The therapeutic activity of most anticancer drugs in clinical use is limited by their general toxicity to proliferating cells, including some normal cells. Although, chemists continue to develop novel cytotoxic agents with unique mechanisms of action, many of these compounds still lack tumor selectivity and have not been therapeutically useful. Monoclonal antibodies that bind to specific markers on the surface of tumor cells offer an alternative therapy that is tumor specific and thus less toxic. Although highly selective, very few monoclonal antibodies are therapeutically useful since they only display modest cell killing activity. The linkage of monoclonal antibodies to highly cytotoxic drugs can be viewed as a means of (a) conferring higher tumor selectivity to cytotoxic drugs that are too toxic to be used on their own or (b) conferring cell killing power to monoclonal antibodies that are tumor-specific but not sufficiently cytotoxic. This Account provides a brief history of the development of antibody...

Targeted cancer therapy: conferring specificity to cytotoxic drugs.

Traditional cancer chemotherapy is often accompanied by systemic toxicity to the patient. Monoclonal antibodies against antigens on cancer cells offer an alternative tumor-selective treatment approach. However, most monoclonal antibodies are not sufficiently potent to be therapeutically active on their own. Antibody-drug conjugates (ADCs) use antibodies to deliver a potent cytotoxic compound selectively to tumor cells, thus improving the therapeutic index of chemotherapeutic agents. The recent approval of two ADCs, brentuximab vedotin and ado-trastuzumab emtansine, for cancer treatment has spurred tremendous research interest in this field. This Review touches upon the early efforts in the field, and describes how the lessons learned from the first-generation ADCs have led to improvements in every aspect of this technology, i.e., the antibody, the cytotoxic compound, and the linker connecting them, leading to the current successes. The design of ADCs currently in clinical development, and results from mechanistic studies and preclinical and clinical evaluation are discussed. Emerging technologies that seek to further advance this exciting area of research are also discussed.

Antibody-drug conjugates: an emerging concept in cancer therapy

The use of photochemical transformations is a powerful strategy that allows for the formation of a high degree of molecular complexity from relatively simple building blocks in a single step. A central feature of all light-promoted transformations is the involvement of electronically excited states, generated upon absorption of photons. This produces transient reactive intermediates and significantly alters the reactivity of a chemical compound. The input of energy provided by light thus offers a means to produce strained and unique target compounds that cannot be assembled using thermal protocols. This review aims at highlighting photochemical transformations as a tool for rapidly accessing structurally and stereochemically diverse scaffolds. Synthetic designs based on photochemical transformations have the potential to afford complex polycyclic carbon skeletons with impressive efficiency, which are of high value in total synthesis.

Photochemical Approaches to Complex Chemotypes: Applications in Natural Product Synthesis

Metabolites from symbiotic bacteria

The potential of immunoconjugates of cytotoxic drugs for the treatment of cancer has not yet been realized owing to the difficulty of delivering therapeutic concentrations of these drugs to the target cells. In an effort to overcome this problem we have synthesized maytansinoids that have 100- to 1000-fold higher cytotoxic potency than clinically used anticancer drugs. These maytansinoids are linked to antibodies via disulfide bonds, which ensures the release of fully active drug inside the cells. The conjugates show high antigen-specific cytotoxicity for cultured human cancer cells (50% inhibiting concentration, 10 to 40 pM), low systemic toxicity in mice, and good pharmacokinetic behavior.

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Immunoconjugates containing novel maytansinoids: promising anticancer drugs.

Extracts of Euphorbia esula L. and Croton tiglium L., two members of the Euphorbiaceae which have been used widely in folk medicine for treating cancers, showed antileukemic activity against the P-388 lymphocytic leukemia in mice. Systematic fractionation of the extract of Euphorbia esula L. led to characterization of a major antileukemic component as the new diterpenoid diester, ingenol 3,20-dibenzoate. Similar fractionation of Croton oil led to characterization of phorbol 12-tiglate 13-decanoate as an active principle.

AR Branfman

Papers

Antileukemic Principles Isolated from Euphorbiaceae Plants

The maytansinoids. Isolation, structural elucidation, and chemical interrelation of novel ansa macrolides.