Biomedical subjects

James Lee

Publications and source records attributed to James Lee.

At least 19 recordsLinked to original sources

PubMed2007

Early-life family structure and microbially induced cancer risk.

BACKGROUND: Cancer may follow exposure to an environmental agent after many decades. The bacterium Helicobacter pylori, known to be acquired early in life, increases risk for gastric adenocarcinoma, but other factors are also important. In this study, we considered whether early-life family structure affects the risk of later developing gastric cancer among H. pylori+ men. METHODS AND FINDINGS: We examined a long-term cohort of Japanese-American men followed for 28 y, and performed a nested case-control study among those carrying H. pylori or the subset carrying the most virulent cagA+ H. pylori strains to address whether family structure predicted cancer development. We found that among the men who were H. pylori+ and/or cagA+ (it is possible to be cagA+ and H. pylori- if the H. pylori test is falsely negative), belonging to a large sibship or higher birth order was associated with a significantly increased risk of developing gastric adenocarcinoma late in life. For those with cagA+ strains, the risk of developing gastric cancer was more than twice as high (odds ratio 2.2; 95% confidence interval 1.2-4.0) among those in a sibship of seven or more individuals than in a sibship of between one and three persons. CONCLUSIONS: These results provide evidence that early-life social environment plays a significant role in risk of microbially induced malignancies expressing five to eight decades later, and these findings lead to new models to explain these interactions.

Aged↗

PubMed2006

Systemic polyethylene glycol-modified (PEGylated) superoxide dismutase and catalase mixture attenuates radiation pulmonary fibrosis in the C57/bl6 mouse.

PURPOSE: Since oxidative injury is implicated in radiation-induced tissue damage to the lung, we studied systemically administered polyethylene glycol (PEGylated) antioxidant enzymes (AOEs) as pulmonary radioprotectors in mice. METHODS AND MATERIALS: C57/bl6 Mice received 13.5 Gy single-dose irradiation to the thorax. One cohort also received 100 microg of a 1:1 mixture of PEG-AOEs {PEG-catalase and PEG-superoxide dismutase (SOD)} intravenously, pre-irradiation and subgroups were evaluated at variable time-points for inflammation and fibrosis. Potential for AOE tumor protection was studied by thoracic irradiation of mice with Lewis lung carcinoma. RESULTS: At 48 h post-irradiation, control irradiated mice had marked elevations of tissue p21, Bax and TGF-beta1 in lungs, not seen in irradiated, PEG-AOE-treated mice. TUNEL staining of lung sections was performed at just one time-point (24 h post-irradiation) and revealed a decrease in apoptotic cells with AOE treatment. At four months post-irradiation, these mice had significantly increased pulmonary fibrosis as measured by hydroxyproline content. Mice treated with PEG-AOE prior to irradiation had 4-month hydroxyproline levels that were similar to that of unirradiated controls (p = 0.28). This corresponded to less pulmonary fibrosis as visualized histologically when compared with mice irradiated without AOEs. PEG-AOEs did not prevent post-irradiation pulmonary inflammation or lung cancer response to irradiation. CONCLUSIONS: A mixture of PEG-SOD and PEG-CAT successfully diminished radiation pulmonary fibrosis in mice. There was also a corresponding effect on several early biomarkers of lung injury and decreased apoptosis. There were no significant effects on acute pneumonitis or tumor protection.

Animals↗

PubMed2006

Hook needle-guided excision of recurrent differentiated thyroid cancer in previously operated neck compartments: a safe technique for small, nonpalpable recurrent disease.

CONTEXT: As a result of more sensitive techniques to detect recurrent thyroid cancer, the number of patients presenting with small, nonpalpable recurrent thyroid cancer in cervical lymph nodes is increasing. Surgical excision of nonpalpable recurrent thyroid cancer can be difficult, particularly in a previously operated area. OBJECTIVE: The objective of this study was to investigate whether preoperative insertion of a hook needle under ultrasound guidance is useful in neck reoperations for recurrent thyroid cancer. PATIENTS: Ten consecutive patients presenting over a 4-month period with nonpalpable, ultrasound-visible, fine needle biopsy-proven recurrent thyroid cancer in previously operated neck compartment(s) were studied. MAIN OUTCOME MEASURES: We measured whether it was technically possible to insert a hook needle preoperatively, rate of negative neck exploration, and complication rate. RESULTS: The hook needle was inserted in seven patients. In three patients, the hook needle was not inserted; one patient had palpable disease 4 months after the preoperative clinic visit, one patient had a tumor too close to the carotid artery, and one patient had multiple bilateral foci of recurrent disease in the central neck. One patient had bleeding after insertion of the needle due to a penetration of an anterior jugular vein that was easily managed at neck reexploration. No other complication occurred during the hook needle insertion, and the only surgical complication was a transient recurrent nerve palsy. All pathology reports showed malignant disease. CONCLUSION: Hook needle-guided excision of recurrent thyroid cancer is feasible and appears to be a promising tool for safe and successful reoperation of patients with small recurrent thyroid cancer in cervical lymph nodes.

