Human ovarian cancer and cisplatin resistance: possible role of inhibitor of apoptosis proteins.

The inhibitor of apoptosis proteins (IAPs) constitutes a family of highly conserved apoptosis suppressor proteins that were originally identified in baculoviruses. Although IAP homologs have recently been demonstrated to suppress apoptosis in mammalian cells, their expression and role in human ovarian epithelial cancer and chemotherapy resistance are unknown. In the present study we used cisplatin-sensitive and -resistant human ovarian surface epithelial (hOSE) cancer cell lines and adenoviral antisense and sense complementary DNA expression to examine the role of IAP in the regulation of apoptosis in human ovarian cancer cells and chemoresistance. Antisense down-regulation of X-linked inhibitor of apoptosis protein (Xiap), but not human inhibitor of apoptosis protein-2 (Hiap-2), induced apoptosis in cisplatin-sensitive and, to a lesser extent, in -resistant cells. Cisplatin consistently decreased Xiap content and induced apoptosis in the cisplatin-sensitive, but not cisplatin-resistant, cells. Hiap-2 expression was either unaffected or inhibited to a lesser extent. The inhibition of IAP protein expression and induction of apoptosis by cisplatin was time and concentration dependent. Infection of cisplatin-sensitive cells with adenoviral sense Xiap complementary DNA resulted in overexpression of Xiap and markedly attenuated the ability of cisplatin to induce apoptosis. Immunohistochemical localization of the IAPs in hOSE tumors demonstrated the presence of Xiap and Hiap-2, with their levels being highest in proliferative, but not apoptotic, epithelial cells. These studies indicate that Xiap is an important element in the control of ovarian tumor growth and may be a point of regulation for cisplatin in the induction of apoptosis. These results suggest that the ability of cisplatin to down-regulate Xiap content may be an important determinant of chemosensitivity in hOSE cancer.

Apoptosis and chemoresistance in human ovarian cancer: is Xiap a determinant?

Cisplatin-induced apoptosis in epithelial ovarian cancer cells is in part a consequence of suppressed Xiap expression and upregulation of the Fas/FasL system. Changes in the expression of these 'cell death' and 'cell survival' genes lead to activation of caspase-3, and cleavage of MDM2 and FAK. Failure of cancer cells to maintain a balance in the expression of these genes in favor of apoptotic cell death may be an important factor of chemoresistance. Xiap may be a novel target for gene therapy of human ovarian epithelial cancer and, dependent on P53 status, expression of Xiap antisense alone or in combination with wild-type P53 sense may offer a new approach for the treatment of the chemoresistant cancer.

Sustained suppression of Fas ligand expression in cisplatin-resistant human ovarian surface epithelial cancer cells.

Although cisplatin derivatives are first line chemotherapeutic agents for the treatment of ovarian epithelial cancer, chemoresistance is a major therapeutic problem. Although the cytotoxic effect of these agents are believed to be mediated through the induction of apoptosis, the role of the Fas/FasL system in chemoresistance in human ovarian epithelial cancer is not fully understood. In the present study, we have used cultures of established cell lines of cisplatin-sensitive human ovarian epithelial tumours (OV2008 and A2780-s) and their resistant variants (C13* adn A2780-cp, respectively) to asses the role of Fas/FasL system in the chemo-responsiveness of ovarian cancer cell to cisplatin. Cisplatin was effective in inducing the expression of cell-associated Fas and FasL, soluble FasL and apoptosis in concentration and time-dependent fashion in both cisplatin-sensitive cell lines (OV2008 and A2780-s). In contrast, while cisplatin was effective in increasing cell-associated Fas protein content in C13*, it failed to up-regulate FasL (cell-associated and soluble forms) and induce apoptosis, irrespective of concentration and duration of cisplatin treatment. Concentrated spent media for OV208 cultures after cisplatin treatment were effective in inducing apoptosis in C13* cells which was partly inhibited by the antagonistic Fas monoclonal antibody (mAb) suggesting that the soluble FasL present in the spent media was biologically active. In the resistant A2780-cp cells, neither Fas nor FasL upregulation were evident in the presence of the chemotherapeutic agent and apoptosis remained low compared to its sensitive counterpart. Activation of the Fas signalling pathway, by addition to the cultures an agonistic Fas mAb, was equally effective in inducing apoptosis in the cisplatin-sensitive (OV2008) and -resistant variant C13*, although these responses were of lower magnitude compared to that observed with cisplatin in the chemosensitive cells. A significant interaction between cisplatin and agonistic Fas mAb was observed in the apoptotic response in OV2008 and C13* when cultured in the presence of both agents. Immunohistochemistry of human ovarian epithelial carcinomas reveals the presence of Fas in low abundance in proliferatively active cells but in high levels in quiescent ones. Although the expression pattern of FasL in the tumour was similar to tha tof Fas, the protein content was considerably lower. Taken together, these data suggest that the dysregulation of the Fas/FasL system may be an important determinant in cisplatin-resistance in ovarian epithelial cancer cells. Our results are also supportive of the notion that combined immuno- and chemo-therapy (i.e., agonistic Fas mAb plus cisplatin) may provide added benefits in the treatment of both chemo-sensitive and -resistant ovarian tumours.

