Chapter 080. Cancer Cell Biology and Angiogenesis (Part 2)

Cancer Cell Biology The treatment of most human cancers with conventional cytoreductive agents has been unsuccessful due to the Gompertzian-like growth kinetics of solid tumors (i.e., tumor growth is exponential in small tumors, with increasing doubling times as tumors expand; since conventional chemotherapeutic agents target proliferating cells, noncycling cells in large tumors are relatively resistant). Genetic instability is inherent in most cancer cells and predisposes to the development of intrinsic and acquired drug resistance. Thus, although tumors arise from a single cell (i.e., they are clonal), large tumors become very heterogeneous with multiple related subclones, some of which will...
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Chapter 080. Cancer Cell Biology and Angiogenesis (Part 2) Chapter 080. Cancer Cell Biology and Angiogenesis (Part 2) Cancer Cell Biology The treatment of most human cancers with conventional cytoreductiveagents has been unsuccessful due to the Gompertzian-like growth kinetics of solidtumors (i.e., tumor growth is exponential in small tumors, with increasingdoubling times as tumors expand; since conventional chemotherapeutic agentstarget proliferating cells, noncycling cells in large tumors are relatively resistant).Genetic instability is inherent in most cancer cells and predisposes to thedevelopment of intrinsic and acquired drug resistance. Thus, although tumors arisefrom a single cell (i.e., they are clonal), large tumors become very heterogeneouswith multiple related subclones, some of which will be resistant to specifictherapies, leading to the selection of progressively more resistant tumors astreatment progresses. Since a 1-cm tumor often contains 109 cells, and patientstypically present to their physicians with 1010–1011 tumor cells, the obstacle tocurative treatment becomes more understandable. Rationally designed, target-based therapeutic agents, directed against the specific molecular derangements thatdistinguish malignant from nonmalignant cells, have become possible withadvances in the understanding of oncogene and tumor-suppressor pathways. Thischapter describes the convergence of scientific, pharmacologic, and medicalknowledge that has led to the targeted therapy of cancer. Therapeutic Approaches to Cell Cycle Abnormalities in Cancer The mechanism of cell division is substantially the same in all dividingcells and has been conserved throughout evolution. The process assures that thecell accurately duplicates its contents, especially its chromosomes. The cell cycleis divided into four phases. During M-phase, the replicated chromosomes areseparated and packaged into two new nuclei by mitosis and the cytoplasm isdivided between the two daughter cells by cytokinesis. The other three phases ofthe cell cycle are called interphase: G1 (gap 1), during which the cell determinesits readiness to commit to DNA synthesis; S (DNA synthesis), during which thegenetic material is replicated and no re-replication is permitted; and G2 (gap 2),during which the fidelity of DNA replication is assessed and errors are corrected. Deregulation of the molecular mechanisms controlling cell cycleprogression is a hallmark of cancer. Progression from one phase of the cell cycleto the next is controlled by the orderly activation of cyclin-dependent kinases(CDKs) that are regulated by signaling events that couple a cells physiologicresponse to its extracellular milieu. In normal cells, specific molecular signals,called checkpoints, prevent progression into the next phase of the cell cycle untilall requisite physiologic processes are complete. Cancer cells often have defectivecell cycle checkpoints. The transition through G1 into S-phase is a criticalregulator of cell proliferation, and the phosphorylation state of the retinoblastomatumor-suppressor protein (pRB) at the restriction point in late G1 determineswhether a cell will enter S-phase. The complex of CDK4 or CDK6 with D typecyclins forms a G1-specific kinase whose activity is regulated by growth factors,nutrients, and cell-cell and cell-matrix interactions. Subsequent formation of anactive CDK2/cyclin E complex results in full phosphorylation of pRB, relieving itsinhibitory effects on the S-phase-regulating transcription factor E2F/DP1, andpermitting the activation of genes required for S-phase (such as dihydrofolatereductase, thymidine kinase, ribonucleotide reductase, and DNA polymerase). Theactivity of CDK/cyclin complexes can be blocked by CDK-inhibitors includingp21Cip1/Waf1, p16Ink4a, and p27Kip1, which block S-phase progression by preventingthe phosphorylation of pRB. Genetic lesions that render the retinoblastoma pathway nonfunctional arethought to occur in all human cancers. Loss of function of pRB as guardian of theG1 restriction point enables cancer cells to enter a mitotic cycle without the normalinput from external signals. Current therapeutic efforts to reverse thederangements of the retinoblastoma pathway have taken two main approaches. Allkinases require the binding of ATP (and substrate) to the enzyme active site,followed by transfer of the γ-phosphate to serine, threonine, or tyrosine residues ofthe substrate. Flavopiridol was the first relatively selective CDK inhibitoridentified, with Ki or IC50s in the 40- to 400-nM range. Although flavopiridol wasinitially thought to prevent tumor cell proliferation by inhibition of cell cycleCDKs, it is now clear that regulation of cellular tra ...