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ABSTRACT: Donor livers are precious resources and it is, therefore, ethically imperative that we employ optimally sensitive and specific transplant selection criteria. Current selection criteria, the Milan criteria, for liver transplant candidates with hepatocellular carcinoma (HCC) are primarily based on radiographic characteristics of the tumor. Although the Milan criteria result in reasonably high survival and low-recurrence rates, they do not assess an individual patient's tumor biology and recurrence risk. Consequently, it is difficult to predict on an individual basis the risk for recurrent disease. To address this, we employed microarray profiling of microRNA (miRNA) expression from formalin fixed paraffin embedded tissues to define a biomarker that distinguishes between patients with and without HCC recurrence after liver transplant. In our cohort of 64 patients, this biomarker outperforms the Milan criteria in that it identifies patients outside of Milan who did not have recurrent disease and patients within Milan who had recurrence. We also describe a method to account for multifocal tumors in biomarker signature discovery.
American Journal of Transplantation 02/2012; 12(2):428-37. · 6.39 Impact Factor
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ABSTRACT: The donation of livers by living donors entails complex processes, both surgically and psychosocially, potentially involving risks in both domains. Thorough psychosocial evaluation is necessary to minimize those risks, yet little has been written about the donor assessment process. This article describes one such process, utilized by a transplant program in upstate New York.
Donor candidates undergo multiple psychosocial interviews early in the overall transplant evaluation process. Evaluators subsequently meet as a group, along with an independent ethicist, to determine psychosocial candidacy prior to final medical/surgical clearance.
Between 2003 and 2007, 416 donor candidates initiated and/or underwent full evaluation, resulting in a 17.5% surgery and 55.5% exclusion rate among those individuals. Of those ruled out, 20.8% were for (medical or psychosocial) reasons associated with the recipient, and 8.7% were for donor-related psychosocial issues.
Given the primacy ofpsychosocial and ethical issues in living liver donor candidate evaluation, the multiple interview process, followed by team discussion and overseen by an ethicist removed from other transplant program functions, has advantages as a donor assessment model.
The International Journal of Psychiatry in Medicine 01/2011; 41(4):295-308. · 1.03 Impact Factor
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ABSTRACT: Donor safety has been scrutinized by both the medical community and the media. Variability exists in reported donor complications and associated risk factors are ill defined. Use of administrative data can overcome the bias of single-center studies and explore variables associated with untoward events. A retrospective cohort study identifying living liver donors in two large healthcare registries yielded 433 right and left lobe donors from 13 centers between 2001 and 2005. Perioperative complications were identified using International Classification of Diseases, 9th Revision (ICD-9) coding data and classified according to the Clavien system. Logistic regression models identified factors associated with complications. There was one perioperative death (0.23%). The overall complication rate was 29.1% and major complication rate defined by a Clavien grade >or=3 was 3.5%. Center living-donor volume (OR = 0.97, 95% CI = 0.95-0.99) and the ratio of living-donors to all donors (living and deceased) (OR = 0.94, 95% CI = 0.92-0.96) were associated with a lower risk of all complications. Donor age >50 years (OR = 4.25, 95% CI = 1.22-14.87) was associated with a higher risk of major complications. Living liver donation is currently performed with a low risk of major morbidity. Use of administrative data represents an important tool to facilitate a better understanding of donor risk factors.
American Journal of Transplantation 10/2007; 7(10):2344-9. · 6.39 Impact Factor
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ABSTRACT: Nephrogenic systemic fibrosis (NSF) is a recently characterized systemic fibrosing disorder developing in the setting of renal insufficiency. NSF's rapidly progressive nature resulting in disability within weeks of onset makes early diagnosis important. Two reports of NSF after liver transplantation are known of. We present three cases of NSF developing within a few months after liver transplantation and review the current literature. Loss of regulatory control of the circulating fibrocyte, its aberrant recruitment, in a milieu of renal failure and a recent vascular procedure appear important in its development. Known current therapies lack consistent efficacy. Only an improvement in renal function has the greatest likelihood of NSF's resolution. Delayed recognition may pose a significant barrier to functional recovery in the ubiquitously deconditioned liver transplant patient. Early recognition and implementation of aggressive physical therapy appear to have the greatest impact on halting its progression.
