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Cancer Biology Research Laboratory, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305
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ABSTRACT |
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Introduction |
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Many genes have been identified that affect the extent to which certain cell types undergo apoptosis during normal development and after pathological stress. Together with the assumption that apoptosis plays a major role in cell killing by DNA-damaging agents, these genetic studies have led to the present hypothesis that tumors with mutations in p53, high levels of bcl-2, or high ratios of bcl-2:bax should be resistant to cancer treatment (1 , 2 , 5) . Because there is now a wealth of data from clinical studies in which outcome has been correlated with the status of these and other genes affecting apoptosis, this hypothesis would seem an easy one to test. However, a major problem with such analyses is that it is often impossible to separate treatment sensitivity from patient prognosis. For example, tumors with mutated p53 can be more anaplastic, can have a higher proportion of proliferating cells, can be more metastatic, and in general can have a more aggressive phenotype that similar tumors with wild-type p53 (6) . This can lead to a worse prognosis for patients whose tumors have mutated p53 independent of treatment sensitivity (7) . Having said this, there are numerous examples in the literature where p53 mutations (or high levels of p53 protein by immunohistochemistry) either do not affect patient prognosis (8 , 9) or lead to better outcome after treatment (10 , 11) . In a comprehensive review of the clinical significance of p53 mutations in human tumors, Bosari and Viale (12) concluded (in 1995) that a definite answer could not yet be given to the question or whether p53 aberrations led to a more aggressive phenotype or to treatment resistance.
Apoptosis and Sensitivity to Anticancer Therapy: The Present View.
As we point out above, because mutations in p53 or other genes may affect tumor aggressiveness and patient prognosis, it is difficult to obtain from clinical data an answer to the question of the role of p53 or of apoptosis in treatment sensitivity. However, experimental systems can be not only free of such biases, they can also use modern gene knockout, transgene, and other molecular techniques to answer the narrower question of: "Does the level of apoptosis and/or genes controlling apoptosis affect the sensitivity of cancer cells to killing by genotoxic agents?"
The present view is that this is the case (1 , 2 , 5 , 13 , 14) . It has become widely accepted that cell death after DNA damage by anticancer agents is primarily the result of apoptosis, and that cells that can evade apoptosis will be resistant to cell killing. Often cited for this view, and in particular the role of mutated p53 in radiation and anticancer drug resistance, are pioneering studies with dominant oncogene-transformed normal fibroblasts from embryos of p53 wild-type (p53+/+) and p53 knockout mice (p53-/-) (15 , 16) , as well as highly significant associations of mutated p53 with drug resistance in the National Cancer Institute panel of 60 cell lines used for screening novel potential anticancer drugs (17) .
However, despite the seemingly strong case that cells die from cancer treatment due to apoptosis largely controlled by wild-type p53, several investigators have reported results that contradict this hypothesis, particularly when they have measured both apoptosis and overall cell killing by a colony-forming assay. For example, it has been reported that large changes in apoptosis do not lead to any changes in eventual cell killing (18, 19, 20, 21, 22, 23) , or that the status of p53 does not affect sensitivity to DNA-damaging agents. However, the present confusion can be largely resolved if two facts are borne in mind.
(a) Many investigators have used methods for assessing the extent of cell killing by anticancer drugs and radiation based on early functional changes (such as dye uptake), or on growth inhibition, rather than on colony formation. These assays can lead to incorrect assessments of overall cell kill, largely because they ignore kinetic differences in the manifestation of cell death.
(b) Conclusions derived from normal cells transformed with dominant oncogenes such as E1A and myc have been extrapolated to tumor cells. However, apoptosis, particularly the early apoptosis characteristic of cells of lymphoid origin and oncogene-transformed normal cells, is often an insignificant mode of cell death for the cells of the majority of solid tumors, irrespective of the status of genes such as p53 and bcl-2.
Both of these issues are explored in more depth in the following sections.
Short-Term Assays Can Underestimate Overall Cell Killing.
How should cell killing be measured after a toxic insult? This would not seem to be a particularly difficult problem; a dead cell has many distinct morphological features, loses metabolic functions, and fails to exclude dyes such as propidium iodide and trypan blue. If death is due to apoptosis, then a number of well-characterized features occur including chromatin condensation and fragmentation, formation of nucleosomal "DNA ladders," and exposure of phosphatidyl serine in the outer cell membrane that can be detected with annexin V. Thus, dead cells can be readily identified, and their proportion in a population readily quantitated. However, identification of dead cells once they have died is not the problem. The problem is that cells do not die immediately after treatment; they can take hours to many days before dying, and this is highly dependent upon the cell type and the toxic agent being investigated (19
, 24, 25, 26)
. Despite this, many investigators assessing cellular sensitivity to genotoxic agents measure viability by total population staining [the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide or XTT3
assays] or assess the extent of cell death from the proportion of cells incorporating a dye excluded by live cells, such as trypan blue or propidium iodide, at short times (1–4 days) after treatment. As we point out below, this can lead to an underestimate of the overall level of cell killing.
The problem of correctly assessing the fraction of cells surviving a given treatment was solved for mammalian cells in the mid-1950s by Puck and Marcus (27) , who developed the technique of cloning individual cells in vitro. The ability of a single cell to grow into a colony (usually defined as >50 cells) is an assay that tests every cell in the population for its ability to undergo unlimited division. It is, for mammalian cells, the exact counterpart of assays measuring bacterial or yeast survival after treatment with cytotoxic agents. The assay has become widely used for assessing the response to cytotoxic agents of cells in vitro, as well as cells in normal tissues and tumors in vivo. When the logarithm of the percentage of surviving cells determined by the clonogenic assay is plotted against the dose of agent used, a straight line (sometimes with an initial "shoulder" region) is usually obtained, implying an exponential relationship between dose and cell kill. Both for radiation and anticancer drugs, this "log cell kill" hypothesis for cell survival has been demonstrated under many different conditions to be effective in predicting the radiation or chemotherapy dose needed to cure experimental mouse tumors or multicellular spheroids (28, 29, 30) .