Adolescent↗

PubMed2006

Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells.

Interleukin 27 (IL-27) was first characterized as a proinflammatory cytokine with T helper type 1-inducing activity. However, subsequent work has demonstrated that mice deficient in IL-27 receptor (IL-27R alpha) show exacerbated inflammatory responses to a variety of challenges, suggesting that IL-27 has important immunoregulatory functions in vivo. Here we demonstrate that IL-27R alpha-deficient mice were hypersusceptible to experimental autoimmune encephalomyelitis and generated more IL-17-producing T helper cells. IL-27 acted directly on effector T cells to suppress the development of IL-17-producing T helper cells mediated by IL-6 and transforming growth factor-beta. This suppressive activity was dependent on the transcription factor STAT1 and was independent of interferon-gamma. Finally, IL-27 suppressed IL-6-mediated T cell proliferation. These data provide a mechanistic explanation for the IL-27-mediated immune suppression noted in several in vivo models of inflammation.

Animals↗

PubMed2006

Influence of garlic (Allium sativum) on the pharmacokinetics of docetaxel.

PURPOSE: The herbal supplement garlic (Allium sativum) is commonly used by cancer patients. Preclinical studies have shown that allicin, a major component of garlic, may affect cytochrome P450 3A4 (CYP3A4) activity. This study examines the influence of garlic supplementation on the pharmacokinetics of docetaxel, a CYP3A4 substrate. EXPERIMENTAL DESIGN: Women with metastatic breast cancer were treated with docetaxel (30 mg/m(2)) given weekly for 3 of 4 weeks. Three days after the initial dose of docetaxel, patients received 600 mg of garlic twice daily for 12 consecutive days. Docetaxel pharmacokinetics were assessed during the first three administrations. RESULTS: In 10 evaluable patients, the mean baseline clearance of docetaxel was 30.8 L/h/m(2) [95% confidence intervals (95% CI), 16.7-44.9]. Coadministration of garlic reduced mean clearance of docetaxel to 23.7 L/h/m(2) (95% CI, 15.5-31.8) and 20.0 L/h/m(2) (95% CI, 13.3-26.7) on days 8 and 15, respectively (P = 0.17). Additional pharmacokinetic variables of docetaxel, including peak concentration (P = 0.79), area under the curve (P = 0.36), volume of distribution (P = 0.84), and half-life (P = 0.36), were also not statistically significantly different. The mean area under the curve ratio between day 15 and day 1 was 3.74 in three individuals with the CYP3A5*1A/*1A genotype (all African American) compared with 1.02 in six individuals with the CYP3A5*3C/*3C genotype (all Caucasian). CONCLUSIONS: This study indicates that garlic does not significantly affect the disposition of docetaxel. However, it cannot be excluded that garlic decreases the clearance of docetaxel in patients carrying a CYP3A5*1A allele.

Adenocarcinoma↗

PubMed2006

Intracranial drug-delivery scaffolds: biocompatibility evaluation of sucrose acetate isobutyrate gels.

