression, and safety assessments. Results: The study was terminated after three years due to slow enrollment; 60 pts were planned and 44 enrolled and were treated. The ORR was 41% (95% CI: 26.4%-55.4%; 4 complete responses, 14 partial responses). Investigator-assessed median (95% CI) PFS, TTR, and DOR were 24.1 (16.9-36.7), 7.5 (7.1–8.1), and 32.0 (18.0-42.3) weeks, respectively. Survival data are not available since data collection was terminated after discontinuation of study treatment. All pts experienced at least 1 adverse event (AE). Conclusions: The combination of L plus V resulted in a 41% ORR and was generally well tolerated. However, definitive conclusions could not be drawn as the study was terminated early and not powered for inference testing. Further exploration of L plus V is warranted to clearly define the role of this novel combination in the treatment of HER2+ MBC. Clinical trial information: NCT00709618. [Table: see text]

Abstract 2053: F-XA7, a novel derivative of vinca alkaloid with potent antitumor activity, efficiently overrides P-glycoprotein-mediated drug resistance both in vitro and in vivo.

Abstract Vinorelbine, a semi-synthetic vinca alkaloid, is widely used for the treatment of non-small cell lung cancer, metastatic breast cancer and ovarian cancer by inhibiting microtubule assembly. However, drug resistance mediated by P-glycoprotein (P-gp) and neurotoxic side effect possibly caused by microtubule paracrystal are major obstacles to vinorelbine application in clinic. Here, we describe a vinorelbine derivative F-XA7 as a novel microtubule-disrupting agent. F-XA7 inhibits microtubule assembly by binding to tubulin at the same site as vinorelbine and thus inhibiting the proliferation of cultured tumor cells. In vivo, F-XA7 exhibits potent antitumor activity against human tumor xenografts in nude mice. More importantly, F-XA7 is active against vinorelbine-resistant tumor cells mediated by P-gp-overexpression and significantly suppresses the growth of P-gp-overexpressing tumor xenograft in vivo, indicating that F-XA7 efficiently overrides P-gp-mediated drug resistance. In addition, the activity of F-XA7 to induce microtubule paracrystal is much weaker than that of vinorelbine in cultured cells, suggesting it may have less neurotoxic side effect. Collectively, these results indicate that F-XA7 is a novel and promising microtubule-disrupting agent for cancer therapy. Citation Format: Haitian Quan, Yongping Xu, Lihong Hu, Liguang Lou. F-XA7, a novel derivative of vinca alkaloid with potent antitumor activity, efficiently overrides P-glycoprotein-mediated drug resistance both in vitro and in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2053. doi:10.1158/1538-7445.AM2013-2053

Novel aspects of natural and modified vinca alkaloids.

The clinical interest of Vinca alkaloids was clearly identified as early as 1965 and so this class of compounds has been used as anticancer agents for more than 30 years. Today, two natural compounds, vinblastine and vincristine and two semi-synthetic derivatives, vindesine and vinorelbine, have been registered and thus Vinca alkaloids can be considered to represent a chemical class of definite utility in cancer chemotherapy. Today, relatively few groups actively research in the chemistry of Vinca alkaloids. However, using superacidic chemistry, a new family of such compounds was synthesised and vinflunine, a difluorinated derivative, was selected for clinical testing. A consideration of the pharmacological data relating to these new derivatives appears to reveal a lack of any marked correlation between in vitro and in vivo results. Furthermore, structure/activity relationships have failed to assist the chemist in the rational design. Such rational design of new derivatives is limited by the fact that the Vinca binding site(s) on tubulin and the exact mechanism(s) of action of Vinca alkaloids remain unclear. Nevertheless, the preclinical evaluations of the new derivative vinflunine have already suggested that certain in vitro assays, in addition to in vivo experiments, could be proposed to select more rationally newer generation Vincas. Moreover, recent studies have demonstrated that certain newly identified properties, such as antiangiogenic activities, could enlarge the therapeutic usage of natural and semi-synthetic Vinca alkaloids. Thus, Vinca alkaloids remain a drug family with a continuing interest for future anticancer therapy.

Phase I and Pharmacokinetic Study of IV Vinflunine in Combination With Carboplatin in Chemonaive Patients With Advanced Non-small Cell Lung Cancer

Vinflunine (VFL) (Javlor(®)), a novel fluorinated semisynthetic vinca alkaloid has shown significant antitumor activity in advanced non-small cell lung cancer (NSCLC). We propose to define the recommended dose (RD) of VFL in combination with carboplatin in advanced NSCLC patients. This phase I and pharmacokinetic study was designed to determine the maximum tolerated dose and to establish the RD of VFL in combination with carboplatin. Twenty-one chemonaive patients with advanced NSCLC were treated with a first-line chemotherapy of VFL and carboplatin both given on day 1 every 3 weeks with 3 dose levels. Five patients experienced a dose limiting toxicity consisting of constipation in 2 patients and febrile neutropenia in 2 patients. One patient experienced grade 3 abdominal pain concurrent with grade 4 neutropenia. The combination of VFL (320 mg/m(2)) and carboplatin AUC6 was defined as the maximum tolerated dose. The RD was established at the dose of VFL (320 mg/m(2)) combined with carboplatin AUC5. At the RD, 12 patients received a median number of 3 cycles of the combination. Neither VFL nor carboplatin seemed to be influencing the pharmacokinetics of the other. Among 19 patients evaluable for tumor response, 7 had a partial response and 7 experienced stable disease. The combination of VFL (320 mg/m(2)) and carboplatin AUC 5 given once every 3 weeks is established as the RD of the combination, which was shown to be active in these chemonaive NSCLC patients.

Reversible Posterior Leukoencephalopathy Syndrome Induced by Vinorelbine

Reversible posterior leukoencephalopathy syndrome (RPLS) was first described in 1996; clinical symptoms include the presence of headache, visual disturbance,seizure, hypertension, and encephalopathy. The syndrome is most commonly encountered in association with chemotherapeutic agents or targeted therapy. Many chemotherapeutic agents, such as cisplatin,gemcitabine, methotrexate, were reported to be associated with RPLS. Vinorelbine is commonly used for the treatment of metastatic breast cancer, but vinorelbine-induced RPLS has not been reported. We reported a 34-year-old woman, diagnosed with invasive ductal carcinoma of the left breast, who experienced acute hypertension after vinorelbine intravenous infusion. Accompanied symptoms included headache,seizure, and conscious disturbance. Magnetic resonance imaging of the brain showed symmetric signal hyperintensity with the cortical and subcortical white matter of bilateral frontal, parietal, and occipital (predominant) lobes. Vinorelbine is a semisynthetic vinca alkaloid and prevents cell division by inhibiting tubulin polymerization.Brain metastasis or leptomeningeal carcinomatosis is an important issue for patients with breast cancer who present with headache, seizure, or altered consciousness.However, now RPLS may be a new consideration,especially with the presentation of acute hypertension. Unlike brain or meningeal metastasis, RPLS is usually benign, and most patients recover within 2 weeks. Our case highlights an association between vinorelbine and RPLS, and the drug has not been described as a predisposing factor of RPLS in past reports. In the era of cancer treatment with chemotherapy or targeted therapy,clinicians should be aware of this syndrome.