Fig. 1
shows data illustrating the problem of using short-term assays to assess the influence of p53 on the sensitivity of cells to anticancer therapy. In this experiment, MEFs from wild-type (p53+/+) or p53 knockout mice (p53-/-) and transformed with E1A and ras (15)
were exposed to different concentrations of etoposide for 1 h and assayed either by the XTT assay or by clonogenic survival. The oncogene-transformed p53+/+ are very sensitive to apoptosis and start to die 3–6 h after treatment, whereas the p53-/- cells die much later (1–2 days after exposure). Thus, viability measured at 1 day after treatment, as in the XTT assay above, markedly underestimates eventual cell killing in the apoptotically insensitive cells.
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. Here we have grown the E1A- and ras-transformed MEFs from wild-type (p53+/+) and p53 knockout mice (p53-/-) as tumors in severe combined immunodeficient mice and measured their response to a single dose of irradiation. Because the p53+/+ cells undergo early apoptosis, leading to rapid and extensive tumor shrinkage, an assessment of tumor response by measuring tumor size within 2 weeks of irradiation would conclude that the p53+/+ tumors were more radiosensitive. This is because the rate and/or extent of tumor shrinkage is largely governed by the rate of cell death rather than by the overall level of cell kill. However, growth delay, usually to 2–3 times treatment volume, is a way of assessing tumor response that is not affected by the rate of cell death (31
, 32)
and, as can be seen in Fig. 2
, suggests that the initial apoptotic response observed in the p53 wild-type tumors has little or no effect on the final growth delay of these tumors.
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When used with care, the clonogenic assay is probably the most reliable method for assessing cell killing after genotoxic agents (35)
. With this in mind, we can now ask the question of whether apoptosis is a reliable determinant of cell killing to radiation and anticancer drugs when assayed by clonogenic survival. Although there are many examples in the literature, particularly for cells of hematological origin, where apoptosis and cell killing assayed by clonogenic survival are well correlated, there are also many examples, particularly for cells of nonhematological origin, where this is not the case. Fig. 3
, for example, shows some of our own results in which the response of HCT 116 cells that are either p21+/+ or p21-/- have been assessed both for apoptosis and for clonogenic survival under identical treatment conditions to radiation, to etoposide, and to the bioreductive drug tirapazamine. It is clear from these data, and from other examples in the literature (18, 19, 20
, 36)
, that the extent of apoptosis is not a reliable indicator of cellular sensitivity to anticancer agents. The message from Fig. 3
is that cells can die from apoptosis at different rates, and that the dominant mode of cell death may, or may not be, apoptosis.
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Of note from the data in Figs. 1
and 3
is that the sensitivity of cells to killing as assessed by their ability to form a colony is greater than that for the short-term assay that measures the proportion of cells undergoing apoptosis. In other words, for a given toxic insult, more cells are killed when assessed by clonogenic assay than undergo apoptosis. This has been noted previously by several investigators (19
, 37
, 38)
, but it is contrary to the widely held view that the traditional mode of cell killing by radiation and anticancer drugs requires a greater amount of DNA damage than is required for apoptotic death. However, it is important to be aware of the fact that it can be difficult in some circumstances, particularly for tissues and tumors in vivo, to assess apoptosis, because it is a dynamic process and not all of the cells destined to die by apoptosis may be visible at any one time (37
, 39)
.
These data lead to the conclusion that the response of tumor cells either in vitro or in vivo to genotoxic damage may, or may not, correlate with the extent of apoptosis after exposure. In the next section, we examine one particular aspect of genotype and sensitivity, i.e., the impact of wild-type or mutant p53 on cellular sensitivity to genotoxic damage.
Does p53 Status Affect the Sensitivity of Cells of Nonhematological Origin to Genotoxic Damage?
Although there are many studies of the influence of p53 status on the sensitivity of cells to genotoxic agents, in view of the above discussion concluding that short-term assays can be misleading, we have considered only those studies that have used clonogenic survival (which is not affected by the rate of cell death). We have also focused primarily on those investigations using ionizing radiation. This is because different anticancer drugs have different mechanisms of action that could involve p53 directly independent of apoptosis (e.g., involving nucleotide excision repair), and because investigators use a wide variety of exposure conditions for drugs but use much more defined radiation exposure conditions. There are also more studies with ionizing radiation than with all anticancer drugs combined.
In reviewing the literature on the question of the influence p53 on the radiation response of cells, we have therefore applied the following criteria:
(a) Only cells or tissues of nonhematological origin have been considered.
(b) Only investigations in which clonogenic survival was used to assess cell killing were considered.
We have also excluded from the analysis studies in which wild-type p53 was massively overexpressed in cells using viral vectors before irradiation. Typically, this results in radiation-induced apoptosis and radiation sensitization (40 , 41) .
The data in the literature conforming to these criteria fall into two main categories: (a) First are those papers in which a group of nongenetically matched cell lines have been assessed for statistical differences in radiation sensitivity between those that have wild-type p53 and those that have mutant p53. Of the 27 publications in the total pool, 10 fall into this category, of which 3 find p53 mutated cells more radioresistant (42, 43, 44)
, 3 find p53 mutations make no difference to radiation sensitivity (45, 46, 47)
, and 4 find p53 mutated cells more radiation sensitive (48, 49, 50, 51)
. Illustrative data from the two largest published series, each assessing radiation sensitivity and p53 status in cell lines or primary cultures from human cancers, are shown in Fig. 4
.
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Clearly, these data do not justify the conclusion that p53 mutated or null cells are in general more resistant to radiation-induced cell kill than are p53 wild-type cells.
