A Review of Paclitaxel and Novel Formulations Including Those Suitable for Use in Dogs

Abstract

Paclitaxel is a commonly used chemotherapeutic agent with a broad spectrum of activity against cancers in humans. In 1992, paclitaxel was approved by the U.S. Food and Drug Administration (FDA) as Taxol® for use in advanced ovarian cancer. Two years later, it was approved for the treatment of metastatic breast cancer. Paclitaxel was originally isolated from the bark of the Pacific yew tree, Taxus brevifolia in 1971. Taxanes are a family of microtubule inhibitors. As a member of this family, paclitaxel suppresses spindle microtubule dynamics. This activity results in the blockage of the metaphase‐anaphase transitions, and ultimately in the inhibition of mitosis, and induction of apoptosis in a wide spectrum of cancer cells. Additional anticancer activities of paclitaxel have been defined that are independent of these effects on the microtubules and may include the suppression of cell proliferation as well as antiangiogenic effects. Based on its targeting of a fundamental feature of the cancer phenotype, the mitotic complex, it is not surprising that paclitaxel has been found to be active in a wide variety of cancers in humans. This review summarizes the evidence in support of paclitaxel's broad anticancer activity and introduces the rationale for, and the progress in development of novel formulations of paclitaxel that may preferentially target cancers and that are not associated with the risks for hypersensitivity in dogs. Of note, a novel nanoparticle formulation of paclitaxel that substantially limits hypersensitivity was recently given conditional approval by the FDA Center for Veterinary Medicine for use in dogs with resectable and nonresectable squamous cell carcinoma and nonresectable stage III, IV and V mammary carcinoma.

Induction of cell cycle arrest by increasing GTP-RhoA levels via Taxol-induced microtubule polymerization in renal cell carcinoma

“…Taxol may stabilize microtubules and subsequently cause cell death by arresting the cell cycle at G2/M (21,22). The present study demonstrated that Taxol-induced MT polymerization is accompanied by an increase in GTP-RhoA protein expression levels and cell cycle arrest in RCC cells.…”

Liposome‐encapsulated chemotherapy: Current evidence for its use in companion animals

“…Simultaneously, a few non‐cytotoxic drugs have been registered, such as liposomal amphotericin B (Ambiosome) for fungal infections and liposomal morphine (DepoDur) for prolonged analgesia. No liposomal cancer drugs are currently registered for use in veterinary patients, but 1 micellar nanodrug containing paclitaxel (Paccal Vet) previously obtained conditional FDA approval for use in untreated dogs with squamous cell carcinomas (SCC) or stage III‐V mammary carcinomas . The Paccal Vet FDA approval was, however, recently withdrawn at the company's request.…”

“…Dogs seem to be exceptionally sensitive, limiting paclitaxel's use in this species. Methods to overcome this have focused on new formulations, which among others include the albumin‐based Abraxane (FDA approved), as well as the previously mentioned micellar‐based drug Paccal Vet . Concurrently, liposome‐encapsulated paclitaxel formulations have also been evaluated in healthy dogs in 2 recent studies .…”

Epigallocatechin-3-gallate inhibits paclitaxel-induced apoptosis through the alteration of microRNA expression in human dermal papilla cells

“…Paclitaxel-mediated regulation repressed mitotic activity and then induces apoptosis. Thus, it is generally used in therapy of metastatic breast cancer, ovarian cancer, and non-small cell lung cancer (Khanna et al 2015;Chen et al 2011;Jordan and Wilson 2004).…”