There is compelling evidence that human lung cancers are characterized by disruption of several important physiological pathways that govern proliferation, apoptosis, intracellular signaling, and cell-cell interactions. Uncontrolled cellular proliferation is one of the hallmarks of malignant tumors, and it is usually owing to abrogation of one or more checkpoints that regulate the cell cycle. The best-characterized checkpoint controls progression from G1 to S phase. The most important component of this late G1 restriction point is the protein product of the retinoblastoma gene, pRB (1). In its hypophosphorylated form, pRB binds E2F-family transcription factors. Functional inactivation of pRB leads to release of these transcription factors which then activate a program that moves the cell into S phase (1) . The most effective way to abrogate the late G1 checkpoint is a hemizygous mutation in theRBgene, with concomitant loss of the second allele-the prototypic mechanism of tumor suppressor gene inactivation. This occurs in almost all small cell lung cancers (SCLC), as well as in 15-25% of non-small cell lung cancers (NSCLC) (2 -5) .