For anticancer drugs, there have been surprisingly few studies using clonogenic survival to determine the influence of p53 on the sensitivity of cells of nonhematological origin. However, when this assay has been used, loss of wild-type p53 has been found to have no effect on the sensitivity of cells to the topoisomerase I inhibitor, camptothecin (61) , to doxorubicin (19 , 68) , or to taxol or vincristine (68) . Interestingly, mutations in p53 have been shown to confer sensitivity to drugs whose toxicity is modulated by nucleotide excision repair, such as nitrogen mustard and cisplatin (38 , 68) . The study with murine teratocarcinoma cells is of particular interest because the absence of p53 protected against cisplatin-induced apoptosis, yet sensitized to cell kill determined by colony formation (38) . This can be readily understood in terms of the drug doses used; to reach 90% cell kill by apoptosis in the most apoptotically sensitive cell line required some 50 times more cisplatin exposure than to produce an equal level of cell kill by clonogenic assay in the same cell line.
Given the above evidence that p53 status does not generally affect the sensitivity of cells to radiation and anticancer drugs, it is pertinent to ask how such a belief arose. Several factors have probably contributed.
(a) Lymphocytes, thymocytes, and lymphoma cells, are highly sensitive to anticancer therapy and invariably die a rapid apoptotic death that is dependent on wild-type p53 (3 , 69) .
(b) Short-term assays, rather than clonogenic survival, have often been used to assess cell killing. These can be markedly affected by the rate at which cells die, which, in turn, can be dependent on the mode of cell death (e.g., apoptosis or necrosis), and on the cellular genotype.
(c) As mentioned earlier, conclusions derived from normal cells transformed with dominant oncogenes have been extrapolated to tumor cells. We point out in the following section that these transformed normal cells are hypersensitive both to apoptosis and to killing as measured by clonogenic survival. The hypersensitive phenotype likely results from a synergy between oncogene activation of p53 and the DNA damage response and is not the case for tumor cells in general.
(d) The highly significant correlation of mutated p53 with resistance to active anticancer agents (that act principally by damaging DNA) in the National Cancer Institute screen of 60 different cell lines (17) is actually a correlation, not of cell kill, but of 2-day growth inhibition, with p53 status. Because wild-type p53 is required for growth arrest after DNA damage (70) , such a correlation of sensitivity to growth inhibition with wild-type p53 is expected. Because there is little or no correlation of growth inhibition with cytotoxicity across different cell lines (71) , these data do not provide evidence for the involvement of p53 in drug sensitivity to cell killing.
In summary, although wild-type p53 can influence the decision of whether cells undergo apoptosis after genotoxic insult, and, importantly, this leads to differences in the rate at which cells die, the available data do not support a role for p53 in determining the overall level of cell kill in tumor cells.
Having said this, there may be subtle influences of p53 abrogation on sensitivity to radiation or some anticancer drugs in some cells types. For example, Yount et al. (55) showed that although abrogating p53 function did not change the overall radiosensitivity of human glioblastoma cells, it did increase the resistance of synchronized cells when irradiated in early G1. It also appears that mutant p53, through its inability to transactivate p21, increases the sensitivity of chemotherapeutic agents, such as cisplatin and nitrogen mustard, that require nucleotide excision repair in their repair pathway (68) .
Are There Situations in Which Apoptosis Can Contribute to Sensitivity to Cytotoxic Agents?
Apoptosis is a major form of cell death that is dependent on wild-type p53 after DNA damage for certain normal cells, such as those of the early embryo and those of lymphoid origin (3
, 4) . There are also several examples in the literature where apoptosis clearly contributes to the overall sensitivity of cells to treatment with radiation or chemotherapeutic agents as assessed either by in vivo treatments (15
, 72)
or by clonogenic assays in vitro (69
, 72
, 73)
. However, a major difference between these studies and ones that have failed to find a link between apoptosis and overall sensitivity has been the choice of the cells used in the study. For cells of nonlymphoid origin, the cases in which apoptosis does contribute to overall sensitivity have in large part been those that used cells derived from normal tissues genetically engineered to express dominant oncogenes. Introduction of viral or cellular oncogenes such as E1A (74
, 75) , myc (72
, 76)
, or human papillomavirus E7 (77)
renders cells dramatically more sensitive to apoptosis in response to various genotoxic or nongenotoxic stresses and can also make these cells hypersensitive to overall killing by radiation (15
, 78) and various chemotherapeutic agents.5
Apoptosis in these cases is characteristic of lymphoid cells: death is usually rapid after treatment, is dependent on the status of p53 (16
, 79) , and can be inhibited by overexpression of bcl-2 (72
, 80, 81, 82)
. For example, in MEFs transformed with E1A and Ha-ras, cells with wild-type p53 undergo rapid apoptosis in response to genotoxic and nongenotoxic stress, whereas similarly transformed cells from p53 knockout mice do not (16
, 82)
. This dramatic difference in apoptosis also translates into an increased sensitivity of the transformed p53+/+ MEFs in terms of the overall sensitivity as determined either by clonogenic survival5 or by tumor response in vivo (15)
.
The recent discovery of ARF, a protein encoded by an alternative reading frame within the INK4a locus (83) and subsequent studies into ARFs function, provide a possible explanation for the hypersensitivity to overall killing observed in these cell lines. ARF up-regulates p53 in response to oncogene activation, including E1A (84) and myc (85) , resulting in activation of p53 target genes and cell cycle arrest or apoptosis (86) . However, ARF is not required for p53 induction after DNA damage (87) . In the previously described p53-wild-type MEFs expressing E1A, there are thus two separate pathways that activate p53 and p53-dependent apoptosis. The fact that both of these pathways are functional in these minimally transformed cells provides a synergy that can account for the dramatically increased propensity of these cells to undergo apoptosis after genotoxic or nongenotoxic stress (84) . In these hypersensitive cells, modulation of overall cell killing occurs when one of the pathways is disrupted, e.g., loss of p53. It is important to realize that the loss of p53 in the transformed MEFs results not so much in resistance to treatment as much as it does in an elimination of the unusually hypersensitive response (in this case, due to apoptosis) that is found after expression of E1A. The p53 null transformed MEFs revert back to an overall sensitivity that is closer to the untransformed parental p53 wild-type cells. In other words, in normal MEFs, p53 modulates the hypersensitive phenotype induced by oncogenic activation. Interestingly, this synergy also appears to be lost in E1A transformed cells that have lost ARF but retain wild-type p53 (84) .
