Problems in the development of target-based drugs.
Numerous molecular targets of cancer chemotherapy have been identified based on progress made in molecular biology, and new categories of anticancer drugs have been developed. These include inhibitors for signal transduction, cyclin-dependent kinase, angiogenesis, and matrix metalloproteinase, gene therapy, etc. They are variously called target-based drugs, noncytotoxic drugs, or cytostatic drugs. Such drugs have interesting mechanisms of action and appear promising. However, preclinical and clinical evaluations are difficult. Some drugs have a direct antitumor effect, with demonstrated tumor shrinkage. Others show no direct cytotoxicity. The majority of recent phase I trials have evaluated the maximum tolerated dose, pharmacokinetics, adverse events, and antitumor effect. Unusual, unacceptable toxicities have been noted with some target-based drugs. Few phase I trials or preclinical studies have attempted to demonstrate target inhibition. So far very few studies has shown that there is a correlation between target inhibition and antitumor effect. In general, phase II studies are undertaken with compounds such as trastuzumab which have direct antitumor activity. Phase III trials of most target-based drugs are undertaken immediately after phase I studies since the design of appropriate phase II studies is difficult. The ultimate endpoint of phase III trials of target-based drugs is the same as that for cytotoxic drugs, such as improved cure and survival rates.
Saijo
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N
Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan. nsaijo@gan2.ncc.go.jp
Tamura
T
T
Nishio
K
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D015195:Drug Design; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents