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PubMed2005

The regionalization of radical cystectomy to specific medical centers.

PURPOSE: Regionalization of high risk surgical procedures to larger teaching hospitals has been suggested as a means to improve the quality of care. We established a novel framework for characterizing regionalization, implemented it to determine the extent to which regionalization of radical cystectomy has occurred and delineated whether specific patient characteristics are associated with this phenomenon. MATERIALS AND METHODS: We used the Nationwide Inpatient Sample to identify 22,088 patients who underwent radical cystectomy for bladder cancer from 1988 to 2000. Regionalization was assessed using 5 structural hospital measures, including teaching status, urban location, discharge volume, cystectomy volume and bed capacity. Adjusted models were developed to identify the significance of temporal trends and assess the association of demographic factors with structural qualities. RESULTS: Compared with 1988 to 1990 subjects were more likely to undergo cystectomy at teaching hospitals (OR 1.8), high cystectomy volume hospitals (OR 1.2), high discharge volume hospitals (OR 1.7) and large bed capacity medical centers (OR 1.4) in 1998 to 2000. The concentration of cystectomy to urban medical centers during the study years was 90% to 92%. The proportion of subjects undergoing partial cystectomy decreased from 23.9% to 16.6% as regionalization occurred. Older subjects were less likely to be treated at these regionalized centers. CONCLUSIONS: Without broad legislation from health care payers radical cystectomy has increasingly regionalized to specific medical centers. Despite this regionalization disparities in its use exist among specific, vulnerable patients. Addressing this may facilitate further concentration of this procedure.

Aged↗
PubMed1997

Community respiratory virus infections in immunocompromised patients with cancer.

Community respiratory viruses, such as respiratory syncytial virus (RSV), influenza viruses, parainfluenza viruses, adenoviruses, and picornaviruses, are an important cause of respiratory disease in the immunocompromised adult with cancer. Recent studies have demonstrated that a minimum of 31% of adult bone marrow transplant (BMT) recipients and 18% of adults with leukemia who are hospitalized with an acute respiratory illness have a community respiratory virus infection. The temporal occurrence of these infections in immunocompromised patients tends to mirror their occurrence in the community. The clinical illnesses range from self-limited upper respiratory illnesses to fatal pneumonias, depending on the type of virus and the type and degree of immunosuppression. The pneumonias may be viral, bacterial/fungal, or mixed. The highest frequency of progression to fatal viral pneumonia has been reported for RSV infections in recently transplanted BMT recipients and myelosuppressed patients with leukemia. Studies have suggested that early therapy for RSV pneumonia with a combination of aerosolized ribavirin and intravenous immunoglobulin may be of benefit. Defining effective prophylactic and therapeutic strategies will be a challenge, given the diversity of viruses, the wide spectrum of immunocompromised patients with varying vulnerability to serious community respiratory virus disease, and the frequent presence of other opportunistic infections and medical problems. A combination of antiviral drugs and immunotherapy may need to be considered for their potential additive effect as well as to prevent the emergence of resistant virus, as occurs during monotherapy for influenza with amantadine or rimantadine. The optimal therapies need to be defined in controlled trials; however, it appears that a favorable response will hinge on the initiation of therapy at an early stage of the respiratory illness.

Adenoviridae↗
PubMed2006

Physician-assisted suicide: a review of the literature concerning practical and clinical implications for UK doctors.

BACKGROUND: A bill to legalize physician-assisted suicide in the UK recently made significant progress in the British House of Lords and will be reintroduced in the future. Until now there has been little discussion of the clinical implications of physician-assisted suicide for the UK. This paper describes problematical issues that became apparent from a review of the medical and psychiatric literature as to the potential effects of legalized physician-assisted suicide. DISCUSSION: Most deaths by physician-assisted suicide are likely to occur for the illness of cancer and in the elderly. GPs will deal with most requests for assisted suicide. The UK is likely to have proportionately more PAS deaths than Oregon due to the bill's wider application to individuals with more severe physical disabilities. Evidence from other countries has shown that coercion and unconscious motivations on the part of patients and doctors in the form of transference and countertransference contribute to the misapplication of physician-assisted suicide. Depression influences requests for hastened death in terminally ill patients, but is often under-recognized or dismissed by doctors, some of whom proceed with assisted death anyway. Psychiatric evaluations, though helpful, do not solve these problems. Safeguards that are incorporated into physician-assisted suicide criteria probably decrease but do not prevent its misapplication. SUMMARY: The UK is likely to face significant clinical problems arising from physician-assisted suicide if it is legalized. Terminally ill patients with mental illness, especially depression, are particularly vulnerable to the misapplication of physician-assisted suicide despite guidelines and safeguards.

