In vivo/Ex vivo and in situ assays used in cancer research: A brief review

Abstract

Predicting whether a potential new anticancer agent will have a positive therapeutic index in patients remains a challenge. This brief review provides examples of preclinical in vivo/ex vivo and in situ assays used to assess the therapeutic potential of experimental anticancer therapeutics. Excision assays involving removal of tumor, bone marrow, and other tissues from the host after treatment to determine the effects of therapy in ex vivo assays are important preclinical tools. The survival of malignant cells from tumors treated in vivo and then excised is often determined by colony formation (CFU) in culture. When mice bearing in vivo alkylating agent-resistant tumors were treated with anticancer drugs such as cyclophosphamide, the survival pattern of bone marrow granulocyte-macrophage-colony forming units (CFU-GM) paralleled tumor cell survival. When TNP-470 and minocycline, an antiangiogenic combination, were added to treatment with cytotoxic anticancer therapies, tumor response markedly increased. TNP-470/minocycline-treated mice had higher tissue drug levels than did mice treated with the drug alone. Enzastaurin, an antiangiogenic protein kinase β inhibitor, treatment decreased intratumoral vessels to one half to one quarter of controls. Simultaneous and sequential treatment regimens with enzastaurin and BCNU delayed tumor growth and increased lifespan in mice bearing subcutaneous or intracranial human T98G glioblastoma multiforme. Both TNP-470 and enzastaurin have undergone clinical trials. Enzastaurin is currently in Phase III clinical trials.