An illustration of the role that apoptosis can play in minimally transformed cells was demonstrated recently using Rat1 cells engineered to conditionally express myc (72) . In this study, induced expression of myc increased the in vitro radiation sensitivity to both apoptosis and clonogenic survival, and this increased sensitivity was inhibited by expression of bcl-2. When grown as tumors in mice, expression of myc enhanced the sensitivity of these cells to fractionated doses of radiation, and this was abrogated by expression of bcl-2, indicating that apoptosis was directly influencing tumor response to radiation. This experiment thus provides direct evidence that expression of oncogenes in cells originally isolated from normal tissues can induce an apoptotically sensitive phenotype that is hypersensitive to treatment with anticancer therapies. Because myc has also been shown to activate ARF (85) , it is possible that the enhanced sensitivity observed in these cells and tumors is also due to a synergy between oncogene-dependent and DNA damage-dependent pathways to p53 induction and p53-dependent apoptosis.
It has been studies such as these using engineered minimally transformed cells that have, in large part, shaped the current opinion that apoptosis is also an important determinant of the response of human tumor cells to cancer therapy. As discussed earlier, it has led to the notion that a tumor cell with mutant p53 will be more resistant than the same cell with wild-type p53, or that increased expression of bcl-2 in cancer cells will be protective. Acceptance of this hypothesis assumes that cells derived from human tumors will behave similarly to the virally or oncogenically transformed normal cells described above. However, a clear distinction between tumor cells and genetically engineered cells from normal tissues is the requirement of the tumor cells, during their evolution, to overcome any apoptotically sensitive state that may have been induced by initial oncogenic transformation. The selection against this apoptotically sensitive state is driven by the selective forces produced by microenvironmental stresses such as hypoxia (82)
, reduced growth factor and nutrient supply (76)
, and the requirement for anchorage independent survival (88
, 89
; Fig. 5
).
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Summary |
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TopABSTRACTIntroductionSummaryREFERENCES |
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Our conclusions that apoptosis and the genes affecting apoptosis such as p53 and members of the Bcl-2 family may not contribute significantly to the sensitivity of cancer cells to anticancer agents does not mean that these genes do not affect the prognosis of human tumors. Tumors with mutated p53 for example can be more anaplastic, have a higher rate of proliferation, and have a more aggressive phenotype than similar tumors with wild-type p53, thereby giving rise to a worse prognosis. Our conclusions also do not apply to cancers of hematological origin for which apoptosis appears to be the dominant form of cell death after exposure to anticancer agents, nor do they apply to death receptor (e.g., Fas)-mediated apoptosis. Finally, the fact that apoptosis is a critical determinant of treatment sensitivity in minimally transformed normal cells warrants further research efforts to understand the loss of apoptotic sensitivity that invariably occurs during solid tumor evolution in hopes of providing more effective cancer therapy.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by United States National Cancer Institute Grant CA 15201 (to J. M. B.) and by a National Cancer Institute of Canada Research Fellowship (to B. G. W.). 
2 To whom requests for reprints should be addressed, Cancer Biology Research Laboratory, GK103, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305-5468.
3 The abbreviations used are: XTT, 2,3-bislsqb;2-methyl-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt; MEF, mouse embryo fibroblast.
4 B. G. Wouters and J. M. Brown, unpublished data.
Received 11/25/98. Accepted 2/ 2/99.
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D. L. Morse, H. Gray, C. M. Payne, and R. J. Gillies Docetaxel induces cell death through mitotic catastrophe in human breast cancer cells Mol. Cancer Ther., October 1, 2005; 4(10): 1495 - 1504. [Abstract] [Full Text] [PDF]
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M. F. Aguero, M. M. Facchinetti, Z. Sheleg, and A. M. Senderowicz Phenoxodiol, a Novel Isoflavone, Induces G1 Arrest by Specific Loss in Cyclin-Dependent Kinase 2 Activity by p53-Independent Induction of p21WAF1/CIP1 Cancer Res., April 15, 2005; 65(8): 3364 - 3373. [Abstract] [Full Text] [PDF]
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 J. M. Brown Drug Resistance: The Role of Genes Involved in Apoptosis Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 119 - 122. [Full Text] [PDF]
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 M. Brown How much is apoptosis involved in the response of solid tumors to therapy? AACR Meeting Abstracts, April 1, 2005; 2005(1): 1469 - 1470. [Abstract]
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R. Gerl and D. L. Vaux Apoptosis in the development and treatment of cancer Carcinogenesis, February 1, 2005; 26(2): 263 - 270. [Abstract] [Full Text] [PDF]