INTRODUCTION: Sucrose acetate isobutyrate (SAIB) is a water insoluble, biodegradable gel used for controlled-release oral and subcutaneous drug delivery. We investigated SAIB compatibility in the rat central nervous system (CNS) by implanting solutions of SAIB in adult and in neonatal brains. METHODS: 10-15 microL solutions of SAIB gels in 0-30% ethanol were injected into the cerebral cortex of adult Fischer 344 rats. Control animals were implanted with a 10 mg biodegradable poly anhydride copolymer of poly [bis (p-carboxyphenoxy) propane] anhydride and sebacic acid (PCPP:SA). Adult rats were evaluated for signs of pain and distress, including changes in posture, facial signs, and grooming behavior. 1-2 microL solutions of SAIB gels in 15% ethanol were injected into brains of 12-24 h-old rats. Neonatal rats were evaluated for survival. Adult and neonatal brains were examined by histopathology 3-48 days after implant. RESULTS: Gel implants produced elliptical compression of cortical tissue, cell loss, and inflammation. Cell loss appeared to be confined to the implantation wound and associated neuronal fields. In adult rats, neurophil compression, inflammation, and cell loss appeared similar with the 10-mg PCPP:SA implants and the 10-mg SAIB implants. There was no clinical evidence of pain or distress from SAIB implants. 1-2 microL implants of SAIB-15% ethanol had no effect on survival of neonatal animals. CONCLUSION: Brain implants of SAIB induce a mild to moderate inflammatory response and associated neuronal cell damage. The implants appeared to be biocompatible in adult and neonatal animals. These results suggest that further studies of SAIB as an injectable drug-delivery scaffold for CNS therapeutic agents are warranted.

Animals↗

PubMed2006

Effect of repeated oral administrations of the oral adsorbent AST-120 on serum creatinine and other markers of renal function. A randomized controlled study in patients with chronic kidney disease.

BACKGROUND: AST-120 is an orally administered adsorbent used in Japan for prolonging time to initiation of hemodialysis and improving uremic symptoms in patients with chronic kidney disease (CKD). As AST-120 is suspected to reduce the progression of CKD by adsorbing renal toxins in the gastrointestinal tract, the objective of the current study was to determine whether binding of AST-120 to creatinine in the intestines could acutely alter creatinine balance, thereby limiting the utility of serum creatinine (sCr) as a measure of progression of renal function. Such information may be critical for the design of future studies to assess the efficacy of AST-120 in CKD patients. METHODS: Patients with CKD (n = 20) received oral doses of AST-120(3 g t.i.d.) and placebo in a two-way crossover study. Blood and urine were collected for determination of sCr, 24-hour urinary creatinine (UcrV), creatinine clearance (Ccr), and urea nitrogen clearance (URCL). Differences between treatments were assessed using an ANCOVA model. RESULTS: Following AST-120 and placebo treatments, mean sCr (1.73 and 1.79 mg/dl, respectively) and UcrV (1,264.73 and 1,286.05 mg) values were not significantly different. No significant differences were observed for Ccr and URCL. CONCLUSION: These results indicate that AST-120 has no acute impact on creatinine balance in patients with CKD. Consequently, sCr and other markers of renal function are acceptable measures for assessing changes in renal function following AST-120 treatment.

Analysis of Variance↗

PubMed2006

Selective use of steroid replacement after adrenalectomy: lessons from 331 consecutive cases.

HYPOTHESIS: Only selected patients require steroid replacement therapy following adrenalectomy. DESIGN: Retrospective review. SETTINGS: University tertiary care center and veterans' hospital. PATIENTS: A total of 331 patients who underwent adrenalectomy by 1 surgeon (Q.-Y.D.) between April 1, 1993, and August 31, 2005. INTERVENTIONS: Laparoscopic, open, and hand-assisted adrenalectomy. Steroid replacement therapy was administered using a standardized hydrocortisone taper protocol. MAIN OUTCOME MEASURES: Indications for adrenalectomy, operative approach, requirement for postoperative steroid replacement, and episodes of acute adrenocortical insufficiency. RESULTS: Of the 331 adrenalectomies, 304 were laparoscopic, 23 were open, and 4 were hand assisted. There were 299 unilateral adrenalectomies and 32 bilateral adrenalectomies performed. Fifty-seven (17%) of the 331 patients required steroid replacement after adrenalectomy. Of the 57 patients requiring steroid replacement, 52 had Cushing syndrome and 5 had bilateral pheochromocytomas. The 52 patients with Cushing syndrome included 16 with pituitary tumors who had failed pituitary resection and/or medical therapy, 14 with unilateral adrenal adenomas, 9 with ectopic corticotropin-secreting tumors who had failed resection and/or medical therapy, 7 with incidentalomas and subclinical Cushing syndrome, 4 with macronodular hyperplasia, and 2 with adrenocortical carcinoma. No patients undergoing unilateral adrenalectomy for non-Cushing adrenal disease required steroid replacement. Four (7%) of the 57 patients receiving steroid replacement had episodes of acute adrenocortical insufficiency following operation and required increased steroid supplementation. There were no cases of acute adrenocortical insufficiency in the 274 patients who did not receive steroid replacement. CONCLUSIONS: Steroid replacement therapy after adrenalectomy should be reserved for patients with Cushing syndrome (overt or subclinical) and patients undergoing bilateral adrenalectomy. Patients undergoing adrenalectomy for unilateral non-Cushing adrenal tumors do not require postoperative steroid replacement.

