Vinorelbine Tartrate

Description: IC50 Value: 1.25 nM (Hela cell) [1] Vinorelbine is an anti-mitotic chemotherapy drug that is given as a treatment for some types of cancer, including breast cancer and non-small cell lung cancer. in vitro: Vinorelbine, more significantly, inhibits the proliferation of HeLa cells with IC50 of 1.25 nM, compared to vinflunine with IC50 of 18 nM. Vinorelbine blocks cell cycle progression in mitosis with IC50 of 3.8 nM, which is only slightly higher than the IC50 value for inhibition of proliferation, indicating that mitotic block is a major contributor to antiproliferative action. Vinorelbine has the greatest effect, 29%, on reduction of the spindle length compared to 20% by vinflunine and 22% by vinblastine at the IC50 concentrations of the three drugs [1]. Vinorelbine induces concentration- and time-dependent increases in the protein levels of both p53 and p21 in hormone-dependent (AD) LNCaP cells, and can restore p21 expression in androgen-independent (AI) prostate cancer cells through both p53-dependent and-independent pathways [2]. in vivo: Nineteen dogs were treated with vinorelbine as a 5-minute IV infusion every 7 days at starting dosages ranging from 10 to 20 mg/m2. The median number of treatments per dog was 7 (range, 1-11). The maximum tolerated dosage varied between 15 and 18 mg/m2, and a starting dosage of 15 mg/m2 is recommended [3]. Sixty-one VRL treatments were administered. Median number of treatments was 2 (range, 1-9). Starting dosages were 9-12 mg/m(2) . Maximal dosage administered was 15.5 mg/m(2) . The MTD was 11.5 mg/m(2) . Acute DLTs were neutropenia, vomiting, and nephrotoxicity. Other notable toxicities were weight loss and anemia [4]. Toxicity: Acute DLTs were neutropenia, vomiting, and nephrotoxicity. Other notable toxicities were weight loss and anemia [4]. Clinical trial: XeNa: Phase II Trial With Metronomic, Capecitabine Plus Oral Vinorelbine for Metastatic Breast Cancer. Phase 2

Visual, turbidimetric, and particle-content assessment of compatibility of vinorelbine tartrate with selected drugs during simulated Y-site injection.[Pubmed:8017415]

Am J Hosp Pharm. 1994 Feb 15;51(4):495-9.

The compatibility of Vinorelbine Tartrate with selected drugs during simulated Y-site administration was studied. A 5-mL sample of Vinorelbine Tartrate 1 mg/mL in 0.9% sodium chloride injection was combined with a 5-mL sample of each of 91 other drugs at concentrations used clinically. Each combination was prepared in duplicate, with the order of mixing being reversed between the two; storage was in constant fluorescent light at 22 degrees C. The admixtures were examined visually in normal fluorescent light and with a Tyndall beam at zero, one, and four hours after preparation. A turbidimeter was used to measure the turbidity of each drug combination at the same intervals. Samples showing visual or turbidimetric evidence of incompatibility were subjected to particle counting and sizing. The majority of the drugs tested were compatible with Vinorelbine Tartrate; most combinations had a turbidity of less than 0.1 nephelometric turbidity unit. Turbidity measurements showed that cefazolin sodium, ceforanide, and cefuroxime sodium were incompatible with Vinorelbine Tartrate. Visual observation showed incompatibility of Vinorelbine Tartrate with acyclovir sodium, aminophylline, amphotericin B, ampicillin sodium, cefoperazone sodium, ceforanide, cefotetan sodium, ceftriaxone sodium, fluorouracil, furosemide, ganciclovir sodium, methylprednisolone sodium succinate, mitomycin, piperacillin sodium, sodium bicarbonate, thiotepa, and trimethoprimsulfamethoxazole. Vinorelbine Tartrate 1 mg/mL in 0.9% sodium chloride injection was compatible with the majority of the drugs tested for up to four hours at 22 degrees C but was incompatible with 19 drugs.

The effects of vinflunine, vinorelbine, and vinblastine on centromere dynamics.[Pubmed:12748304]

Mol Cancer Ther. 2003 May;2(5):427-36.