American Journal of Transplantation 10/2006; 6(9):2212-7. · 6.39 Impact Factor
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ABSTRACT: Jejunoileal bypass (JIB) was, at one time, a popular surgical technique for the treatment of morbid obesity. However, this operation was also associated with major complications. Consequently, many such procedures were eventually reversed. One of the most serious of these complications was liver failure. For those patients who developed cirrhosis, liver transplantation was one therapeutic alternative. Tacrolimus is one of the primary immunosuppressive agents used in liver transplantation. It is effective to prevent acute rejection episodes, but shows a narrow therapeutic index and can cause nephrotoxicity and neurotoxicity. This report describes the change in tacrolimus absorption that was observed after JIB reversal in a 57-year-old female liver transplant recipient.
Prior to JIB reversal, the mean tacrolimus dose was 7 mg twice daily with a whole-blood tacrolimus concentration ranging from 5.2 to 6.4 ng/mL. There was no appreciable peak in tacrolimus concentration, and the area under the concentration-time curve (AUC) was 10.9 ng/mL/h. After reversal, the daily tacrolimus dose was decreased to 5 mg twice daily, with a now-discernable peak concentration at 3 hours postdose. Furthermore, the AUC increased 90% to 20.7 ng/mL/h.
After JIB reversal, the patient showed higher systemic levels of tacrolimus and required lower steady-state doses. It is therefore imperative that such patients be monitored closely to avoid tacrolimus-related toxicity.
Transplantation Proceedings 10/2005; 37(7):3165-7. · 1.00 Impact Factor
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ABSTRACT: Hepatitis C virus (HCV)-related liver disease is the most common indication for liver transplantation in the United States. Recurrence of HCV infection in these recipients is almost uniform. The currently available antiviral treatment is known to cause significant side effects, and the rate of sustained viral response is low. There is still controversy about whether such patients should undergo subsequent transplantations for HCV disease. This study compared outcomes for hepatic retransplantation performed in HCV(+) and HCV(-) recipients at a single center.
From December 1994 through November 2003, 68 patients at our institution received a second liver allograft. Nineteen of the recipients were HCV(+) (group A) and 49 were HCV(-) (group B). All patients were followed until January 2004. The mean follow-up time after initial retransplantation was 37 +/- 29 months. Patient and graft survival for the two groups were compared.
Seven recipients in group A (36.8%) and 22 recipients in group B (44.9%) died during follow-up. The actuarial 3-year patient survival after initial retransplantation for groups A and B were 61.7% and 51.6%, respectively. Nine patients required a second retransplantation, 3 (15.8%) in group A and 6 (12.2%) in group B. The actuarial 3-year graft survival from initial retransplantation for groups A and B were 56.3% and 45.7%, respectively.
We observed slightly better patient and graft survivals at 3 years from initial retransplantation in HCV(+) recipients compared to HCV(-) recipients. This may be due to younger donor age and better selection of HCV(+) recipients in this series.
Transplantation Proceedings 10/2005; 37(7):3159-61. · 1.00 Impact Factor
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ABSTRACT: With the shortage of donor organs, increasing number of hepatitis B core antibody (HBcAb)-positive [HBcAb(+)] liver allografts are being used for liver transplantation (LTx) in patients who are HBcab-negative [HBsAb(-)]. This study was aimed at assessing outcomes for hepatitis C virus (HCV)-positive [HCV(+)] and HCV-negative [HCV(-)] patients who received HBcAb(+) liver grafts from deceased donors and also received a short course of hepatitis B immunoglobulin (HBIg) with long-term lamivudine therapy after LTx.
From February 1995 through February 2003, 28 patients (mean age 53.8 +/- 10.2 years, 19 men and nine women, 16 HCV[-]; 12 HCV[+]) received HbcAb(+) liver allografts. All recipients received a short course of HBIg prophylaxis (10,000 units/day for 4 days) and long-term lamivudine 100 mg/d after LTx in addition to a tacrolimus-based immunosuppressive regimen.
Seven (25%) of the 28 recipients died during follow-up and three recipients required retransplantation. Three recipients (10.7%) developed HBV infection during follow-up, one of whom died 36 months after LTx and the other two had YMDD mutant HBV. The overall 6-year actuarial patient survival after transplantation was 74.4% and those for HCV(-) and HCV(+) recipients were 81.3% and 66.6%, respectively (P = .46). The overall 6-year actuarial graft survival was 63.9% and those for HCV(+) and HCV(-) recipients were 68.8% and 57.1%, respectively (P = .6).
We conclude that HBcAb(+) liver grafts can be used for both HCV(+) patients and HCV(-) patients who are critically ill, have early hepatocellular carcinoma, or have been exposed to HBV in the past. A short course of HBIg-lamivudine combination therapy provides effective prophylaxis against HBV infection in 89% of recipients of HBcAb(+) grafts.
Transplantation Proceedings 10/2005; 37(7):3187-9. · 1.00 Impact Factor
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ABSTRACT: Cytomegalovirus (CMV) infection after solid organ transplantation is one of the most common viral infections, causing significant morbidity and mortality if not treated promptly. Ganciclovir has proven to be effective for the prophylaxis and treatment of CMV. However, oral absorption of ganciclovir is poor. Recently, oral administration of valganciclovir hydrochloride (Valcyte) has been observed to display 10-fold better absorption than oral ganciclovir. Valganciclovir has increasingly been used as prophylaxis against CMV after solid organ transplantation. The purpose of this study was to examine the efficacy of valganciclovir prophylaxis therapy after primary liver transplantation.
Between July 2001 and May 2003, 203 consecutive liver transplant recipients, including 129 men and 74 women of overall mean age 53 +/- 11 years, received valganciclovir (900 mg/d or 450 mg every other day depending on renal function) for 3 to 6 months after primary liver transplantation. All patients were followed up for a minimum of 6 months. Mean follow-up was 19 +/- 5.8 months. CMV DNA in peripheral blood was tested using polymerase chain reaction (PCR) amplification. Symptomatic CMV was stratified according to the CMV immunoglobulin (Ig)G status of the donor and recipient at the time of liver transplantation. Donors and recipients were classified preoperatively into groups according to the presence or absence of CMV as follows: group 1 (n = 73; donor CMV+, recipient CMV+); group 2 (n = 41; donor CMV-, recipient CMV+); group 3 (n = 54; donor CMV+, recipient CMV-; high-risk group); and group 4 (n = 35; donor CMV-, recipient CMV-).
Twenty-nine patients (14.3%) developed symptomatic CMV disease at 169 +/- 117 days after liver transplantation: group 1, 16.4% versus group 2, 7.3% versus group 3, 25.9% versus group 4, 0%. Of these patients, 5 also had invasive CMV on liver biopsy, which was performed owing to abnormal liver functions. All 29 patients were treated with intravenous ganciclovir. One patient died owing to disseminated CMV, whereas the remaining 28 patients responded to treatment. Interestingly, 8 patients, including 1 who had invasive CMV hepatitis, developed symptomatic CMV within 90 days of liver transplantation even while on prophylactic valganciclovir.
Valganciclovir failed to provide adequate prophylaxis following liver transplantation in our patients. The overall rate of CMV in seropositive donors and/or recipients was 17%, and in the high-risk group was 26%. Further prospective studies with measurement of ganciclovir concentrations are needed to elucidate the reasons for this unexpected failure.
Transplantation Proceedings 10/2005; 37(7):3182-6. · 1.00 Impact Factor
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ABSTRACT: Older donor allografts are being accepted for liver transplantation (LTx) due to shortage of organs. Hepatitis C virus (HCV) infection-related disease is presently the most common indication of LT in the United States. We studied the impact of donor age on patient and graft survivals in patients with HCV infection.