Aged↗
PubMed2000

Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis.

Metastasis is a frequent complication of cancer, yet the process through which circulating tumor cells form distant colonies is poorly understood. We have been able to observe the steps in early hematogenous metastasis by epifluorescence microscopy of tumor cells expressing green fluorescent protein in subpleural microvessels in intact, perfused mouse and rat lungs. Metastatic tumor cells attached to the endothelia of pulmonary pre-capillary arterioles and capillaries. Extravasation of tumor cells was rare, and it seemed that the transmigrated cells were cleared quickly by the lung, leaving only the endothelium-attached cells as the seeds of secondary tumors. Early colonies were entirely within the blood vessels. Although most models of metastasis include an extravasation step early in the process, here we show that in the lung, metastasis is initiated by attachment of tumor cells to the vascular endothelium and that hematogenous metastasis originates from the proliferation of attached intravascular tumor cells rather than from extravasated ones. Intravascular metastasis formation would make early colonies especially vulnerable to intravascular drugs, and this possibility has potential for the prevention of tumor cell attachment to the endothelium.

Animals↗
PubMed1993

Glutathione, cell proliferation, and 1,3-bis-(2-chloroethyl)-1-nitrosourea in K562 leukemia.

We have pursued our findings of glutathione reductase (GSSG-R) deficiency and disturbed glutathione in cancer patients treated with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), by investigating how thiol metabolism, cell proliferation, and the nitrosourea interact in human K562 leukemia. Fasting cells arrested in G greatly increased their reduced glutathione (GSH) in response to growth factors. The rise in thiol began after several hours, peaked before DNA synthesis, and resulted from increased production. BCNU inactivated GSSG-R rapidly, and later retarded, doubled, and greatly prolonged GSH formation before stopping DNA synthesis. Pretreatment unlike post treatment with buthionine-S-R-sulfoximine (BSO) diminished BCNU's ability to block GSSG-R. Enzyme inhibition decreased with falling cellular GSH. In the leukemia system as in vivo, sequential BCNU-induced thiol alterations heralded delayed antiproliferative effects. Drug timing markedly affected both thiol and DNA syntheses. By destroying GSSG-R and delaying the upregulation of thiol synthesis while escalating GSH utilization and requirements, the nitrosourea created a striking and previously unrecognized window of vulnerability for GSH-dependent processes. During this period, altered GSH metabolism could contribute indirectly to BCNU's pleiotropic effects by interfering with DNA alkylation repair, glucose decarboxylation, deoxyribose formation, and possibly by influencing other aspects of proliferation. Acquired GSSG-R deficiency was also an early and sensitive marker for prodrug breakdown and activation.

Buthionine Sulfoximine↗
PubMed2004

Baseline mood and psychosocial characteristics of patients developing depressive symptoms during interleukin-2 and/or interferon-alpha cancer therapy.

It has been suggested that patients with subclinical mood symptoms prior to initiating cytokine treatment (as revealed by elevated baseline scores on depression rating scales) are more likely to become clinically depressed during the course of cytokine therapy. The present study was designed to identify which specific preexisting symptoms predict development of depressive symptomatology during treatment with the cytokines, interleukin-2 (IL-2) and/or interferon-alpha (IFN-alpha), in patients with cancer. Thirty-two patients with renal cell carcinoma or malignant melanoma eligible to receive treatment with IL-2 and/or IFN-alpha were enrolled in the study. At baseline and after one month of cytokine therapy (endpoint), depressive symptoms were assessed using the clinician-administered Montgomery-Asberg depression rating scale (MADRS). Illness-related coping strategies, social support, somatic complaints, quality of sleep and demographic factors were also assessed as relevant baseline predictive factors. MADRS scores significantly increased during cytokine therapy. Patients with moderate to marked depressive symptomatology at study endpoint exhibited higher baseline scores in dimensions of the MADRS scale assessing emotional (especially reported sadness), cognitive (especially pessimistic thoughts) and neurovegetative (sleep disturbances) symptoms compared to patients who remained free of depressive symptoms during cytokine therapy. Interestingly, only emotional symptoms and sleep disturbance at baseline, along with low social support, predicted severity of depressive symptoms at the end of the first month of therapy. By documenting specific behavioral vulnerability factors for cytokine-induced depressive symptoms, these findings may help identify patients at risk for mood disturbances during cytokine treatment and help target specific patient populations and specific symptoms for preventative strategies.

