ビンブラスチン

A: Vinblastine is a microtubule inhibitor that exerts its anticancer effects primarily by binding to tubulin, a protein crucial for microtubule formation [, , , , , , , , ]. Microtubules are essential for various cellular processes, including cell division (mitosis), intracellular transport, and maintaining cell shape. By disrupting microtubule dynamics, vinblastine leads to mitotic arrest, ultimately resulting in cell death.

A: While all Vinca alkaloids target microtubules, vinflunine and vinorelbine, newer members of this class, exhibit distinct effects on microtubule dynamics compared to vinblastine []. Unlike vinblastine, these newer agents do not increase the time microtubules spend in an attenuated state. They also have a less pronounced inhibitory effect on microtubule treadmilling compared to vinblastine. These differences might contribute to the unique efficacy and toxicity profiles of these drugs.

A: Research suggests that vinblastine might influence the interaction between calmodulin, a calcium-binding protein, and stable tubule only polypeptide (STOP), a microtubule-associated protein []. This interaction is involved in regulating microtubule dynamics, and its disruption by vinblastine could further contribute to the drug's antimitotic activity.

A: Studies in rats demonstrate that vinblastine can inhibit ferritin clearance from circulation and stimulate the release of endogenous ferritin into the serum and bile []. This effect suggests a potential interaction with iron metabolism, although the exact mechanisms remain unclear.

ANone: The molecular formula of vinblastine is C46H58N4O9, and its molecular weight is 811.0 g/mol.

A: Modifying vinblastine's structure can significantly impact its activity and potency. For example, creating C20' urea and thiourea derivatives of vinblastine led to some derivatives exhibiting up to 10-fold greater potency than vinblastine itself []. This finding highlights the potential for developing more effective vinblastine analogs through structural modifications.

A: While specific details on vinblastine's ADME profile are not provided in the research papers, one study mentions that vinblastine can be detected in the urine of dogs undergoing chemotherapy []. This finding suggests that renal excretion might be one of the elimination pathways for vinblastine.

A: Studies demonstrate that flubendazole, an antihelmintic drug with microtubule-inhibiting properties, displays synergistic effects when combined with vinblastine in preclinical models of leukemia []. This combination therapy resulted in enhanced tumor growth delay compared to either drug alone, suggesting potential benefits for treating these hematologic malignancies.

A: Clinical trials investigating weekly vinblastine administration in children with recurrent or refractory low-grade gliomas demonstrated sustained responses with manageable toxicity [, ]. This finding suggests vinblastine could be a valuable treatment option for this patient population.

A: Research using a naturally-occurring canine model of invasive urothelial carcinoma indicated that combining vinblastine with piroxicam, a non-selective cyclooxygenase inhibitor, significantly improved remission rates and progression-free survival compared to vinblastine alone []. This study highlights the potential of combination therapies in enhancing vinblastine's efficacy.

A: Overexpression of P-glycoprotein, a transmembrane protein that pumps drugs out of cells, is one mechanism of resistance to vinblastine and other drugs [, , , ]. This overexpression can limit the intracellular accumulation of vinblastine, thereby reducing its efficacy.

A: Studies using renal cell carcinoma cell lines revealed that exposure to vinblastine can alter the expression of beta 1 integrins, specifically VLA-2, which are involved in cell adhesion and migration []. This finding suggests that vinblastine might influence the metastatic potential of tumor cells.

A: Research exploring the use of vinblastine-loaded platelets (VLP) for treating platelet-phagocytizing tumors shows that VLPs could potentially deliver vinblastine specifically to tumor sites, as evidenced by higher drug levels in tumor-infiltrated bone marrow compared to peripheral blood [].

A: Research suggests that a single nucleotide polymorphism (SNP) in the promoter region of the CEP72 gene (TT allele at rs924607) is associated with an increased risk of vincristine-induced peripheral neuropathy []. This finding could potentially guide personalized chemotherapy approaches by identifying patients at higher risk of developing this side effect.

A: Radioimmunoassay is one method mentioned in the research papers for measuring vinblastine concentrations in biological samples []. Additionaly, liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) is a highly sensitive and specific method for quantifying vinblastine and other chemotherapeutic drugs in biological matrices, such as urine [].

A: Yes, matrix-assisted laser desorption/ionization-ion mobility separation-mass spectrometry imaging (MALDI-IMS-MS) has been successfully employed to visualize the distribution of vinblastine in whole-body tissue sections []. This technique allows for the detection and localization of both the parent drug and its metabolites, providing valuable insights into drug distribution and pharmacokinetics.

A: Studies evaluating the biodegradability of vinblastine, vincristine, and vindesine using the closed bottle test (CBT) and Zahn-Wellens test (ZWT) indicated that these compounds exhibit low biodegradability in aquatic environments []. This finding highlights potential concerns regarding the persistence of these drugs in the environment and their possible ecological impact.

A: Yes, vinblastine is a known substrate of P-glycoprotein (P-gp), a transmembrane efflux transporter responsible for pumping drugs out of cells [, , , ]. This interaction can lead to reduced intracellular drug accumulation and contribute to drug resistance.

A: Yes, several compounds have been identified that can modulate vinblastine's interaction with P-glycoprotein. For example, staurosporine derivatives, particularly NA-382, have shown the ability to enhance vinblastine accumulation in adriamycin-resistant P388 (P388/ADR) cells by inhibiting P-gp activity []. Similarly, the isoquinolinesulfonamide compound H-87 has been shown to reverse vinblastine resistance in rat ascites hepatoma AH66 cells by inhibiting the binding of vinblastine to P-gp [].

A: Flubendazole, an antihelmintic drug, has emerged as a potential alternative to vinblastine in treating leukemia and myeloma []. It inhibits tubulin polymerization through a distinct mechanism and shows efficacy even in vinblastine-resistant cells. Moreover, flubendazole displays synergistic effects when combined with vinblastine in preclinical models, suggesting its potential as both an alternative and a synergistic agent.