"Alkylating Agents" TUMOR TIDBITS, A BIWEEKLY EMAIL NEWSLETTER FROM GULF COAST VETERINARY ONCOLOGY Number 89; February 21, 2003. ======================================================================= THIS WEEK'S TUMOR TIDBIT: Alkylating Agents ======================================================================= Spring is almost here and March 15th is our Second Annual Patient Celebration in ouston - all are welcome. Contact Ms. Julie Ormond for additional details (713.693.1166). Visit our web site for other exciting information. ======================================================================= Alkylating agents are among the most widely used anticancer drugs and are major components of combination regimens for both solid and hematopoietic tumors. They are chemically diverse drugs. The major similarity among the alkylating agents is the cytotoxic element of the molecule, an immonium ion (-N-CH2CH2-). Most alkylating agents undergo transformation to produce reactive intermediates that are electron deficient. These reactive groups can form covalent linkages with chemical groups on biologic molecules that have an excess of electrons (i.e. nucleophilic) including amino, phosphate, sulfhydryl, and hydroxyl groups. The process of covalent binding of alkyl groups to these groups is known as alkylation. As a class, the alkylating agents are cytotoxic, mutagenic, and carcinogenic. Cytotoxicity occurs due to alkylation of the bases of DNA and is non-cell cycle specific. Alkylating agents may contain 1 or 2 reactive groups and are referred to as monofunctional or bifunctional, respectively. Bifunctional alkylating agents produce interstrand and intrastrand DNA-DNA cross links and these cross links are responsible for the inhibition of DNA synthesis and for cytotoxicity. Cytotoxicity of monofunctional alkylating agents may be related to single strand breaks in DNA or to damaged bases. Similar to most chemotherapy agents, emergence of alkylating agent resistant tumor cells is a major problem that limits the clinical effectiveness. Possible mechanisms of resistance include decreased drug entry into cells and increased ability to repair damage to DNA. Resistance may also occur due to increases in intracellular glutathione levels. Increased sulfhydryls react with and inactivate alkylating agents. Lastly, resistance may be due to enzymatic detoxification mechanisms that conjugate intermediates or metabolize them to inactive derivatives. Generally, there is not cross-resistance between alkylating agents. A tumor that is resistant to one alkylating agent may remain significantly responsive to another. Examples of clinically useful alkylating agents in veterinary medicine include cyclophosphamide (Cytoxan), chlorambucil (Luekeran), lomustine (CCNU), and melphalan (Alkeran). For additional information regarding drug dosages or protocols, visit our web site at www.gcvs.com/oncology. ======================================================================= As always, we hope this info helps and don't hesitate to call or email us Gulf Coast Veterinary Oncology! Kevin A. Hahn, DVM, PhD, Diplomate ACVIM (Oncology), drhahn@gcvs.com Janet K. Carreras, VMD, Diplomate ACVIM (Oncology), drcarreras@gcvs.com Glen K. King, DVM, MS, Diplomate ACVR (Radiology & Radiation Therapy), drking@gcvs.com Gulf Coast Veterinary Diagnostic Imaging & Oncology 1111 West Loop South, Suite 150, Houston, TX 77027 P: 713.693.1166 F: 713.693.1167 W: www.gcvs.com