Adaptation, Psychological↗
PubMed2000

Induction of differentiation of leukaemic (HL-60) or prostate cancer (LNCaP, JCA-1) cells potentiates apoptosis triggered by onconase.

Onconase (Onc) is a ribonuclease from amphibian oocytes that is cytostatic and cytotoxic to many tumour lines. It shows in vivo antitumour activity in mouse tumour models and is currently in Phase III clinical trials. The present study was designed to test whether cytotoxic effects of ONC can be modulated by differentiating agents. Human leukaemic HL-60 and prostate cancer LNCaP and JCA-1 cells were treated with Onc in the absence and presence of several inducers of differentiation and frequency of apoptosis was assessed using three different cytometric methods and confirmed by analysis of cell morphology. A moderate degree of apoptosis observed after 48-72 h incubation of HL-60 cells in the presence of 0.42 microM Onc alone was markedly potentiated by administration of retinoic acid (all trans), sodium butyrate or dimethylsulfoxide at concentrations known to induce differentiation but be minimally cytotoxic. Likewise, the frequency of apoptosis of LNCaP and JCA-1 cells treated with Onc was increased in the cultures to which phenylbutyrate was added. Although cell treatment with Onc alone, with each of the differentiating agents alone or with Onc in combination with the differentiating agents led to an increase in the proportion of G1 cells, no specific cell cycle phase preference in induction of apoptosis was observed. The data suggest that cells undergoing differentiation are particularly vulnerable to Onc; a combination of Onc and differentiating agents should be considered for further in vivo tests to assess its possible usefulness in the clinic.

Antineoplastic Agents↗
PubMed1994

Public policy and AIDS.

In summary of some of the major issues raised by AIDS (Table 1), social, political, and economic forces all impact on the global outbreak of AIDS. Conversely the epidemiologic and medical realities of this disease have forced a reconsideration of moral and ethical values, prioritization of resource allocation, and pervasion of virtually every aspect of the health care delivery system. Advocates for AIDS funding have set a model for other espousing the significance of diseases ranging from rare disorders to breast cancer. As this issue was written (summer 1993), it was apparent that attention of the media had shifted to numerous other domestic and foreign concerns. Hopefully, when the Clinics next present perinatal AIDS, the pendulum will have swung back and there will be a wider variety of effective therapeutic agents available permitting longer survival of greater quality.

AIDS Serodiagnosis↗
PubMed2005

New advances in the DNA damage response network of Fanconi anemia and BRCA proteins. FAAP95 replaces BRCA2 as the true FANCB protein.

Fanconi anemia (FA) proteins function in a DNA damage response pathway that appears to be part of the network including breast cancer susceptibility gene products, BRCA1 and BRCA2. In response to DNA damage or replication signals, a nuclear FA core complex of at least 6 FA proteins (FANCA, FANCC, FANCE, FANCF, FANCG and FANCL) is activated and leads to monoubiquitination of the downstream FA protein, FANCD2. One puzzling question for this pathway is the role of BRCA2. A previous study has proposed that BRCA2 could be identical to two FA proteins: FANCD1, which functions either downstream or in a parallel pathway; and FANCB, which functions upstream of the FANCD2 monoubiquitination. Now, a new study shows that the real FANCB protein is not BRCA2, but a previously uncharacterized component of the FA core complex, FAAP95, suggesting that BRCA2 does not act upstream of the FA pathway. Interestingly, the newly discovered FANCB gene is X-linked and subject to X-inactivation. The presence of a single active copy of FANCB and its essentiality for a functional FA-BRCA pathway make it a potentially vulnerable component of the cellular machinery that maintains genomic integrity.

BRCA1 Protein↗
PubMed1991

The effect of age on treatment choice and survival in elderly breast cancer patients.

