20–8 Virtually all cancer treatments are designed to kill cancer cells, usually by inducing apoptosis. However, one particular cancer—acute promyelocytic leukemia (APL)— has been successfully treated with all-trans-retinoic acid, which causes the promyelocytes to differentiate into neutrophils. How might a change in the state of differentiation of APL cancer cells help the patient?
20–9 One major goal of modern cancer therapy is to identify small molecules—anticancer drugs—that can be used to inhibit the products of specific cancer-critical genes. If you were searching for such molecules, would you design inhibitors for the products of oncogenes or the products of tumor suppressor genes? Explain why you would (or would not) select each type of gene.
(lost to cell)
Figure Q20–2 Two models to explain the multiple, localized chromosome rearrangements found in some cancers (Problem 20–7). The progressive rearrangements model shows a sequence of rearrangements that disrupts the chromosome, generating increasingly complex chromosomal configurations. The chromosome catastrophe model shows the chromosome being fragmented and then reassembled randomly, with some pieces left out.
20–10 PolyADP-ribose polymerase (PARP) plays a key role in the repair of DNA single-strand breaks. In the presence of the PARP inhibitor olaparib, single-strand breaks accumulate. When a replication fork encounters a sin-gle-strand break, it converts it to a double-strand break, which in normal cells is then repaired by homologous recombination. In cells defective for homologous recombination, however, inhibition of PARP triggers cell death.
Patients who have only one functional copy of the Brca1 gene, which is required for homologous recombination, are at much higher risk for cancer of the breast and ovary. Cancers that arise in these tissues in these patients can be treated successfully with olaparib. Explain how it is that treatment with olaparib kills the cancer cells in these patients, but does not harm their normal cells.
20–11 The Tasmanian devil, a carnivorous Australian marsupial, is threatened with extinction by the spread of a fatal disease in which a malignant oral–facial tumor interferes with the animal’s ability to feed. You have been called in to analyze the source of this unusual cancer. It seems clear to you that the cancer is somehow spread from devil to devil, very likely by their frequent fighting, which is accompanied by biting around the face and mouth. To uncover the source of the cancer, you isolate tumors from 11 devils captured in widely separated regions and examine them. As might be expected, the karyotypes of the tumor cells are highly rearranged relative to that of the wild-type devil (Figure Q20–3). Surprisingly, you find that the karyotypes from all 11 tumor samples are very similar. Moreover, one of the Tasmanian devils has an inversion on chromosome 5 that is not present in its facial tumor. How do you suppose this cancer is transmitted from devil to devil? Is it likely to arise as a consequence of an infection by a virus or microorganism? Explain your reasoning.
Figure Q20–3 Karyotypes of cells from Tasmanian devils (Problem 20–11). (A) A Tasmanian devil. (B) Normal karyotype for a male Tasmanian devil. The karyotype has 14 chromosomes, including XY.
(C) Karyotype of cancer cells found in each of the 11 facial tumors studied. The karyotype has 13 chromosomes, no sex chromosomes, no chromosome 2 pair, one chromosome 6, two chromosomes 1 with deleted long arms, and four highly rearranged marker chromosomes (M1–M4). (A, reproduced courtesy of Museum Victoria; B and C, from
A.M. Pearse and K. Swift, Nature 439:549, 2006. With permission from Macmillan Publishers Ltd.)