mature established blood vessels and so might even constitute a unique target for cancer therapy (Boehm and others 1997).
Damage caused by high-and low-LET radiation exposure appears to create a genetically unstable state in which further chromosomal and genetic changes can be observed many generations after the exposure. That was first observed for alpha particles by Kadhim and others (1994; 1992) who detected chromatid and chromosomal type aberrations in clonal descendants and nonclonal cultures of both mouse and human hematopoietic stem cells. The instability is not confined to high-LET radiation, and it can even be induced by ionization produced outside the nucleus. Abnormal karyotypes were observed several passages after irradiation; this indicated that heritable changes were transmitted to progeny cells and resulted in new chromosomal rearrangements during later cell cycles. There is evidence that those changes can involve a wide variety of genetic events, including rearrangements, gene amplification, and mutation. DNA sequence rearrangements can lead to mutations, the production of new fusion genes, or changes in gene regulation by position effects that are known to be involved in chromosomal activation of oncogenes in several human and rodent malignancies (Rabbitts 1994). The mechanism of instability might involve rearrangements that result in inappropriate gene expression that then triggers later genetic events. Alternatively, it could involve persistent changes in gene expression through p53 and other gene products that act as altered transcriptional regulators.
The high frequency of chromosomal abnormalities and mutations in human cancers indicates that a "mutator" phenotype is often involved in multistep carcinogenesis (Loeb 1994; 1991). The spontaneous-mutation rate in normal diploid cells is insufficient to account for the high frequency of mutations in cancer cells. Rather, the genomes of cancer cells are unstable, and this results in a cascade of mutations that cumulatively enable cancer cells to bypass the host regulatory processes (Loeb 1994). The development of genetic instability, especially the capacity for gene amplification, is acquired in stages through preneoplastic to fully neoplastic cells, and this capacity appears to depend on the progressive loss of p53 function (Tlsty 1996; Tlsty and others 1995).
DNA damage of various kinds is particularly effective in inducing genomic instability, whether produced by α-particles or x rays or endogenously. For example, an anoxia-inducible endonuclease activity has been reported that cleaves DNA without specificity for sequence (Stoler and others 1992). That activity could account for the induction of gene amplification in anoxic cells and could be associated with break-related genomic instability. Repeat sequences, such as interstitial telomere-like repeats might also be hot spots for recombination, break-