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J. Thiery, S. Abouzahr, G. Dorothee, A. Jalil, C. Richon, I. Vergnon, F. Mami-Chouaib, and S. Chouaib p53 Potentiation of Tumor Cell Susceptibility to CTL Involves Fas and Mitochondrial Pathways J. Immunol., January 15, 2005; 174(2): 871 - 878. [Abstract] [Full Text] [PDF]
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 X. Zhuo, N. Zheng, C. A. Felix, and I. A. Blair KINETICS AND REGULATION OF CYTOCHROME P450-MEDIATED ETOPOSIDE METABOLISM Drug Metab. Dispos., September 1, 2004; 32(9): 993 - 1000. [Abstract] [Full Text] [PDF]
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A. B. Werner, S. W. G. Tait, E. de Vries, E. Eldering, and J. Borst Requirement for Aspartate-cleaved Bid in Apoptosis Signaling by DNA-damaging Anti-cancer Regimens J. Biol. Chem., July 2, 2004; 279(27): 28771 - 28780. [Abstract] [Full Text] [PDF]
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 A. Egle, A. W. Harris, P. Bouillet, and S. Cory Bim is a suppressor of Myc-induced mouse B cell leukemia PNAS, April 20, 2004; 101(16): 6164 - 6169. [Abstract] [Full Text] [PDF]
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 R. Schneider-Stock, C. Mawrin, C. Motsch, C. Boltze, B. Peters, R. Hartig, P. Buhtz, A. Giers, A. Rohrbeck, B. Freigang, et al. Retention of the Arginine Allele in Codon 72 of the p53 Gene Correlates with Poor Apoptosis in Head and Neck Cancer Am. J. Pathol., April 1, 2004; 164(4): 1233 - 1241. [Abstract] [Full Text] [PDF]
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G. Kramer, H. Erdal, H. J. M. M. Mertens, M. Nap, J. Mauermann, G. Steiner, M. Marberger, K. Biven, M. C. Shoshan, and S. Linder Differentiation between Cell Death Modes Using Measurements of Different Soluble Forms of Extracellular Cytokeratin 18 Cancer Res., March 1, 2004; 64(5): 1751 - 1756. [Abstract] [Full Text] [PDF]
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X. Zheng, P. M. Chou, B. L. Mirkin, and A. Rebbaa Senescence-initiated Reversal of Drug Resistance: Specific Role of Cathepsin L Cancer Res., March 1, 2004; 64(5): 1773 - 1780. [Abstract] [Full Text] [PDF]
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 D. Starenki, H. Namba, V. Saenko, A. Ohtsuru, and S. Yamashita Inhibition of Nuclear Factor-{kappa}B Cascade Potentiates the Effect of a Combination Treatment of Anaplastic Thyroid Cancer Cells J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 410 - 418. [Abstract] [Full Text] [PDF]
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A. Vekris, D. Meynard, M.-C. Haaz, M. Bayssas, J. Bonnet, and J. Robert Molecular Determinants of the Cytotoxicity of Platinum Compounds: The Contribution of in Silico Research Cancer Res., January 1, 2004; 64(1): 356 - 362. [Abstract] [Full Text] [PDF]
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 M. Marabese, F. Vikhanskaya, C. Rainelli, T. Sakai, and M. Broggini DNA damage induces transcriptional activation of p73 by removing C-EBP{alpha} repression on E2F1 Nucleic Acids Res., November 15, 2003; 31(22): 6624 - 6632. [Abstract] [Full Text] [PDF]
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M. A. Sheard, S. Uldrijan, and B. Vojtesek Role of p53 in Regulating Constitutive and X-Radiation-Inducible CD95 Expression and Function in Carcinoma Cells Cancer Res., November 1, 2003; 63(21): 7176 - 7184. [Abstract] [Full Text] [PDF]
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Z. Chen, K. S. Koeneman, and D. R. Corey Consequences of Telomerase Inhibition and Combination Treatments for the Proliferation of Cancer Cells Cancer Res., September 15, 2003; 63(18): 5917 - 5925. [Abstract] [Full Text] [PDF]
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 K. Tsuruya, M. Tokumoto, T. Ninomiya, M. Hirakawa, K. Masutani, M. Taniguchi, K. Fukuda, H. Kanai, H. Hirakata, and M. Iida Antioxidant ameliorates cisplatin-induced renal tubular cell death through inhibition of death receptor-mediated pathways Am J Physiol Renal Physiol, August 1, 2003; 285(2): F208 - F218. [Abstract] [Full Text] [PDF]
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B. B.Y. Ma, R. G. Bristow, J. Kim, and L. L. Siu Combined-Modality Treatment of Solid Tumors Using Radiotherapy and Molecular Targeted Agents J. Clin. Oncol., July 15, 2003; 21(14): 2760 - 2776. [Abstract] [Full Text] [PDF]
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K. Ott, H. Vogelsang, J. Mueller, K. Becker, M. Muller, U. Fink, J. R. Siewert, H. Hofler, and G. Keller Chromosomal Instability Rather Than p53 Mutation Is Associated with Response to Neoadjuvant Cisplatin-based Chemotherapy in Gastric Carcinoma Clin. Cancer Res., June 1, 2003; 9(6): 2307 - 2315. [Abstract] [Full Text] [PDF]
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 O. S. Frankfurt and A. Krishan Microplate Screening for Apoptosis with Antibody to Single-Stranded DNA Distinguishes Anticancer Drugs from Toxic Chemicals J Biomol Screen, April 1, 2003; 8(2): 185 - 190. [Abstract] [PDF]
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A. Ito, Y.-i. Koma, K. Watabe, T. Nagano, Y. Endo, H. Nojima, and Y. Kitamura A Truncated Isoform of the Protein Phosphatase 2A B56{gamma} Regulatory Subunit May Promote Genetic Instability and Cause Tumor Progression Am. J. Pathol., January 1, 2003; 162(1): 81 - 91. [Abstract] [Full Text] [PDF]
