化合物信息

Description

Cancer

Description

Vinorelbine (Navelbine) is an anti-mitotic agent which inhibits the proliferation of Hela cells with IC50 of 1.25 nM.

Targets

IC₅₀

In Vitro

Vinorelbine, a semisynthetic derivative of vinca alkaloid, is effective in non–small-cell lung cancer, metastatic breast cancer, and ovarian cancer and shows promise in lymphoma, esophageal cancer, and prostatic carcinoma. 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

Vinorelbine treatment at 2.5 and 5 mg/kg significantly increases the median survival time (MST) of NCI-H460 tumor bearing mice from 21 days to 24 and 35 days, respectively. Vinorelbine in combination with the Bcl-2 antisense oligonucleotide oblimersen induces highly significant tumor growth suppression in a dose-dependent manner than either drug used alone and without showing significant signs of undesirable toxicity. ^[3] Administration of Vinorelbine at a dose of 3 mg/kg once weekly for 6 weeks produces 22% reduction in the tumor volume of human breast cancer xenografts in athymic mice. The anticancer activity can be significantly enhanced in combination with 2-MeO-E2 (30 mg/kg) with tumor growth almost completely inhibited during the first 2 weeks. ^[4]

Clinical Trials

A Phase III study to explore if the combination of Vinorelbine and gemcitabine is better than Vinorelbine and carboplatin for the treatment of advanced non-small cell lung cancer, in terms of survival, quality of life and need for palliative radiotherapy has been completed.

Features

Cell Lines

HeLa cells

Concentrations

0.5-5 nM

Incubation Time

20 hours

Methods

Hela cells are exposed to Vinorelbine (0.5-5 nM) for 20 hours. Live cells are counted using a hemocytometer, with trypan blue dye beimg used to distinguish living from dead cells. Cell proliferation is calculated from the difference in cell number at the beginning and at the end of the Vinorelbine incubation, relative to the increase in cell number for control cultures during the same period. For the determination of mitotic index, both detached and attached cells are collected, fixed, and their microtubules and chromosomes stained. The numbers of cells in mitosis and in interphase are then determined by microscopy.

Animal Models

Male severe combined immunodeficient (SCID)-RAG2 mice implanted with NCI-H460 cells subcutaneously or through the chest wall into the left pleural space

Formulation

Dissolved in sterile 0.9% NaCl solution

Doses

5 or 10 mg/kg

Administration

Intravenously every 4th day