Hepatobiliary abnormalities of AIDS.

Liver disease, although usually asymptomatic, is a frequent accompaniment of AIDS. Hepatomegaly and macrosteatosis are prevalent but non-specific findings. Evidence of remote hepatitis B virus infection is extremely common; however, the HBsAg carrier state, chronic active hepatitis, or cirrhosis occur no more frequently in AIDS patients than in the general population. Opportunistic intrahepatic infections (such as MAI, fungi, and CMV) or neoplasms (such as lymphoma or KS) usually reflect a disseminated process; liver involvement generally does not directly cause morbidity or result in death. Although biochemical liver tests are commonly elevated in the AIDS population, alkaline phosphatase has proved to be the most specific enzyme for infiltrative processes. Percutaneous liver biopsy has a high diagnostic yield, although the treatment options are currently limited. Acalculous cholecystitis and biliary tract obstruction have been recently described and probably result from CMV and/or cryptosporidial infection. Radiologic features of papillary stenosis and/or sclerosing cholangitis have been demonstrated. In contrast to hepatic parenchymal disease, these entities may be amenable to surgical or endoscopic therapeutic maneuvers.

Hepatic disease in patients with the acquired immune deficiency syndrome (AIDS).

The spectrum of liver disease in patients with acquired immune deficiency syndrome (AIDS) and the clinical impact of diagnostic percutaneous liver biopsy in this population were evaluated by a retrospective review of hepatic histology, clinical features and laboratory data in 85 patients (26 biopsies, 59 autopsies). Only 1 (3.8%) biopsy and 9 (15%) postmortem livers were histologically normal. Macrosteatosis and nonspecific portal inflammation were the most common histologic abnormalities. Intrahepatic AIDS-specific opportunistic infections or malignancies were detected in 42% of both biopsy and autopsy groups, with Mycobacterium avium-intracellulare the most frequent pathogen seen. Kaposi's sarcoma, although not detected on biopsy, was the most common postmortem AIDS-related hepatic finding. Intrahepatic lymphoma, cytomegalovirus hepatitis and hepatic mycoses were less frequently observed. In general, hepatic involvement represented part of a previously diagnosed, widely disseminated disease process, and liver biopsy led to new AIDS-specific diagnoses in only two patients. We conclude that while liver biopsy is a useful diagnostic tool in selected patients with AIDS, the information provided by biopsy rarely influences therapy or leads to improved survival.

Papillary stenosis and sclerosing cholangitis in the acquired immunodeficiency syndrome.

Eight homosexual men with the acquired immunodeficiency syndrome (AIDS) presented with clinical, biochemical, and radiologic features of stenosis of the papilla of Vater and sclerosing cholangitis. This newly recognized complication of AIDS produces abdominal pain, nausea, and vomiting and may predispose patients to superimposed bacterial cholangitis. Marked elevation of serum alkaline phosphatase levels and lesser changes in hepatic aminotransferase levels are common. Although abdominal ultrasonography and computed tomography detect ductal abnormalities, endoscopic retrograde cholangiography best shows precise ductal irregularities and provides therapeutic intervention. Prompt relief of symptoms follows endoscopic sphincterotomy, often with resolution of biochemical evidence of cholestasis. Biliary tract infection with cytomegalovirus or cryptosporidia and resultant viral or coccidial cholangitis are the proposed pathophysiologic mechanisms.

Intestinal ischemia and infarction associated with oral contraceptives.

PIP: The authors analyze 41 cases of temporary intestinal ischemia (15) or frank infarction (26) reported in the literature among oral contraceptive users. Like women with other thromboembolic diseases, duration of pill use was not a factor: these women had been taking orals for 10 days to 10 years, mean 2.2 years. Reversible ischemia resolved in days or weeks after discontinuing oral contraceptives, with supportive treatment. The best diagnostic tool was barium contrast radiogaphy. Neither arteriography or colonoscopy were helpful. Lesions were continuous, narrow, spastic, often with "thumbprinting", sometimes with proximal dilation. Intestinal infarction, usually determined at laparotomy, was fatal in 31%. Resection was necessary for gangrenous, pale or edematous small or large intestine or both. Most often the superior mesenteric artery or vein were involved. 42% needed a second laparotomty. Only 2 women developed ischemia or necrosis after oral contraceptives had been discontinued: both had documented arterial occlusion in all 3 major vascular trunks. The physiological cause of oral contraceptive-related ischemia or infarction is controversial. Several mechanisms including blood clotting factors, lipoproteins, platelet activity are reviewed. The evidence for the pill being involved in these cases is the young age and lack of preexisting risk factors, and especially resolution of the condition on stopping the pill, in the affected women.^ieng