Antitubulin Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
Eribulin (HalavenTM) (Figure 4.10) is a fully synthetic macrocyclic ketone analog of the marine natural product halichondrin B which was isolated from a sponge in 1986. Eribulin was synthesized in the late 1990s and approved for clinical use in breast cancer in 2010. It is a potent mitotic inhibitor of microtubule dynamics, binding predominantly to a small number of high-affinity sites at the positive ends of existing microtubules. This inhibits the polymerization of tubulin and the assembly of microtubules, resulting in the inhibition of mitotic spindle assembly and induction of cell-cycle arrest in the G2/M phase. It exerts its anticancer activity by triggering apoptosis in cancer cells following prolonged and irreversible mitotic blockade. It was approved by the FDA in 2010 for the treatment of metastatic breast cancer in patients who have received at least two prior chemotherapy regimens for late-stage disease, including both an anthracycline and a taxane. Eribulin is administered by intravenous infusion and cannot be given orally. Myelosuppression, peripheral neuropathy, and QT-interval prolongation are the most significant side effects.
Chemotherapy in pregnancy
Hung N. Winn, Frank A. Chervenak, Roberto Romero in Clinical Maternal-Fetal Medicine Online, 2021
Vincristine is a vinca alkaloid antimicrotubule agent derived from the periwinkle Catharanthus roseus plant. It is indicated for the treatment of choriocarcinoma, brain tumors, thyroid cancer, leukemia, lymphoma, sarcomas, and several other malignancies. As noted above, vincristine has been used in combination with bleomycin and other agents, delivering infants without abnormalities. Tewari et al. reported on the neoadjuvant treatment of cervical cancer with cisplatin and vincristine in two pregnant women, both of whom experienced significant reductions in tumor volume (19). No adverse fetal effects were noted. Bader et al. also reported on the use of cisplatin and vincristine in a patient for the neoadjuvant treatment of a cervical cancer beginning in the 23rd week of pregnancy (85). At 33 weeks, the patient then underwent a cesarean radical hysterectomy, delivering a normal infant. There have been some sporadic reports of atrial septal defects, renal hypoplasia, and pancytopenia following the use of vincristine in pregnancy (45,86,87). Several other authors have reported the successful use of vincristine, most frequently in combination with other agents, leading to the delivery and normal development of healthy infants (88,89).
Advanced Formulation Techniques Including Innovative Materials
Heather A.E. Benson, Michael S. Roberts, Vânia Rodrigues Leite-Silva, Kenneth A. Walters in Cosmetic Formulation, 2019
Among the drugs that have been loaded in TyroSpheres, a significant effort has been made to develop and characterize paclitaxel-TyroSphere formulations aimed at treating skin disorders such as psoriasis. Paclitaxel is a mitotic inhibitor drug and is marketed for cancer therapy. Paclitaxel also prevents cellular over-proliferation and therefore can potentially be used to treat psoriasis. However, the poor solubility of paclitaxel and its toxicity limits the medical applications of this drug. TyroSpheres were able to load paclitaxel with up to 8.4% w/w loading efficiency and provided substantial enhancement of its solubility (1160 µg/mL). In a 72-hour in vitro drug release study using dialysis cassettes, a sustained release pattern was observed with paclitaxel-TyroSpheres. In 72 h about 44 and 58% of the drug was released from the paclitaxel-TyroSpheres with 5.0 and 8.4 wt% drug loading, respectively, while no burst release was observed. A viscous formulation of paclitaxel-TyroSpheres was prepared by adding 1% HPMC to the formulation, which showed a similar drug release profile to the TyroSphere liquid formulation. Following a skin permeation study using human cadaver skin, paclitaxel–TyroSpheres in both aqueous dispersion and gel-like formulation delivered significant amounts of the drug to the epidermis, and the delivery to the receptor compartment – representing the systemic circulation – was minimal (Kilfoyle et al., 2012).
Efficacy of nab-paclitaxel in treating metastatic melanoma
Published in Expert Opinion on Pharmacotherapy, 2019
nab-Paclitaxel is a solvent-free human serum albumin-paclitaxel nanoparticle of approximately 130 nm in size, where the paclitaxel is present in a non-crystalline, amorphous state. Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or ‘bundles’ of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis [7]. Upon intravenous administration of nab-paclitaxel, the nanoparticles dissociate rapidly into soluble, albumin bound paclitaxel complexes of approximately 10 nm in size. Albumin is known to mediate endothelial caveolar transcytosis of plasma constituents, and in vitro studies demonstrated that the presence of albumin in nab-paclitaxel enhances transport of paclitaxel across endothelial cells. It is hypothesized that this enhanced transendothelial caveolar transport is mediated by the gp-60 albumin receptor, and that there is enhanced accumulation of paclitaxel in the area of tumor due to the albumin-binding protein Secreted Protein Acidic Rich in Cysteine (SPARC) [7].
Docetaxel-induced acute myositis: a case report with review of literature
Published in Journal of Chemotherapy, 2021
Sariya Wongsaengsak, Miguel Quirch, Somedeb Ball, Anita Sultan, Nusrat Jahan, Mohamed Elmassry, Shabnam Rehman
Docetaxel is a medication in the Taxane group. Docetaxel is an antimicrotubule agent that inhibits the reorganization of the microtubule network that is needed for mitosis, thereby leading to cancer cell apoptosis.1 Docetaxel was first approved by the Food and Drug Administration (FDA) in 1996 as a second-line treatment of locally advanced and metastatic breast cancer based on the positive results from clinical trials which showed that it was a highly effective antineoplastic agent for breast cancer.2 Since then, its indications have expanded to the treatment of many other solid tumors such as non small cell lung cancer, prostate cancer, gastric adenocarcinoma, and squamous cell carcinoma of head and neck.3 The well-established side effects of docetaxel are myelosuppression, severe neutropenia, peripheral neuropathy, fluid retention, and asthenia.1,2 The most commonly reported musculoskeletal adverse event is myalgia and joint pain. A few studies reported that 78%-87% of patients who have been exposed to taxanes experienced mild to moderate myalgia at some point in the course of treatment.1,4,5 Unfortunately, severe acute myositis remains an unusual complication. We report a case of acute myositis related to docetaxel in a patient with breast cancer.
Antibody–drug conjugates harboring a kinesin spindle protein inhibitor with immunostimulatory properties
Published in OncoImmunology, 2022
Anette Sommer, Sandra Berndt, Hans-Georg Lerchen, Sabrina Forveille, Allan Sauvat, Dominik Mumberg, Guido Kroemer, Oliver Kepp
The pro-ICD activity of the payload of the TWEAKR-KSPi-ADCs requires future mechanistic exploration. TWEAKR is a member of the TNF receptor family, and prior work supports the idea that direct activation of the extrinsic pathway of apoptosis by the activation of such receptors is sufficient to stimulate caspase-8-dependent ICD.54,55 Ligation of TWEAKR by its ligand TWEAK can activate this pathway, and some TWEAKR-specific antibodies have similar effects,56–58 spurring the launch of clinical trials using anti-TWEAKR antibodies without a payload.46,50 KSPi acts as a mitotic inhibitor and as such might perturb cellular physiology in a similar fashion as do microtubule inhibitors.47,59 However, this conjecture needs further exploration. Altogether, efficient ICD induction by TWEAKR-KSPi-ADCs might involve the antibody moiety, the payload or the combination of both. Irrespective of this incognita, it appears obvious that TWEAKR-KSPi-ADCs deserve further clinical characterization.
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