One hundred fifty four consecutive HCV(+) LTx recipients (117 men, 37 women) were studied. The mean follow-up period was 41.0 +/- 30.2 months. The population was divided into four groups according to donor age: group I (< or =20 years); group II (21 to 40 years); group III (41 to 60 years); group IV (>60 years).
Thirty-two (20.8%) patients died during follow-up and 16 patients (10.4%) required retransplantation. The actuarial 7-year patient survivals for groups I, II, III, and IV were 87.1%, 73.7%, 69.3%, and 68.5%, respectively (P = .4). Patient survivals for donor age groups III + IV (n = 95) and groups I + II (n = 59) were 68.9% and 77.2%, respectively (P = .19). The 7-year graft survivals for groups I, II, III, and IV were 82.7%, 71.8%, 65.8%, and 62.5%, respectively (P = .17). Graft survivals for groups III + IV and groups I + II were 58.4% and 76.2%, respectively (P = .03).
Patient and graft survivals for HCV-positive liver transplant recipients in this study decreased progressively as the donor age increased. Patient and graft survivals were best for group I recipients. There were significant differences in graft survivals when recipients were grouped with a cutoff donor age of 40 years.
Transplantation Proceedings 09/2005; 37(7):3162-4. · 1.00 Impact Factor
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ABSTRACT: Right-lobe living donor liver transplantation has emerged as an alternative to cadaveric transplantation. An appreciation of the unique anatomy and behavior of the right lobe has emerged and has precipitated technical modifications. Living donors underwent right lobectomy, including preservation of significant inferior hepatic veins. The parenchyma was divided following a plane approximating the right border of the posterior two thirds of the midhepatic vein (MHV), but deviating anteriorly to include the distal one third of the MHV with the graft. Large venous tributaries from segment VIII were preserved. Anastomosis in the recipient was accomplished by means of complete cavoplasty. Significant inferior veins, tributaries to the MHV, and the distal portion of the MHV were reconstructed when technically possible. Forty-eight right-lobe resections and transplantations were performed in the manner described. There were no donor complications attributable to the technique. Forty-six of the 48 recipients are alive, and 44 of the 46 surviving patients have their original graft. Venous tributaries from segment VIII and/or the distal portion of the MHV were reconstructed in only 3 patients. Outflow obstruction was recognized intraoperatively in 2 patients; 1 patient had a caval web excised and the other patient required revision of the main anastomosis. Neither organ was lost. There were no other significant venous complications. The incidence of ascites was the same as that in recipients of whole organs. These methods of parenchymal transection and venous reconstruction resulted in a low rate of complications. The wide anastomosis and collateral pathways between the MHV and right hepatic vein seem to be more critical than reconstruction of tributaries from segment VIII or the distal MHV.
Liver Transplantation 11/2001; 7(10):845-52. · 3.39 Impact Factor
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ABSTRACT: Double hepatic arterial and portal venous branches are common anatomic variations of the isolated right hepatic lobe. Reconstruction of these vessels during transplantation can be challenging because of their small caliber, close proximity to other hilar structures, and abnormal alignment with the native vasculature. Practical techniques for the creation of these anastomoses would simplify the recipient surgery and might minimize the incidence of vascular complications. Alternative methods for management of these structures are summarized. The recipient's proper hepatic artery and its bifurcation are resected for use as an arterial Y-type graft. The donor arteries are individually anastomosed at the bifurcation of the recipient's hepatic artery at the back table. The free end of the Y graft is then replaced at the origin of the gastroduodenal artery using standard branch-patch technique. Reconstruction of a second donor portal branch is similarly facilitated by ex situ placement of a Y-type vascular conduit derived from the recipient's portal vein. Surgical management of these vessels and reconstruction of other hilar structures are noticeably less cumbersome. There have been no short-term vascular complications. The use of autologous vascular conduits with ex situ reconstruction facilitates management of double donor arterial and portal venous branches. The incidence of complications attributable to these methods is expected to be low.
