sirolimus and vinflunine

Since the middle of 1990s, the development of combinatorial chemistry along with the high throughput screening have led to some lack of interest for natural products from the pharmaceutical industry. Moreover, purification and optimization of natural compounds are very often difficult and animal experimentations need enough supply of natural sources or alternatively need sophisticated total synthesis. In oncology, this increased disinterest was also closely connected with the rapid expansion of monoclonal antibodies and synthetic protein kinase inhibitors. However since 2005, with the approval of five new drugs by the FDA (trabectedin, ixabepilone, temsirolimus, everolimus and Vinflunine), it appears that natural products are still present as direct or indirect sources of drugs. On the other hand, a third generation of natural product has arisen, which relies upon bioengineering using genetically altered producer organisms. This is particularly true of the polyketides where bioengineering harnesses their natural flexibility to expand their structural diversity. Several programs are going on to produce antibiotics, anticancer drugs or immunosuppressant. This combinatorial approach makes drug discovery by bioengineering complementary with conventional medicinal chemistry. With the approval of Mylotarg by the FDA, increased interest has also been devoted to immunoconjugates, which represent a way by which highly cytotoxic natural products such as dolastatin, calicheamycin, duocarmycin and maytansin may be targeted to cancer cells while limiting their side-effects.

Topics: Aminoglycosides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bioengineering; Biological Products; Clinical Trials as Topic; Combinatorial Chemistry Techniques; Dioxoles; Drug Approval; Drug Discovery; Drug Screening Assays, Antitumor; Drugs, Investigational; Epothilones; Everolimus; Gemtuzumab; Humans; Immunoconjugates; Maytansine; Sirolimus; Tetrahydroisoquinolines; Trabectedin; United States; United States Food and Drug Administration; Vinblastine

Systemic therapy for breast cancer is undergoing many interesting advances. In recent years, a better understanding of the underlying biology of cancer has led to the identification of several opportunities to target cellular pathways for therapeutic advantage. Hormonal therapy is often chosen as the first line of therapy because it is generally very well tolerated. However, most patients eventually become unresponsive to endocrine manipulation. Improved understanding of the mechanisms of hormonal resistance, and of the interplay between hormone receptors and cellular growth pathways, provides the rationale for combining signal transduction inhibitors and hormonal agents to overcome resistance. Emerging data from preclinical studies suggest that this goal might be achievable in the clinic. Antiangiogenic therapy has shown efficacy in colorectal and lung cancer and appears promising in breast cancer, although improved overall survival has not yet been shown. There have also been advances in cytotoxic chemotherapy. Reformulation of paclitaxel in polyoxy-castor-oil-free albumin nanoparticles (ABI-007) has allowed more convenient, safer, and enhanced drug delivery with associated improvement in outcomes. New agents with novel mechanisms of action are also in development and appear to have activity in cancer cells that are resistant to currently available agents.

Topics: Angiogenesis Inhibitors; Aromatase Inhibitors; Breast Neoplasms; ErbB Receptors; Estradiol; Female; Fulvestrant; Humans; MAP Kinase Signaling System; Paclitaxel; Sirolimus; Vinblastine

Relapse after initial first-line chemotherapy shows a poor prognosis in metastatic urothelial cancer. Currently, several chemotherapeutic agents and targeted drugs are under evaluation for platin-resistant advanced urothelial carcinoma. Vinflunine has been approved for second-line treatment in this indication. We present a patient with initial T4 advanced and subsequently metastasized bladder cancer, who has shown prolonged survival of 44 months after radical cystectomy. During her clinical course, the patient received two different platinum-containing therapies, temsirolimus within a phase II protocol and subsequent vinflunine chemotherapy. Treatment duration was 15 weeks with temsirolimus and 9 weeks with vinflunine, respectively, with a stable disease period of 3.8 months under temsirolimus therapy. This case is an example of how patients can derive a survival benefit from adequate sequencing of surgery and medical treatment including the newest therapies, even in advanced disease.

Topics: Antineoplastic Agents; Carcinoma, Transitional Cell; Disease Progression; Female; Humans; Middle Aged; Sirolimus; Time Factors; Treatment Outcome; Urinary Bladder; Urinary Bladder Neoplasms; Vinblastine