larotaxel and Neoplasms

Significant advances in cancer treatment have been achieved with novel targeted and state-of-the-art treatments. While the targeted treatments have received much attention in recent years, the more 'traditional' chemotherapeutic agents continue to play an important role in several malignancies. Former taxanes such as docetaxel and paclitaxel, with their broad anticancer activity, have contributed significantly to the improved treatment of a number of neoplastic diseases. Unfortunately, until now, the achievements obtained with these compounds have been mitigated by clinical limitations such as acquired or intrinsic resistance of tumors, poor CNS activity, allergic reactions and unfavorable toxicity profiles. Larotaxel (RPR 109881A) is a taxane analogue with a broad spectrum of activity and different toxicity profile and with the possible advantages of surpassing some mechanisms of resistance and penetrating into the CNS. The development path of this drug, its core clinical data and future treatment perspectives are discussed in this article.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Discovery; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Multidrug Resistance-Associated Proteins; Neoplasms; Structure-Activity Relationship; Taxoids

Spatiotemporal delivery of nanoparticles (NPs) at the "cellular level" is critical for nanomedicine, which is expected to deliver as much cytotoxic drug into cancer cells as possible when NPs accumulate in tumors. However, macrophages and cancer-associated fibroblasts (CAFs) that are present within tumors limit the efficiency of spatiotemporal delivery. To overcome this limitation, glutathion pulse therapy is designed to promote reduction-sensitive Larotaxel (LTX) prodrug NPs to escape the phagocytosis of macrophages and penetrate through the stromal barrier established by CAFs in the murine triple negative breast cancer model. This therapy improves the penetration of NPs in tumor tissues as well as the accumulation of LTX in cancer cells, and remodels the immunosuppressive microenvironment to synergize PD-1 blockade therapy. More importantly, a method is established that can directly observe the biodistribution of NPs between different cells in vivo to accurately quantify the target drugs accumulated in these cells, thereby advancing the spatiotemporal delivery research of NPs at the "cellular level."

Topics: Animals; Glutathione; Humans; Mice; Nanoparticles; Neoplasms; Prodrugs; Programmed Cell Death 1 Receptor; Taxoids; Tissue Distribution; Tumor Microenvironment

Taxoids are a class of successful drugs and have been successfully used in chemotherapy for a variety of cancer types. However, despite the hope and promises that these taxoids have engendered, their utility is hampered by some clinic limitations. Extensive structure-activity relationship (SAR) studies of toxoids have been performed in many different laboratories. Whereas, SAR studies that based on the new-generation toxoid, larotaxel, have not been reported yet. In view of the advantages in preclinical and clinical data of larotaxel over former toxoids, new taxoids that strategicly modified at the C3'/C3'-N and C2 positions of larotaxel were designed, semi-synthesized, and examined for their potency and efficacy in vitro. As a result, it has been shown that the majority of these larotaxel analogues are exceptionally potent against both drug-sensitive tumor cells and tumor cells with drug resistance arising from P-glycoprotein over expression. Further in vivo antitumor efficacies investigations revealed A2 might be a potent antitumor drug candidate for further preclinical evaluation.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Chemistry Techniques, Synthetic; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Mice, SCID; Molecular Docking Simulation; Neoplasms; Structure-Activity Relationship; Taxoids