Liver Transplantation 09/2001; 7(8):673-9. · 3.39 Impact Factor
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Transplantation 06/1998; 65(12):S128. · 4.00 Impact Factor
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ABSTRACT: Lung cancer demonstrates a strong etiologic association with smoking. Of the two most common histologic lung cancer types, small cell carcinoma (SCLC) is found almost exclusively in smokers, whereas peripheral adenocarcinoma (PAC) also develops in a significant number of nonsmokers. N'-Nitrosonornicotine (NNN) and 4(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), nicotine-derived nitrosamines, are potent lung carcinogens contained in tobacco products. Because of the structural similarity of NNN and NNK with nicotine, we hypothesized that these carcinogens are ligands for nicotinic acetylcholine receptors (nAChRs). Using cell lines derived from human small cell lung carcinoma and pulmonary adenocarcinoma with the site-selective ligands alpha-bungarotoxin (alpha-BTX) and epibatidine (EB) in receptor binding and cell proliferation assays, we found that SCLC expressed neuronal nicotinic receptors with high affinity to alpha-BTX, whereas PAC cells expressed nicotinic receptors with high affinity to EB. NNK bound with high affinity to alpha-BTX-sensitive nAChRs in SCLC cells, while NNN bound with high affinity to EB sensitive nAChRs in PAC cells. The affinity of each nitrosamine to these receptors was several orders of magnitude greater than that of nicotine. NNK stimulated the proliferation of SCLC cells via this mechanism. Our findings suggest that NNK may contribute to the genesis of SCLC in smokers via chronic stimulation of the alpha BTX-sensitive nAChR-subtype expressed in these cells. Both nitrosamines may also contribute to a host of nicotine-related diseases that are currently thought to be caused by the chronic interaction of nicotine with nAChRs expressed in a large spectrum of mammalian cells.
Biochemical Pharmacology 06/1998; 55(9):1377-84. · 4.70 Impact Factor
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ABSTRACT: We evaluated the relation of vesicoureteral reflux, pretransplant nephrectomy, and prior ureteral reimplant with respect to posttransplant urinary tract infection and graft survival.
From 1984 to 1995, 820 renal transplants were performed. Thirty-six (4%) patients had documented vesicoureteral reflux. The patients were divided into three groups: Group I, N = 10 (28%) underwent ureteral reimplantation prior to transplantation; Group II, N = 8 (22%) had bilateral nephrectomy prior to transplantation; and Group III, N = 18 (50%) had persistent reflux at the time of transplantation.
Graft survival at 3 years was 50% (18/36). Patient survival was 94% (34/36). The overall incidence of urinary tract infection was 56% (20/36). Complicated urinary tract infection was seen in 28% (10/36) and uncomplicated urinary tract infection in 47% (17/36) of the patients. The incidence of both complicated and uncomplicated urinary tract infection was lower in Group I. However, graft survival was lower in Group I patients. Overall graft survival was significantly lower in patients with vesicoureteral reflux compared with the rest of the group.
The incidence of urinary tract infection did not appear to be altered significantly whether the patients had bilateral nephrectomy or persistent vesicoureteral reflux. However, those patients who had ureteral reimplantation had fewer episodes of infection. Nephrectomy prior to transplantation should be performed selectively.
