Chris H. Takimoto, MD, PhD

The effective use of cancer chemotherapy requires a thorough understanding of the principles of neoplastic cell growth kinetics, basic pharmacologic mechanisms of drug action, pharmacokinetic and pharmacodynamic variability, and mechanisms of drug resistance. Recent scientific advances in the field of molecular oncology have led to the identification of large numbers of potential targets for novel anticancer therapies. This has resulted in a tremendous expansion of the drug development pipeline, and in the present era, the diversity of clinically useful novel anticancer therapeutic agents is growing at an unprecedented rate. However, the great enthusiasm that surrounds these new agents must be tempered by the challenges they present in optimizing their clinical use and in rationally integrating them with existing anticancer therapies. This discussion focuses on the basic principles underlying the development of modern combination chemotherapy, and it is followed by a description of the major classes of chemotherapeutic drugs and their mechanisms of action.

The effective use of cancer chemotherapy requires a thorough understanding of the principles of neoplastic cell growth kinetics, basic pharmacologic mechanisms of drug action, pharmacokinetic and pharmacodynamic variability, and mechanisms of drug resistance.

The effective use of cancer chemotherapy requires a thorough understandingof the principles of neoplastic cell growth kinetics, basic pharmacologic mechanismsof drug action, pharmacokinetic and pharmacodynamic variability, andmechanisms of drug resistance. Recent scientific advances in the field of molecularoncology have led to the identification of large numbers of potentialtargets for novel anticancer therapies. This has resulted in a tremendous expansionof the drug development pipeline, and in the present era, the diversityof clinically useful novel anticancer therapeutic agents is growing at an unprecedentedrate. However, the great enthusiasm that surrounds these new agentsmust be tempered by the challenges they present in optimizing their clinicaluse and in rationally integrating them with existing anticancer therapies. Thisdiscussion focuses on the basic principles underlying the development of moderncombination chemotherapy, and it is followed by a description of the majorclasses of chemotherapeutic drugs and their mechanisms of action.

Topotecan (Hycamtin) is a promising new topoisomerase I-targeting anticancer agent that first entered clinical trials in 1989 under National Cancer Institute sponsorship in collaboration with SmithKline Beecham. In 1996, it

Numerous new antifolate drugs have been developed in an attempt to overcome the potential mechanisms of tumor cell resistance to methotrexate, which can include decreased drug transport into cells; decreased