To investigate the effect of age on treatment choice and survival in patients with breast cancer, data from the cancer registry of the Netherlands Cancer Institute (NKI, Amsterdam, The Netherlands) on 611 women have been analyzed. All patients 55 years and older admitted to the NKI for primary treatment of breast cancer between 1981 and 1986 were selected. For women 75 years and older, physicians were less likely to use treatment of adjuvant radiation therapy after a mastectomy and more often employed primary hormonal therapy only for local stage disease than for younger patients. Life-table analysis showed that disease-specific survival at 7 years for patients 65 through 74 years of age was significantly better (65%) than that of the youngest (55%) and the oldest age group (50%). In multivariate regression analysis (Cox), age older than 74 years was significantly and independently associated with a shorter disease-specific survival as compared with patients younger than 75 years. This difference in survival, however, does not seem to be the result of the difference in treatment between the age groups, but suggests an influence of age-related factors such as comorbid diseases and weak physical condition, which manifest themselves most strongly in the oldest age category and make the older woman more vulnerable to the course of malignant disease.

Age Factors↗
PubMed2006

Caring or uncaring--meanings of being in an oncology environment.

AIM: This paper reports a study illuminating meanings of being in the physical environment of an oncology centre as narrated by patients, significant others and staff. BACKGROUND: The physical environment of hospitals can convey different messages. For example, landscape pictures, plants and comfortable chairs can convey positive messages, while sparsely decorated and run-down environments can convey negative values. Traditional healthcare environments may be experienced as unfamiliar, strange and alienating, fostering feelings of stress and vulnerability. The majority of research on care environments has employed experimental designs to test different environmental variables, for example sound, colour and architecture, in relation to patient outcomes such as recovery, pain and blood pressure. There is, however, little research-based understanding of the meanings of being in these environments. METHODS: A phenomenological hermeneutic approach was applied to analyse 17 interviews with patients, significant others and staff carried out during the spring of 2004 at an oncology centre in Sweden. FINDINGS: The physical environment was found to influence experiences of care in four ways: first, by being a symbol expressing messages of death and dying, danger, shame and stigma, less social value and worth; second by containing symbols expressing messages of caring and uncaring, life and death; third, by influencing interaction and the balance between being involved and finding privacy; and fourth, by containing objects that could facilitate a shift of focus away from the self: being able to escape the world of cancer, and finding light in the midst of darkness. The comprehensive understanding illuminates the physical environment as not merely a place for caring, but as an important part of caring that needs to be accounted for in nursing care. CONCLUSION: To promote well-being among patients, we need to ask ourselves if the environment imposes rather than eases suffering. Our findings also suggest the importance of not limiting our conceptions of nursing to nurse-patient relationships, but of using the therapeutic potential of the total environment in nursing care.

Adult↗
PubMed2005

[The impact of high apparent temperature on the increase of Summertime Disease-related mortality in Seoul: 1991-2000].

OBJECTIVES: The aim of this paper was to examine the relationship between the summertime (June to August) heat index, which quantifies the bioclimatic apparent temperature in sultry weather, and the daily disease-related mortality in Seoul for the period from 1991 to 2000. METHODS: The daily maximum (or minimum) summertime heat indices, which show synergetic apparent temperatures, were calculated from the six hourly temperatures and real time humidity data for Seoul from 1991 to 2000. The disease-related daily mortality was extracted with respect to types of disease, age and sex, etc. and compared with the time series of the daily heat indices. RESULTS: The summertime mortality in 1994 exceeded the normal by 626 persons. Specifically, blood circulation-related and cancer-related mortalities increased in 1994 by 29.7% (224 persons) and 15.4% (107 persons), respectively, compared with those in 1993. Elderly persons, those above 65 years, were shown to be highly susceptible to strong heat waves, whereas the other age and sex-based groups showed no significant difference in mortality. In particular, a heat wave episode on the 22nd of July 2004 (> 45 degrees C daily heat index) resulted in double the normal number of mortalities after a lag time of 3 days. Specifically, blood circulation-related mortalities, such as cerebral infraction, were predominant causes. Overall, a critical mortality threshold was reached when the heat index exceeded approximately 37 degrees C, which corresponds to human body temperature. A linear regression model based on the heat indices above 37 degrees C, with a 3 day lag time, accounted for 63% of the abnormally increased mortality (> or =+2 standard deviations). CONCLUSIONS: This study revealed that elderly persons, those over 65 years old, are more vulnerable to mortality due to abnormal heat waves in Seoul, Korea. When the daily maximum heat index exceeds approximately 37 degrees C, blood circulation-related mortality significantly increases. A linear regression model, with respect to lag-time, showed that the heat index based on a human model is a more dependable indicator for the prediction of hot weather-related mortality than the ambient air temperature.