Acute Disease↗

PubMed2006

The effect of AST-120 on the single-dose pharmacokinetics of losartan and losartan acid (E-3174) in healthy subjects.

AST-120 is an orally administered adsorbent used to slow the progression of chronic kidney disease (CKD). This was a randomized, open-label, 5-way crossover study to assess the effect of AST-120 on the pharmacokinetics of losartan and its active metabolite (E-3174) in healthy subjects. Losartan (100 mg) was administered alone under fasting (A) and fed (B) conditions, and results were compared when AST-120 (3 g thrice daily for 2 days) was administered 60 minutes after (C), 30 minutes prior to (D), and 30 minutes after (E) losartan. Plasma concentrations of losartan and E-3174 were assayed by high-performance liquid chromatography with mass spectrometry detection. Under fed conditions, treatment C had no significant effect on the AUC(0-t) and Cmax of losartan and E-3174. Treatments D and E resulted in a marked decrease in Cmax of losartan and E-3174. Therefore, administration of AST-120 60 minutes after losartan under fed conditions may be preferred over other dosing regimens for CKD patients.

Adsorption↗

PubMed2006

Comparing costs.

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Family Practice↗

PubMed2005

The epidemiology of molluscum contagiosum in children.

Molluscum contagiosum (MC) is a viral disorder of the skin and mucous membranes characterized by discrete single or multiple, flesh-colored papules. Although MC as a clinical entity is well defined and commonly observed, few data regarding its epidemiology in the pediatric population exist. Our purpose was to collect epidemiologic data on children with MC with regard to age, gender, ethnicity, degree of involvement, relation to pre-existing atopic dermatitis (AD), and immune status. A retrospective chart review was conducted. All subjects were seen at 3 tertiary pediatric dermatology referral centers with two of the sites based at a Children's Hospital. A total of 302 patient charts with the Current Procedural Terminology code diagnosis of MC seen over a 6- to 8-month period were reviewed. Approximately 80% of the patients were younger than 8 years old. The majority of patients (63%) had more than 15 lesions. All but one patient were otherwise healthy, as determined by history and clinical examination. Approximately 24% of the patients presented with a history of previous or active coexistent AD. However, children with AD were at risk for an increased number of lesions. These data provide valuable updated information on the demographics and clinical presentation of MC in pediatric patients in the United States. Limitations include that this was a retrospective study with a population limited to tertiary pediatric dermatology referral centers.

Age Distribution↗

PubMed2005

Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis.

Heparin-induced thrombocytopenia (HIT) is an uncommon but potentially devastating complication of anticoagulation with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Our objective was to determine and compare the incidences of HIT in surgical and medical patients receiving thromboprophylaxis with either UFH or LMWH. All relevant studies identified in the MEDLINE database (1984-2004), not limited by language, and from reference lists of key articles were evaluated. Randomized and nonrandomized controlled trials comparing prophylaxis with UFH and LMWH and measuring HIT or thrombocytopenia as outcomes were included. Two reviewers independently extracted data on thromboprophylaxis (type, dose, frequency, and duration), definition of thrombocytopenia, HIT assay, and rates of the following outcomes: HIT, thrombocytopenia, and thromboembolic events. HIT was defined as a decrease in platelets to less than 50% or to less than 100 x 10(9)/L and positive laboratory HIT assay. Fifteen studies (7287 patients) were eligible: 2 randomized controlled trials (RCTs) measuring HIT (1014 patients), 3 prospective studies (1464 patients) with nonrandomized comparison groups in which HIT was appropriately measured in both groups, and 10 RCTs (4809 patients) measuring thrombocytopenia but not HIT. Three analyses were performed using a random effects model and favored the use of LMWH: (1) RCTs measuring HIT showed an odds ratio (OR) of 0.10 (95% confidence interval [CI], 0.01-0.2; P = .03); (2) prospective studies measuring HIT showed an OR of 0.10 (95% CI, 0.03-0.33; P < .001); (3) all 15 studies measured thrombocytopenia. The OR was 0.47 (95% CI, 0.22-1.02; P = .06). The inverse variance-weighted average that determined the absolute risk for HIT with LMWH was 0.2%, and with UFH the risk was 2.6%. Most studies were of patients after orthopedic surgery.