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R. Koivusalo, E. Krausz, P. Ruotsalainen, H. Helenius, and S. Hietanen Chemoradiation of Cervical Cancer Cells: Targeting Human Papillomavirus E6 and p53 Leads to Either Augmented or Attenuated Apoptosis Depending on the Platinum Carrier Ligand Cancer Res., December 15, 2002; 62(24): 7364 - 7371. [Abstract] [Full Text] [PDF]
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Y. R. Seo, M. R. Kelley, and M. L. Smith From the Cover: Selenomethionine regulation of p53 by a ref1-dependent redox mechanism PNAS, October 29, 2002; 99(22): 14548 - 14553. [Abstract] [Full Text] [PDF]
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J. L. Bronder and R. G. Moran Antifolates Targeting Purine Synthesis Allow Entry of Tumor Cells into S Phase Regardless of p53 Function Cancer Res., September 15, 2002; 62(18): 5236 - 5241. [Abstract] [Full Text] [PDF]
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K. Leroy, C. Haioun, E. Lepage, N. Le Metayer, F. Berger, E. Labouyrie, V. Meignin, B. Petit, C. Bastard, G. Salles, et al. p53 gene mutations are associated with poor survival in low and low-intermediate risk diffuse large B-cell lymphomas Ann. Onc., July 1, 2002; 13(7): 1108 - 1115. [Abstract] [Full Text] [PDF]
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C. G. Ferreira, M. Epping, F. A. E. Kruyt, and G. Giaccone Apoptosis: Target of Cancer Therapy Clin. Cancer Res., July 1, 2002; 8(7): 2024 - 2034. [Abstract] [Full Text] [PDF]
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 M. Kitagawa, S. Yamaguchi, M. Hasegawa, K. Tanaka, T. Sado, K. Hirokawa, and S. Aizawa Friend Leukemia Virus Infection Enhances DNA Damage-Induced Apoptosis of Hematopoietic Cells, Causing Lethal Anemia in C3H Hosts J. Virol., June 27, 2002; 76(15): 7790 - 7798. [Abstract] [Full Text] [PDF]
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M. Kondo, T. Shibata, T. Kumagai, T. Osawa, N. Shibata, M. Kobayashi, S. Sasaki, M. Iwata, N. Noguchi, and K. Uchida 15-Deoxy-Delta 12,14-prostaglandin J2: The endogenous electrophile that induces neuronal apoptosis PNAS, May 28, 2002; 99(11): 7367 - 7372. [Abstract] [Full Text] [PDF]
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Z. Han, W. Wei, S. Dunaway, J. W. Darnowski, P. Calabresi, J. Sedivy, E. A. Hendrickson, K. V. Balan, P. Pantazis, and J. H. Wyche Role of p21 in Apoptosis and Senescence of Human Colon Cancer Cells Treated with Camptothecin J. Biol. Chem., May 3, 2002; 277(19): 17154 - 17160. [Abstract] [Full Text] [PDF]
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A. Bravard, A. Ageron-Blanc, S. Alvarez, P. Drane, Y. le Rhun, F. Paris, C. Luccioni, and E. May Correlation between antioxidant status, tumorigenicity and radiosensitivity in sister rat cell lines Carcinogenesis, May 1, 2002; 23(5): 705 - 711. [Abstract] [Full Text] [PDF]
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 P.-F. Cartron, L. Oliver, S. Martin, C. Moreau, M.-T. LeCabellec, P. Jezequel, K. Meflah, and F. M. Vallette The expression of a new variant of the pro-apoptotic molecule Bax, Bax{psi}, is correlated with an increased survival of glioblastoma multiforme patients Hum. Mol. Genet., March 1, 2002; 11(6): 675 - 687. [Abstract] [Full Text] [PDF]
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M. L. Smith and Y. R. Seo p53 regulation of DNA excision repair pathways Mutagenesis, March 1, 2002; 17(2): 149 - 156. [Abstract] [Full Text] [PDF]
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 I. F. Pollack, S. D. Finkelstein, J. Woods, J. Burnham, E. J. Holmes, R. L. Hamilton, A. J. Yates, J. M. Boyett, J. L. Finlay, R. Sposto, et al. Expression of p53 and Prognosis in Children with Malignant Gliomas N. Engl. J. Med., February 7, 2002; 346(6): 420 - 427. [Abstract] [Full Text] [PDF]
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X. Chen, B. Shen, L. Xia, A. Khaletzkiy, D. Chu, J. Y. C. Wong, and J.-J. Li Activation of Nuclear Factor {kappa}B in Radioresistance of TP53-inactive Human Keratinocytes Cancer Res., February 1, 2002; 62(4): 1213 - 1221. [Abstract] [Full Text] [PDF]
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 T. Plath, M. Peters, K. Detjen, M. Welzel, Z. von Marschall, C. Radke, B. Wiedenmann, and S. Rosewicz Overexpression of pRB in Human Pancreatic Carcinoma Cells: Function in Chemotherapy-Induced Apoptosis J Natl Cancer Inst, January 16, 2002; 94(2): 129 - 142. [Abstract] [Full Text] [PDF]
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D. A. Green, W. E. Antholine, S. J. Wong, D. R. Richardson, and C. R. Chitambar Inhibition of Malignant Cell Growth by 311, a Novel Iron Chelator of the Pyridoxal Isonicotinoyl Hydrazone Class: Effect on the R2 subunit of Ribonucleotide Reductase Clin. Cancer Res., November 1, 2001; 7(11): 3574 - 3579. [Abstract] [Full Text] [PDF]
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 G. Laurent and J.-P. Jaffrezou Signaling pathways activated by daunorubicin Blood, August 15, 2001; 98(4): 913 - 924. [Abstract] [Full Text] [PDF]
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M. Fan, M. E. Goodwin, M. J. Birrer, and T. C. Chambers The c-Jun NH2-terminal Protein Kinase/AP-1 Pathway Is Required for Efficient Apoptosis Induced by Vinblastine Cancer Res., June 1, 2001; 61(11): 4450 - 4458. [Abstract] [Full Text] [PDF]