Adolescent↗
PubMed1986

Unique radiosensitivity of serous cells in rhesus monkey submandibular glands.

The saliva of patients undergoing radiation therapy for head and neck cancer contains increased acidic mucosubstances associated with a reduced serous component. To assess the morphologic features of the acute radiation damage in serous versus mucous acinar cells, the mixed serous/mucous submandibular glands of 18 rhesus monkeys were studied 1-72 hours after irradiation with single doses of 2.5-15.0 Gy. Selective degeneration and necrosis of serous cells was observed with doses of 2.5-7.5 Gy. Doses of 10.0-15.0 Gy caused widespread destruction of whole serous acini, but only isolated mucous cells were affected. The lesions were clearly expressed by 24 hours. Transient exudation of neutrophils was replaced by plasma cells and lymphocytes. Examination at 16, 22 and at 40 weeks revealed that late atrophy was caused solely by loss of serous acini in glands treated with 7.5 and 10.0 Gy. Although both serous and mucous acini were reduced in glands treated with 12.5 and 15.0 Gy, the atrophy was mainly due to loss of serous acini. The finding that serous cells are more vulnerable to radiation injury than mucous cells provides a morphologic explanation for early and late changes in saliva composition after salivary gland irradiation.

Animals↗
PubMed2003

The relationship of APOE genotype to neuropsychological performance in long-term cancer survivors treated with standard dose chemotherapy.

PURPOSE: The primary purpose of this study was to compare the neuropsychological performance of long-term survivors of breast cancer and lymphoma treated with standard dose chemotherapy who carried the epsilon 4 allele of the Apolipoprotein E (APOE) gene to those who carry other APOE alleles. PATIENTS AND METHODS: Long-term survivors (mean=8.8+/-4.3 years post-treatment) of breast cancer (N=51, age=55.9+/-8.8) or lymphoma (N=29, age=55.8+/-11.6) who had been treated with standard-dose chemotherapy completed a standardized battery of neuropsychological and psychological tests. Survivors were also classified into two groups based on the presence (N=17) or absence (N=63) of at least one epsilon 4 allele of APOE. RESULTS: Analysis of covariance, controlling for age, gender, education, diagnosis, and WRAT-3 reading subtest (a proxy measure of baseline IQ), indicated that survivors with at least one epsilon 4 allele scored significantly lower in the visual memory (p<0.03) and the spatial ability (p<0.05) domains and tended to score lower in the psychomotor functioning (p<0.08) domain as compared to survivors who did not carry an epsilon 4 allele. No group differences were found on depression, anxiety, or fatigue. CONCLUSIONS: The results of this study provide preliminary support for the hypothesis that the epsilon 4 allele of APOE may be a potential genetic marker for increased vulnerability to chemotherapy-induced cognitive decline.

Adult↗
PubMed2004

Clinical implications of the differences between diagnostic 123I and post-therapy 131I scans.

BACKGROUND: 123I has been promoted for diagnostic imaging as a means of avoiding 'stunning'. It has also been suggested that the more favourable physical characteristics and consequent enhanced imaging resolution provided by 123I offers a more accurate diagnostic assessment of the extent of disease prior to therapy. This study evaluated pairs of diagnostic 123I and post-therapy 131I scans for differences in patterns of radioiodine uptake. METHODS: Thirty-eight patients (31 women and seven men) with a history of differentiated thyroid cancer underwent 41 diagnostic 123I studies. 131I therapy was administered to 29 patients as soon as possible after positive diagnostic findings were confirmed (with one patient being treated twice during the study period, making 30 treatments). Post-treatment scans were obtained an average of 5.8 days after therapy. RESULTS: Qualitative comparison of diagnostic 123I and post-therapy 131I scans revealed a decrease in the extent of post-treatment uptake in four of the 30 treatments (13%). Seven patients (23%) demonstrated increased uptake on their post-therapy 131I scan. CONCLUSIONS: Because the physical characteristics of 123I make it inconceivable that it could cause stunning, the decrease in post-treatment uptake seen in 13% of patients from this series increases the likelihood that this pattern is due to factors other than stunning, such as differential rates of radioiodine turnover. In addition, the increase in extent of post-therapy uptake seen in 23% of patients suggests that diagnostic imaging with 123I is vulnerable to the same pre-therapy staging inaccuracies as is low-dose diagnostic imaging with 131I. Further work is needed to determine whether larger diagnostic doses of 123I might mitigate this problem.

