From single- to multi-target drugs in cancer therapy

When aspecificity becomes an advantage

Annalisa Petrelli, Silvia Giordano

Research output: Contribution to journalArticle

287 Citations (Scopus)

Abstract

Targeted therapies by means of compounds that inhibit a specific target molecule represent a new perspective in the treatment of cancer. In contrast to conventional chemotherapy which acts on all dividing cells generating toxic effects and damage of normal tissues, targeted drugs allow to hit, in a more specific manner, subpopulations of cells directly involved in tumor progression. Molecules controlling cell proliferation and death, such as Tyrosine Kinase Receptors (RTKs) for growth factors, are among the best targets for this type of therapeutic approach. Two classes of compounds targeting RTKs are currently used in clinical practice: monoclonal antibodies and tyrosine kinase inhibitors. The era of targeted therapy began with the approval of Trastuzumab, a monoclonal antibody against HER2, for treatment of metastatic breast cancer, and Imatinib, a small tyrosine kinase inhibitor targeting BCR-Abl, in Chronic Myeloid Leukemia. Despite the initial enthusiasm for the efficacy of these treatments, clinicians had to face soon the problem of relapse, as almost invariably cancer patients developed drug resistance, often due to the activation of alternative RTKs pathways. In this view, the rationale at the basis of targeting drugs is radically shiffing. In the past, the main effort was aimed at developing highly specific inhibitors acting on single RTKs. Now, there is a general agreement that molecules interfering simultaneously with multiple RTKs might be more effective than single target agents. With the recent approval by FDA of Sorafenib and Sunitinib - targeting VEGFR, PDGFR, FLT-3 and c-Kit - a different scenario has been emerging, where a new generation of anti-cancer drugs, able to inhibit more than one pathway, would probably play a major role.

Original languageEnglish
Pages (from-to)422-432
Number of pages11
JournalCurrent Medicinal Chemistry
Volume15
Issue number5
DOIs
Publication statusPublished - Feb 2008

Fingerprint

Protein-Tyrosine Kinases
Molecules
Monoclonal Antibodies
Pharmaceutical Preparations
Neoplasms
Chemotherapy
Poisons
Cell proliferation
Receptor Protein-Tyrosine Kinases
Cell death
Tumors
Intercellular Signaling Peptides and Proteins
Therapeutics
Chemical activation
Cells
Tissue
Drug Delivery Systems
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Drug Resistance
Cell Death

Keywords

  • Cancer therapy
  • Monoclonal antibodies
  • Small molecules
  • Targeted therapy
  • Tyrosine kinase inhibitors
  • Tyrosine kinase receptors

ASJC Scopus subject areas

  • Organic Chemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Pharmacology

Cite this

From single- to multi-target drugs in cancer therapy : When aspecificity becomes an advantage. / Petrelli, Annalisa; Giordano, Silvia.

In: Current Medicinal Chemistry, Vol. 15, No. 5, 02.2008, p. 422-432.

Research output: Contribution to journalArticle

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