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K. Spring, S. Cross, C. Li, D. Watters, L. Ben-Senior, P. Waring, F. Ahangari, S.-l. Lu, P. Chen, I. Misko, et al. Atm Knock-in Mice Harboring an In-frame Deletion Corresponding to the Human ATM 7636del9 Common Mutation Exhibit a Variant Phenotype Cancer Res., June 1, 2001; 61(11): 4561 - 4568. [Abstract] [Full Text] [PDF]
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G. W. Xu, C. L. Nutt, M. C. Zlatescu, M. Keeney, I. Chin-Yee, and J. G. Cairncross Inactivation of p53 Sensitizes U87MG Glioma Cells to 1,3-bis(2-Chloroethyl)-1-nitrosourea Cancer Res., May 1, 2001; 61(10): 4155 - 4159. [Abstract] [Full Text]
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C. Thibault, C. Lai, N. Wilke, B. Duong, M. F. Olive, S. Rahman, H. Dong, C. W. Hodge, D. J. Lockhart, and M. F. Miles Expression Profiling of Neural Cells Reveals Specific Patterns of Ethanol-Responsive Gene Expression Mol. Pharmacol., April 13, 2001; 58(6): 1593 - 1600. [Abstract] [Full Text]
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T. Hishita, S. Tada-Oikawa, K. Tohyama, Y. Miura, T. Nishihara, Y. Tohyama, Y. Yoshida, T. Uchiyama, and S. Kawanishi Caspase-3 Activation by Lysosomal Enzymes in Cytochrome c-independent Apoptosis in Myelodysplastic Syndrome-derived Cell Line P39 Cancer Res., April 1, 2001; 61(7): 2878 - 2884. [Abstract] [Full Text]
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P. Dent and S. Grant Pharmacologic Interruption of the Mitogen-activated Extracellular-regulated Kinase/Mitogen-activated Protein Kinase Signal Transduction Pathway: Potential Role in PromotingCytotoxic Drug Action Clin. Cancer Res., April 1, 2001; 7(4): 775 - 783. [Full Text]
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T. H. Doyle, F. Mornex, and W. G. McKenna The Clinical Implications of Gemcitabine Radiosensitization Clin. Cancer Res., February 1, 2001; 7(2): 226 - 228. [Full Text]
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T. S. Lawrence, M. A. Davis, A. Hough, and A. Rehemtulla The Role of Apoptosis in 2',2'-Difluoro-2'-deoxycytidine (Gemcitabine)-mediated Radiosensitization Clin. Cancer Res., February 1, 2001; 7(2): 314 - 319. [Abstract] [Full Text]
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S. Harvey, R. Decker, Y. Dai, G. Schaefer, L. Tang, L. Kramer, P. Dent, and S. Grant Interactions between 2-Fluoroadenine 9-{beta}-D-Arabinofuranoside and the Kinase Inhibitor UCN-01 in Human Leukemia and Lymphoma Cells Clin. Cancer Res., February 1, 2001; 7(2): 320 - 330. [Abstract] [Full Text]
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F. Ponten, H. Lindman, A. Bostrom, B. Berne, and J. Bergh Induction of p53 Expression in Skin by Radiotherapy and UV Radiation: a Randomized Study J Natl Cancer Inst, January 17, 2001; 93(2): 128 - 133. [Abstract] [Full Text] [PDF]
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C. J. Kemp, S. Sun, and K. E. Gurley p53 Induction and Apoptosis in Response to Radio- and Chemotherapy in Vivo Is Tumor-Type-dependent Cancer Res., January 1, 2001; 61(1): 327 - 332. [Abstract] [Full Text]
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S. Paglin, T. Hollister, T. Delohery, N. Hackett, M. McMahill, E. Sphicas, D. Domingo, and J. Yahalom A Novel Response of Cancer Cells to Radiation Involves Autophagy and Formation of Acidic Vesicles Cancer Res., January 1, 2001; 61(2): 439 - 444. [Abstract] [Full Text]
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K. Zaugg, S. Rocha, H. Resch, I. Hegyi, C. Oehler, C. Glanzmann, D. Fabbro, S. Bodis, and M. Pruschy Differential p53-dependent Mechanism of Radiosensitization in Vitro and in Vivo by the Protein Kinase C-specific Inhibitor PKC412 Cancer Res., January 1, 2001; 61(2): 732 - 738. [Abstract] [Full Text]
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E. J. Bernhard, E. J. Stanbridge, S. Gupta, A. K. Gupta, D. Soto, V. J. Bakanauskas, G. J. Cerniglia, R. J. Muschel, and W. G. McKenna Direct Evidence for the Contribution of Activated N-ras and K-ras Oncogenes to Increased Intrinsic Radiation Resistance in Human Tumor Cell Lines Cancer Res., December 1, 2000; 60(23): 6597 - 6600. [Abstract] [Full Text]
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C. G. Ferreira, S. W. Span, G. J. Peters, F. A. E. Kruyt, and G. Giaccone Chemotherapy Triggers Apoptosis in a Caspase-8-dependent and Mitochondria-controlled Manner in the Non-Small Cell Lung Cancer Cell Line NCI-H460 Cancer Res., December 1, 2000; 60(24): 7133 - 7141. [Abstract] [Full Text]
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W. F. Symmans, M. D. Volm, R. L. Shapiro, A. B. Perkins, A. Y. Kim, S. Demaria, H. T. Yee, H. McMullen, R. Oratz, P. Klein, et al. Paclitaxel-induced Apoptosis and Mitotic Arrest Assessed by Serial Fine-Needle Aspiration: Implications for Early Prediction of Breast Cancer Response to Neoadjuvant Treatment Clin. Cancer Res., December 1, 2000; 6(12): 4610 - 4617. [Abstract] [Full Text]
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T. Grundei, H. Vogelsang, K. Ott, J. Mueller, M. Scholz, K. Becker, U. Fink, J. R. Siewert, H. Höfler, and G. Keller Loss of Heterozygosity and Microsatellite Instability as Predictive Markers for Neoadjuvant Treatment in Gastric Carcinoma Clin. Cancer Res., December 1, 2000; 6(12): 4782 - 4788. [Abstract] [Full Text]
