Pathways

Metabolites of Vinblastine are predicted with biotransformer.

Vincristine is a vinca alkaloid derived from the Vinca Rosea as is marketed as Marqibo and Vincasar. Vincristine are used as chemotherapy medication such as an antimitotic anticancer agent. The mechanism of vincristine is the inhibition of microtubule dynamics that would cause mitotic arrest and eventual cell death. As a microtubule destabilizing agent, Vincristine stimulates mitotic spindle destruction and microtubule depolymerization at high concentrations. At lower clinically relevant concentrations, vincristine can block mitotic progression. Unlike the taxanes, which bind poorly to soluble tubulin, vincristine can bind both soluble and microtubule-associated tubulin. To be able stabilizing the kinetics of microtule, vincristine rapidly and reversibly bind to soluble tubulin which can increase the affinity of tublin by the induction of conformational changes of tubulin. Vincristine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding between vincristine and solubale tubulin decreases the rate of microtubule dynamics (lengthening and shortening) and increases the duration of attenuated state of microtubules. Therefore, the proper assembly of the mitotic spindle could be prevented; and the tension at the kinetochores of the chromosomes could be reduced. Subsequently, chromosomes can not progress to the spindle equator at the spindle poles. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.

Vincristine (also named leurocristine) is a natural alkaloid isolated from the leaves of the Catharanthus roseus (commonly known as the Madagascar periwinkle). Vincristine are used as chemotherapy medication such as an antimitotic anticancer agent. The mechanism of vincristine is the inhibition of microtubule dynamics that would cause mitotic arrest and eventual cell death. As a microtubule destabilizing agent, Vincristine stimulates mitotic spindle destruction and microtubule depolymerization at high concentrations. At lower clinically relevant concentrations, vincristine can block mitotic progression. Unlike the taxanes, which bind poorly to soluble tubulin, vincristine can bind both soluble and microtubule-associated tubulin. To be able stabilizing the kinetics of microtule, vincristine rapidly and reversibly bind to soluble tubulin which can increase the affinity of tublin by the induction of conformational changes of tubulin. Vincristine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding between vincristine and solubale tubulin decreases the rate of microtubule dynamics (lengthening and shortening) and increases the duration of attenuated state of microtubules. Therefore, the proper assembly of the mitotic spindle could be prevented; and the tension at the kinetochores of the chromosomes could be reduced. Subsequently, chromosomes can not progress to the spindle equator at the spindle poles. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.

Vincristine is a vinca alkaloid isolated from Vinca rosea. It is used as an antineoplastic agent in many cancer treatments (acute leukemia, malignant lymphoma, Hodgkin's disease, acute erythraemia, and acute panmyelosis). This drug is often chosen as part of polychemotherapy because of its lack of significant bone–marrow suppression and its unique clinical toxicity (neuropathy). The mechanism of vincristine is the inhibition of microtubule dynamics that would cause mitotic arrest and eventual cell death. As a microtubule destabilizing agent, Vincristine stimulates mitotic spindle destruction and microtubule depolymerization at high concentrations. At lower clinically relevant concentrations, vincristine can block mitotic progression. Unlike the taxanes, which bind poorly to soluble tubulin, vincristine can bind both soluble and microtubule-associated tubulin. To be able to stabilize the kinetics of microtubule, vincristine rapidly and reversibly bind to soluble tubulin which can increase the affinity of tubulin by the induction of conformational changes of tubulin. Vincristine binds to beta-tubulin subunits at the positive end of microtubules at a region called the Vinca-binding domain. The binding between vincristine and soluble tubulin decreases the rate of microtubule dynamics (lengthening and shortening) and increases the duration of the attenuated state of microtubules. Therefore, the proper assembly of the mitotic spindle could be prevented; and the tension at the kinetochores of the chromosomes could be reduced. Subsequently, chromosomes can not progress to the spindle equator at the spindle poles. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, a mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation of Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. Like other vinca alkaloids, Vincristine may also interfere with 1) amino acid, cyclic AMP, and glutathione metabolism, 2) calmodulin-dependent Ca2+-transport ATPase activity, 3) cellular respiration, and 4) nucleic acid and lipid biosynthesis.

Metabolites of Vincristine are predicted with biotransformer.

Vindesine (also named Eldesine) is a semisynthetic vinca alkaloid. Vindesine are used as chemotherapy medication such as an antimitotic anticancer agent. The mechanism of vindesine is the inhibition of microtubule dynamics that would cause mitotic arrest and eventual cell death. As a microtubule destabilizing agent, vindesine stimulates mitotic spindle destruction and microtubule depolymerization at high concentrations. At lower clinically relevant concentrations, vindesine can block mitotic progression. Unlike the taxanes, which bind poorly to soluble tubulin, vindesine can bind both soluble and microtubule-associated tubulin. To be able stabilizing the kinetics of microtule, vindesine rapidly and reversibly bind to soluble tubulin which can increase the affinity of tublin by the induction of conformational changes of tubulin. Vindesine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding between vindesine and solubale tubulin decreases the rate of microtubule dynamics (lengthening and shortening) and increases the duration of attenuated state of microtubules. Therefore, the proper assembly of the mitotic spindle could be prevented; and the tension at the kinetochores of the chromosomes could be reduced. Subsequently, chromosomes can not progress to the spindle equator at the spindle poles. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.