Controlled Clinical Trials as Topic↗

PubMed2005

A novel brainstem tumor model: guide screw technology with functional, radiological, and histopathological characterization.

OBJECT: Survival rates for high-grade brainstem tumors are approximately 10% and optimal therapy has yet to be determined. Development of a satisfactory brainstem tumor model is necessary for testing new therapeutic paradigms that may prolong survival. The authors report the technique, functional progression, radiological appearance, and histopathological features of a novel brainstem tumor model in rats. METHODS: Thirty female Fischer 344 rats were randomized (10 animals/group) to receive an injection of either 3 ml of 9L gliosarcoma cells (100,000 cells), 3 ml of F98 glioma cells (100,000 cells), or 3 ml of medium (Dulbecco modified Eagle medium) into the pontine tegmentum of the brainstem. Using a cannulated guide screw system implanted in the skull of the animal, rats in each group were injected at coordinates 1.4 mm to the right of the sagittal and 1 mm anterior to the lambdoid sutures, at a depth of 7 mm from the dura mater. The angle of the syringe during injection was anteflexed 5 degrees from the vertical. Postoperatively, the rats were evaluated for neurological deficits by using an automated rotarod test. High-resolution [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) fused with computerized tomography (CT) scans were acquired pre- and postoperatively through the onset of hemiparesis and correlated accordingly. Kaplan-Meier curves were generated for survival and disease progression, and brains were processed postmortem for histopathological investigation. The 9L and F98 tumor cells grew in 95% of the animals in which they were injected and resulted in a statistically significant mean onset of hemiparesis of 16.5 6 0.56 days (p = 0.001, log-rank test), compared with animals in the control group, which had no neurological deficits by Day 45. The FDG-PET studies coregistered with CT scans demonstrated space-occupying brainstem lesions, and this finding was confirmed by histological studies. Animals in the control group showed no functional, radiological, or pathological signs of tumor. CONCLUSIONS: Progression to hemiparesis was consistent in all tumor-injected animals, with predictable onset of symptoms occurring approximately 17 days postsurgery. The histopathological and radiological characteristics of the 9L and F98 brainstem tumors were comparable to those of aggressive primary human brainstem tumors. Establishment of this animal tumor model will facilitate the testing of new therapeutic paradigms for the treatment of these lesions.

Animals↗

PubMed2005

Experimental models of brainstem tumors: development of a neonatal rat model.

OBJECTIVE: Brainstem tumor models are required to advance the treatment for diffuse pontine gliomas in children. The feasibility of creating an experimental rodent model by inoculating newborn pups with tumor cells was examined. The study was performed to create an animal model for diffuse brainstem tumors. METHODS: Eighty-two Fischer rat pups aged 12-24 h were anesthetized by hypothermia. The brainstem was injected with saline to identify anatomical coordinates for subsequent tumor cell challenges. The newborn pups were then inoculated with F98 (n=30) or 9L (n=30) glioma cells. Animals were returned to their mother for nursing. Tumor growth was assessed by survival and histopathology. RESULTS: Twenty-one percent of the saline-treated animals (17 out of 82) and 5% of the tumor cell-challenged pups (3 out of 60) were eliminated by their mothers. Inoculations with 9L and F98 cells produced brainstem tumors in 83% (24 out of 29) and 93% of animals (26 out of 28) respectively that were evaluated. CONCLUSIONS: Our results demonstrate that neonatal rat models for brainstem tumors can be prepared using known injection coordinates and orthotopic cell lines. Decreasing rates of maternal removal during the course of the work suggests that the method involves a learning curve.

Animals↗

PubMed2005

Prospective study of the association of serum triglyceride and glucose with colorectal cancer.