Urology 06/1998; 51(5A Suppl):27-30. · 2.43 Impact Factor
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ABSTRACT: Tolerance for organ allografts would eliminate acute and chronic rejection as well as the need for nonspecific immunosuppression. A potential hazard of tolerance is the susceptibility to graft vs host disease (GVHD) due to unresponsiveness to alloantigen. This study sought to determine if our model of tolerance induction results in susceptibility to GVHD. Chimeras were created by transplantation of T-cell depleted ACI and Lewis bone marrow into lethally irradiated Lewis rats. Chimerism was determined post-BMTx by flow cytometric analysis of recipient spleens for the presence of ACI cells. ACI/Lew chimeras (ALC), animals that reconstituted only with syngeneic (Lewis) marrow (so-called failed chimeras), and ACI/Lew F1 (LACF1) hybrid rats were all given 200 x 10(6) ACI splenocytes i.v. Animals were examined for evidence of GVHD. GVHD was quantified using the popliteal lymph node enlargement assay. All LACF1 (n = 6) rats developed severe lethal GVHD following ACI splenocyte injection. Similarly, ALC (n = 6) developed fatal GVHD. Animals that reconstituted only with syngeneic Lewis marrow (failed chimeras) showed no signs of illness. GVHD was confirmed histologically and immunohistochemically. Failed chimeras receiving ACI splenocyte challenge showed no evidence of GVHD histologically. Popliteal lymph node enlargement indices reflected the presence of GVHD in the chimeras and hybrids but not in the failed chimeras. We conclude that tolerance induction by mixed chimerism results in susceptibility to GVHD if enough donor lymphoid tissue is given to the host at the time of organ transplant. Animals that are not mixed chimeras (failed bone marrow transplant) rejected the allogeneic splenocytes as evidenced by their lack of disease. Tolerance may therefore make the host defenseless against fatal GVHD.
Journal of Surgical Research 06/1997; 69(2):307-15. · 2.25 Impact Factor
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ABSTRACT: We have shown that the nicotine-derived nitrosamine 4-(methyl-nitrosamino)-3-(pyridyl)-1-butanone (NNK) causes a high incidence of neuroendocrine lung tumors in male Syrian golden hamsters when administered to animals maintained in an atmosphere of 60% hyperoxia. In vitro studies with fetal hamster pulmonary neuroendocrine cells (PNE cells) and human neuroendocrine lung cancer cell lines revealed that nicotine and NNK are both potent mitogens for normal and neoplastic PNE cells when the cells were maintained in an atmosphere of high CO2. These effects were completely inhibited by antagonists of nicotinic acetylcholine receptors (nAChR). NNK displaced 3H-(-)L-nicotine from the nAchR in radioreceptor assays with cell membrane fractions from hamster lungs enriched in PNE cells. We therefore hypothesized that NNK acts as an agonist of the nAchR in PNE cells and that stimulation of this receptor in an environment of impaired pulmonary oxygenation is an important molecular event leading to the development of lung tumors with a neuroendocrine phenotype.
To test this hypothesis, we exposed male Syrian golden hamsters maintained in 60% hyperoxia to s.c. injections of nicotine for the duration of their life. To allow for a survival time long enough to assess a potential carcinogenic effect of this treatment, animals demonstrating symptoms of respiratory distress were returned to ambient air for 24 hours throughout the experiment.
A low but significant number of the animals exposed to hyperoxia and nicotine developed tumors of the nasal cavity, lungs, and adrenal glands. All of the tumor-bearing animals had survived 40 weeks or longer. The lung tumors demonstrated focal areas of positive immunoreactivity to neuron-specific enolase (NSE) and 5-hydroxy-tryptamine (5-HT, serotonin), both of which are markers of neuroendocrine differentiation. Hamsters maintained in ambient air and receiving identical injections with nicotine as well as animals maintained in hyperoxia and injected with saline did not develop tumors in any organs. All hamsters exposed to hyperoxia and surviving more than 12 weeks had thickened alveolar walls and emphysema.
Our data support the hypothesis that chronic stimulation of the nAChR in an environment of impaired pulmonary oxygenation contributes to the carcinogenic burden associated with exposure to cigarette smoke and provides selective growth advantage for lung tumors with a neuroendocrine phenotype.