Vinflunine is a novel fluorinated Vinca alkaloid currently in Phase II clinical trials, which in preclinical studies exhibited superior antitumor activity to that of two clinically useful Vinca alkaloids, vinorelbine and vinblastine. All three of the drugs block mitosis at the metaphase/anaphase transition, leading to apoptosis. The mechanism of the mitotic block is not known. On the basis of results with purified microtubules and in living interphase cells, we hypothesized that it involves suppression of spindle microtubule dynamics. Here we measured the effects of the three Vinca alkaloids on dynamics of centromeres and spindle kinetochore-microtubules by a novel approach involving quantitative time-lapse confocal microscopy in living mitotic human U2OS cells. Green fluorescent protein-labeled centromere-binding protein B was used to mark centromeres and kinetochore-microtubule plus ends. In controls, pairs of centromeres on sister chromatids alternated under tension between increasing and decreasing separation (stretching and relaxing). All three of the Vinca alkaloids suppressed centromere dynamics similarly at concentrations that block mitosis. At concentrations approximating the IC(50)s for mitotic accumulation (18.8 nM vinflunine, 7.3 nM vinorelbine, and 6.1 nM vinblastine), centromere dynamicity decreased by 44%, 25%, and 26%, respectively, and the time centromeres spent in a paused state increased by 63%, 52%, and 36%, respectively. Centromere relaxation rates, stretching durations, and transition frequencies all decreased. Thus all three of the drugs decreased the normal microtubule-dependent spindle tension at the centromeres/kinetochores, thereby preventing the signal for mitotic checkpoint passage. The strong correlation between suppression of kinetochore-microtubule dynamics and mitotic block indicates that the primary mechanism by which the Vinca alkaloids block mitosis is suppression of spindle microtubule dynamics.

Mechanism of mitotic block and inhibition of cell proliferation by the semisynthetic Vinca alkaloids vinorelbine and its newer derivative vinflunine.[Pubmed:11408618]

Mol Pharmacol. 2001 Jul;60(1):225-32.

The two second-generation Vinca alkaloids, vinorelbine and vinflunine, affect microtubule dynamics very differently from vinblastine, a first generation Vinca alkaloid. For example, vinblastine strongly suppresses the rate and extent of microtubule shortening in vitro, whereas vinorelbine and vinflunine suppress the rate and extent of microtubule growing events. We asked whether these differences result in differences in mitotic spindle organization that might be responsible for the superior antitumor activities of the two second-generation Vinca alkaloids. IC(50) values for inhibition of HeLa cell proliferation for vinflunine, vinorelbine, and vinblastine were 18, 1.25, and 0.45 nM, respectively, similar to the concentrations that induced mitotic block at the metaphase/anaphase transition (38, 3.8, and 1.1 nM, respectively), indicating that mitotic block is a major contributor to antiproliferative action for all three drugs. Mitotically blocked cells exhibited aberrant spindles, consistent with induction of block by suppression of microtubule dynamics. Despite differences in their actions on individual dynamic instability parameters, morphologically detectable differences in spindle effects among the three drugs were minimal, indicating that overall suppression of dynamics may be more important in blocking mitosis than specific effects on growth or shortening. We also found that the peak intracellular drug concentration at the mitotic IC(50) value was highest for vinflunine (4.2 +/- 0.2 microM), intermediate for vinorelbine (1.3 +/- 0.1 microM), and more than 10-fold lower for vinblastine (130 +/- 7 nM), suggesting that intracellular binding reservoir(s) may be partially responsible for vinflunine's high efficacy and minimal side effects.

Vinorelbine (Navelbine): a third-generation vinca alkaloid.[Pubmed:9316630]

Cancer Invest. 1997;15(5):475-90.

The vinca alkaloids represent one of the oldest classes of antineoplastic agents used in humans with a wide spectrum of activity against both animal and human tumors. These agents are known to inhibit microtubule polymerization. Vinorelbine is a semisynthetic analog that reached clinical trial on the basis of less preclinical evidence of toxicity to neuronal tissue and greater cytotoxic activity in preclinical models than the older compounds of this class. In humans, the clearance of this agent shows a wide variation among subjects with the predominant toxicity being hematological. Significant antitumor activity has been observed in diseases that previously have been shown to respond to vinca alkaloids.