To determine if serum triglyceride and glucose levels are associated with colorectal cancer, a prospective study among 7619 Japanese-American men was conducted. From 1968 to 1998, 376 colon and 124 rectal cancer incident cases were diagnosed. A strong positive association of alcohol intake and pack-years of cigarette smoking with colorectal cancer was observed. Body mass index and heart rate were also positively related to colon, but not to rectal cancer. In contrast, serum triglyceride did not predict the development of either colon or rectal cancer. There was a modest association of serum glucose in the highest quartile group with rectal cancer (relative risk = 1.33; 95% confidence interval, 0.79-2.26), but it was not statistically significant. This study did not find a strong positive association of serum triglyceride or glucose with colorectal cancer, but additional studies including other metabolic consequences associated with increased serum triglyceride and glucose may clarify the relationship.

Adult↗

PubMed2005

Enteric-coated mycophenolate sodium delivers bioequivalent MPA exposure compared with mycophenolate mofetil.

Mycophenolic acid (MPA), the active moiety of mycophenolate mofetil (MMF), is routinely used as an adjunct immunosuppressant therapy in renal transplantation. Although highly effective, MMF therapy is associated with significant gastrointestinal adverse effects. Enteric-coated mycophenolate sodium (EC-MPS) is an advanced formulation delivering MPA. The enteric coat dissolves at pH > 5 allowing for MPA delivery in the small intestine. A single-center, open-label, randomized, three-way crossover study of 24 stable Caucasian renal transplant patients receiving cyclosporine-based immunosuppression, compared the relative bioavailability of two EC-MPS doses (640 and 720 mg) with MMF (1000 mg). Both EC-MPS doses delivered bioequivalent mean MPA exposure (AUC(0-infinity)) compared with 1000 mg MMF: 60.7 microg h/mL for 640 mg EC-MPS, 66.5 microg h/mL for 720 mg EC-MPS, and 63.7 microg h/mL for 1000 mg MMF. Median t(max) was significantly delayed for both EC-MPS doses compared with MMF (2.0 h vs. 0.75 h, respectively; p < 0.01), consistent with a functional enteric coating of EC-MPS. Furthermore, both EC-MPS doses were bioequivalent to 1000 mg MMF for AUC and C(max) for mycophenolic acid glucuronide. All three treatments were well tolerated. The EC-MPS 720 mg dose most closely approximated the MPA exposure of 1000 mg MMF and was selected for subsequent phase III studies.

Adult↗

PubMed2005

Eosinophils, but not eosinophil peroxidase or major basic protein, are important for host protection in experimental Brugia pahangi infection.

The attenuation of eosinophilia by the administration of monoclonal antibodies to CCR3 consistently correlates with impairment in worm elimination following primary intraperitoneal Brugia pahangi infections in mice. Host protection was unimpaired in mice deficient in eosinophil peroxidase (EPO) or major basic protein 1 (MBP-1), suggesting that eosinophils are essential in host protection but that neither EPO nor MBP-1 alone is.

Animals↗

PubMed2004

Phosphorylation of DNA topoisomerase I by the c-Abl tyrosine kinase confers camptothecin sensitivity.

DNA topoisomerase I (topo I) is involved in the regulation of DNA supercoiling, gene transcription, recombination, and DNA repair. The anticancer agent camptothecin specifically targets topo I. The mechanisms responsible for the regulation of topo I in cells, however, are not known. This study demonstrates that c-Abl-dependent phosphorylation up-regulates topo I activity. The c-Abl SH3 domain bound directly to the N-terminal region of topo I. The results demonstrate that c-Abl phosphorylated topo I at Tyr268 in core subdomain II. c-Abl-mediated phosphorylation of topo I Tyr268 in vitro and in cells conferred activation of the topo I isomerase function. Moreover, activation of c-Abl by treatment of cells with ionizing radiation was associated with c-Abl-dependent phosphorylation of topo I and induction of topo I activity. The functional significance of the c-Abl/topo I interaction is supported by the findings that (i) mutant topo I(Y268F) exhibited loss of c-Abl-induced topo I activity, and (ii) c-Abl-/- cells were deficient in the accumulation of protein-linked DNA breaks. In addition, loss of topo I phosphorylation in c-Abl-deficient cells conferred resistance to camptothecin-induced apoptosis. These findings collectively support a model in which c-Abl-mediated phosphorylation of topo I is functionally important to topo I activity and sensitivity to topo I poisons.

Amino Acid Sequence↗