Laboratory Investigation 10/1995; 73(3):448-56. · 3.64 Impact Factor
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ABSTRACT: Peripheral adenocarcinoma (PAC) of the lung has increased dramatically over the last 20 years and is today the leading histological type of lung cancer in smokers and nonsmokers in industrialized countries. There is no apparent explanation for the steep rise in the number of individuals developing this cancer type. Using assays for the assessment of cell proliferation, receptor binding, and production of cyclic AMP (cAMP), we have identified a beta-adrenergic receptor-mediated mitogenic pathway, which activates cAMP down-stream, in cell lines derived from human peripheral adenocarcinomas that express features of Clara cells. Agonists of beta-adrenergic receptors strongly stimulated cell proliferation, whereas antagonists of this receptor and its associated second messenger, cAMP, were potent inhibitors of this effect. Agonists of beta-adrenergic receptors are the active ingredients of many decongestants and bronchodilators, and such medications are, therefore, likely to stimulate this pathway in vivo. Patients suffering from chronic upper and lower respiratory tract diseases and treated with such medications over many years may, therefore, be at a higher risk than the average population to develop PAC, particularly when simultaneously exposed to carcinogenic environmental factors such as smoking. Because the incidence of chronic respiratory tract diseases has risen in industrialized countries during the same time frame as PAC, a potential etiological link between the therapy of such nonneoplastic diseases with beta-adrenergic agonists and the risk for PAC should be investigated.
Cancer Research 09/1995; 55(16):3504-8. · 7.86 Impact Factor
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ABSTRACT: The dihydropyridine Dexniguldipine (B859-35) has been shown to inhibit calmodulin and protein kinase C in vitro, and has a significant therapeutic effect on induced neuroendocrine lung tumours in hamsters. As phase I clinical trials with this agent resulted in the development of stable disease in several patients with non-small-cell cancers and preliminary in vitro studies revealed several non-small-cell cancer cell lines susceptible to the antiproliferative effects of dexniguldipine, the possibility was investigated that this agent may inhibit cell proliferation stimulated by epidermal growth factor (EGF), which is expressed in many non-small-cell cancer types. Experiments conducted with six human lung cancer cell lines showed that dexniguldipine is a potent inhibitor of EGF-stimulated cell proliferation. This agent may therefore also be useful for the therapy of cancers that express the EGF receptor.
Toxicology in Vitro 06/1994; 8(3):455-9. · 2.78 Impact Factor
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ABSTRACT: The dihydropyridine, dexniguldipine hydrochloride (B859-35), has shown therapeutic activity in experimentally induced neuroendocrine hamster lung tumors and demonstrated antiproliferative effects in a mammary cancer cell line via inhibition of Ca2+ calmodulin. Studies in NIH 3T3 fibroblasts have provided evidence that dexniguldipine may also inhibit protein kinase C (PKC). In this study, we have tested the hypothesis that dexniguldipine may inhibit the proliferation of lung cancer cells in response to autocrine or exogenous activation of PKC. Using a panel of human lung cancer cell lines, we show that dexniguldipine is a potent inhibitor of mitogenic signal transduction pathways dependent on PKC activation in several small-cell and non-small-cell lung cancer cell lines while it failed to inhibit cyclic-AMP-dependent cell proliferation.
Journal of Cancer Research and Clinical Oncology 02/1994; 120(6):354-8. · 2.56 Impact Factor
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ABSTRACT: We have recently demonstrated that the dihydropyridine-derivative B859-35 has a selective chemotherapeutic effect on experimentally induced neuroendocrine lung tumors in hamsters. These tumors resembled human atypical lung carcinoids morphologically and expressed mammalian bombesin, calcitonin and neuron-specific enolase. In the hamster model, B859-35 had no antiproliferative effect on pulmonary adenomas of Clara cell origin. In this study, we have tested the antiproliferative effects of B859-35 and of the Ca(2+)-channel blocker Verapamil in vitro on three human lung cancer cell lines. The neuroendocrine cell line NCI-H727 is derived from a lung carcinoid and expresses mammalian bombesin and calcitonin. Two non-neuroendocrine cell lines are derived from peripheral pulmonary adenocarcinomas, with line NCI-H322 expressing features of Clara cells while line NCI-H358 expresses features of alveolar type II cells. B859-35 was a potent antiproliferative agent in the neuroendocrine line NCI-H727 at concentrations as low as 0.001 pM, while it inhibited cell proliferation in the two other cell lines at concentrations of 100 nM and above. Verapamil inhibited cell proliferation in the neuroendocrine line NCI-H727 at concentrations of 1 nM and above.
Carcinogenesis 01/1992; 12(12):2301-3. · 5.70 Impact Factor