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L. J. Ostruszka and D. S. Shewach The Role of Cell Cycle Progression in Radiosensitization by 2',2'-Difluoro-2'-deoxycytidine Cancer Res., November 1, 2000; 60(21): 6080 - 6088. [Abstract] [Full Text]
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 K. L. MURPHY, A. P. DENNIS, and J. M. ROSEN A gain of function p53 mutant promotes both genomic instability and cell survival in a novel p53-null mammary epithelial cell model FASEB J, November 1, 2000; 14(14): 2291 - 2302. [Abstract] [Full Text]
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I. Petak, D. M. Tillman, and J. A. Houghton p53 Dependence of Fas Induction and Acute Apoptosis in Response to 5-Fluorouracil-Leucovorin in Human Colon Carcinoma Cell Lines Clin. Cancer Res., November 1, 2000; 6(11): 4432 - 4441. [Abstract] [Full Text] [PDF]
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F. M. Yakes, B. D. Wamil, F. Sun, H.-P. Yan, C. E. Carter, and C. G. Hellerqvist CM101 Treatment Overrides Tumor-induced Immunoprivilege Leading to Apoptosis Cancer Res., October 1, 2000; 60(20): 5740 - 5746. [Abstract] [Full Text]
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R. J. Sleiman and B. W. Stewart Early Caspase Activation in Leukemic Cells Subject to Etoposide-induced G2-M Arrest: Evidence of Commitment to Apoptosis Rather Than Mitotic Cell Death Clin. Cancer Res., September 1, 2000; 6(9): 3756 - 3765. [Abstract] [Full Text]
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S. Hietanen, S. Lain, E. Krausz, C. Blattner, and D. P. Lane Activation of p53 in cervical carcinoma cells by small molecules PNAS, July 18, 2000; 97(15): 8501 - 8506. [Abstract] [Full Text] [PDF]
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M. S. Orr, P. M. O'Connor, and K. W. Kohn Effects of c-erbB2 Overexpression on the Drug Sensitivities of Normal Human Mammary Epithelial Cells J Natl Cancer Inst, June 21, 2000; 92(12): 987 - 994. [Abstract] [Full Text] [PDF]
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M. L. Smith, J. M. Ford, M. C. Hollander, R. A. Bortnick, S. A. Amundson, Y. R. Seo, C.-X. Deng, P. C. Hanawalt, and A. J. Fornace Jr. p53-Mediated DNA Repair Responses to UV Radiation: Studies of Mouse Cells Lacking p53, p21, and/or gadd45 Genes Mol. Cell. Biol., May 15, 2000; 20(10): 3705 - 3714. [Abstract] [Full Text]
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Y. Nieto, P. J. Cagnoni, S. Nawaz, E. J. Shpall, R. Yerushalmi, B. Cook, P. Russell, J. McDermit, J. Murphy, S. I. Bearman, et al. Evaluation of the Predictive Value of Her-2/neu Overexpression and p53 Mutations in High-Risk Primary Breast Cancer Patients Treated With High-Dose Chemotherapy and Autologous Stem-Cell Transplantation J. Clin. Oncol., May 10, 2000; 18(10): 2070 - 2080. [Abstract] [Full Text] [PDF]
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K. Hofland, B. O. Petersen, J. Falck, K. Helin, P. B. Jensen, and M. Sehested Differential Cytotoxic Pathways of Topoisomerase I and II Anticancer Agents after Overexpression of the E2F-1/DP-1 Transcription Factor Complex Clin. Cancer Res., April 1, 2000; 6(4): 1488 - 1497. [Abstract] [Full Text]
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O. Potapova, M. Gorospe, R. H. Dougherty, N. M. Dean, W. A. Gaarde, and N. J. Holbrook Inhibition of c-Jun N-Terminal Kinase 2 Expression Suppresses Growth and Induces Apoptosis of Human Tumor Cells in a p53-Dependent Manner Mol. Cell. Biol., March 1, 2000; 20(5): 1713 - 1722. [Abstract] [Full Text]
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S. W. Lowe and A. W. Lin Apoptosis in cancer Carcinogenesis, March 1, 2000; 21(3): 485 - 495. [Abstract] [Full Text] [PDF]
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T. Otsuki, O. Yamada, J. Kurebayashi, T. Moriya, H. Sakaguchi, H. Kunisue, K. Yata, M. Uno, Y. Yawata, and A. Ueki Estrogen Receptors in Human Myeloma Cells Cancer Res., March 1, 2000; 60(5): 1434 - 1441. [Abstract] [Full Text]
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T. A. H. Jarvinen, M. Tanner, V. Rantanen, M. Barlund, A. Borg, S. Grenman, and J. Isola Amplification and Deletion of Topoisomerase II{alpha} Associate with ErbB-2 Amplification and Affect Sensitivity to Topoisomerase II Inhibitor Doxorubicin in Breast Cancer Am. J. Pathol., March 1, 2000; 156(3): 839 - 847. [Abstract] [Full Text] [PDF]
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M. Wade and M. J. Allday Epstein-Barr Virus Suppresses a G2/M Checkpoint Activated by Genotoxins Mol. Cell. Biol., February 15, 2000; 20(4): 1344 - 1360. [Abstract] [Full Text]
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Z. Zhang, Q. Liu, L. E. Lantry, Y. Wang, G. J. Kelloff, M. W. Anderson, R. W. Wiseman, R. A. Lubet, and M. You A Germ-Line p53 Mutation Accelerates Pulmonary Tumorigenesis: p53-independent Efficacy of Chemopreventive Agents Green Tea or Dexamethasone/myo-Inositol and Chemotherapeutic Agents Taxol or Adriamycin Cancer Res., February 1, 2000; 60(4): 901 - 907. [Abstract] [Full Text]
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 K. Newton and A. Strasser Ionizing Radiation and Chemotherapeutic Drugs Induce Apoptosis in Lymphocytes in the Absence of Fas or FADD/MORT1 Signaling: Implications for Cancer Therapy J. Exp. Med., January 3, 2000; 191(1): 195 - 200. [Abstract] [Full Text] [PDF]
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