Adolescent↗
PubMed1991

Fractionated irradiation and early changes in salivary glands. Different effects on potassium efflux, exocytotic amylase release and gland morphology.

Irradiation is a potent treatment modality of head and neck cancer. However, the irradiation is usually associated with an influence on salivary glands with ensuing dryness and discomfort for the patients. In the present study we used different in vitro secretory models and morphologic characterization of rat parotid gland. Radiation was given to one gland on a 5-day schedule with 6 MV photons (total dose 20, 30, 35, 40, 45 Gy). The contralateral gland served as control, and the analysis of glands were performed 10 days after the last irradiation treatment. The noradrenaline stimulated electrolyte secretion (86rubidium tracer for potassium) was decreased in relation to the irradiation dose and in comparison to contralateral control glands. Noradrenaline stimulated exocytotic amylase release was not affected by irradiation and, there were no signs of obvious quantitative morphologic alterations after irradiation compared with controls. The results suggest that there are differences in the sensitivity to radiation for the two different secretory processes in salivary glands, and, thus, the structures regulating electrolyte and fluid secretion seem to be more vulnerable to irradiation than the process of exocytosis. The results, however, do not allow discrimination between temporary cellular impairment and irreversible damage leading to cell death.

Amylases↗
PubMed2003

Electrophile and oxidant damage of mitochondrial DNA leading to rapid evolution of homoplasmic mutations.

mtDNA mutations occur in a wide variety of degenerative diseases and cancer. mtDNA seems to be more susceptible to DNA damage and consequently sustains higher rates of mutation than does nuclear DNA (nDNA). Many of the somatic mtDNA mutations in human cancers are located in the displacement loop (D-loop) and in particular in a polycytidine stretch (C-tract) termed D310. The D310 region exhibits polymorphic length variation among individuals and has been described as a "hot spot" for somatic mutations in many cancer types. We used real-time quantitative PCR to analyze mtDNA integrity, damage repair, and induced mutations after exposure of human adult retinal pigment epithelial (ARPE)-19 cells to 4-nitroquinoline 1-oxide, a UV-mimetic and adduct-forming carcinogen, and tert-butyl hydroperoxide, an oxidant. The mtDNA-damage profile depended on the region. Thus, the tRNA coding for glycine (tRNA(G)) was the least affected region, whereas the D-loop, and especially its D310 region, were most sensitive to damage. The time course of repair of mutations of the D-loop and especially the D310 region after exposure to DNA-damaging agents was delayed when compared with other regions and gave rise to common D310 C-tract frame-shift mutations. The induced mutations in the D310 region were predominantly homoplasmic only 7 days after exposure to damage. Our results establish that the D-loop (especially its D310 region) is highly susceptible to mutations because of its vulnerability to DNA damage and inefficient repair mechanisms. Our findings may explain the high frequency of homoplasmic D310 somatic mutations in many tumor types.

Base Sequence↗
PubMed2002

Specific allelic loss of p16 (INK4A) tumor suppressor gene after weeks of iron-mediated oxidative damage during rat renal carcinogenesis.

Oxidative tissue damage has been shown to be associated with carcinogenesis. In human cancers p16(INK4A) is one of the most frequently mutated tumor suppressor genes. The present study used the ferric nitrilotriacetate (Fe-NTA)-induced rat renal carcinogenesis model to determine whether oxidative damage can cause specific allelic loss of p16 (INK4A). By the use of fluorescent in situ hybridization in combination with imprint cytology at single-cell resolution, we found that the number of renal tubular cells with aneuploidy (1 or 3 signals) at the p16(INK4A) locus was significantly and specifically increased (1 week, 37.2 +/- 2.3%; 3 weeks, 37.8 +/- 1.3% vs control, 22.5 +/- 1.9%; mean +/- SE, N = 8; P < 0.001 and P < 0.0001, respectively) after repeated intraperitoneal administration of 5 to10 mg of iron/kg in the form of Fe-NTA for 3 weeks. No increase in aneuploidy was observed at the loci of either the p53 or vhl tumor suppressor gene. Furthermore, the increase in the cells with 3 signals was followed by a continuous increase in those with 1 signal. Therefore, the p16 (INK4A) locus is specifically vulnerable to oxidative damage, leading to its allelic loss within weeks, presumably due to a deficiency in the replication of both the alleles.

Animals↗