Chemotherapeutics

Traditional chemotherapy protocols typically utilize cytotoxic agents that target and kill rapidly proliferating cells – one of the characteristics of most cancer cells. These cytotoxic agents generally interfere with RNA and DNA synthesis or cell division, and therefore, affect cell growth by various mechanisms of action.

Examples of typical cytotoxic agents include:
  • Paclitaxel (cytoskeletal disruptor)
  • Irinotecan and etoposide (topoisomerase inhibitors)
  • Cisplatin (platinum-based DNA intercalating drug)
  • Cyclophosphamide (alkylating agent)
  • Doxorubicin (an anthracycline)
  • Fluorouracil (antimetabolite)

Since these traditional chemotherapeutic agents have the greatest effect on rapidly dividing cells without discriminating normal vs. cancer cells, these drugs also affect the rapidly dividing cells of the intestine and bone marrow, with gastrointestinal toxicity and myelosuppression being common side effects.

More recently, newer antineoplastic agents are being developed that are designed to target cancer cells while having less effects on non-target normal tissues. These agents fall into a variety of classifications from small molecules to large and complex biologics. Examples include imatinib and erlotinib (tyrosine kinase inhibitors), bevacizumab, ocrelizumab and rituximab (monoclonal antibodies), carfilzomib (peptide proteasome inhibitor), brentuximab and vedotin (antibody-drug conjugate). However these molecular targeted therapies, used either alone or in combination with other antineoplastic agents (combination therapies) often present unexpected toxicity, including bone marrow suppression.

References:
1.  T. Hansel et. al., Nature Reviews Drug Discovery. 2010 (Apr), 9: 325-338.
2.  A. Pessina et. al., Toxicologicial Sciences. 2003; 75: 355-367.
3.  E. Clarke et. al., Genetic Engineering & Biotechnology News. 2010 (Feb 15); 14-15.
4.  A. Pessina et. al., Toxicology in Vitro. 2009; 23: 194-200.
5.  E. Clarke et. al. Society of Toxicology 55th Annual Meeting & ToxExpo 2016