Effect of carbon dioxide on human ovarian carcinoma cell growth.

OBJECTIVE: Laparoscopy may be associated with increased risk of ovarian carcinoma wound metastases. This study was designed to determine whether carbon dioxide exposure increases the growth of human ovarian cancer cells in vitro. STUDY DESIGN: Immortalized ovarian epithelial carcinoma cell (SKOV-3 cell line) cultures were exposed to carbon dioxide, nitrous oxide, or culture media with decreased pH for up to 3 hours. Cell growth was determined with the use of a spectrophotometric assay, and the results were compared with control cells by paired t tests and linear regressions analysis. RESULTS: Carbon dioxide exposure increased SKOV-3 cell growth by 52% after 4 days in culture. The increased cell growth had a linear relationship to the length of carbon dioxide exposure. Cells that were exposed to either nitrous oxide or media with pH 6.3 showed a trend toward decreased growth. CONCLUSION: Carbon dioxide exposure increases the in vitro growth of human ovarian carcinoma cells by an effect that is independent of the carbon dioxide-related decrease in the culture media pH.

Cervical primitive neuroectodermal tumor.

BACKGROUND: Primitive neuroectodermal tumors (PNETs) are rare and potentially aggressive malignancies. CASE: A 24-year-old woman in her eighth week of pregnancy presented with a cervical mass. Tissue biopsy demonstrated poorly differentiated carcinosarcoma with neuroendocrine features. Immunohistochemical studies confirmed the diagnosis of PNET. Treatment included alternating courses of cyclophosphamide, adriamycin, vincristine (CAV) and ifosfamide, etoposide (IE). A radical hysterectomy with bilateral ovarian transposition and periaortic lymphadenectomy was performed with postoperative chemotherapy and radiotherapy. The patient remains disease free 2 years from therapy. CONCLUSION: This is a rare case of cervical PNET occurring in a pregnant patient. A review of the literature indicates that cervical PNET is distinguishable from uterine PNET. This tumor affects younger women and may have a different histogenesis. Pregnancy should not delay diagnosis of this potentially aggressive tumor.

Expression and subcellular localization of the cyclin-dependent kinase inhibitor p27(Kip1) in epithelial ovarian cancer.

OBJECTIVE: To determine if p27(Kip1) expression was altered in epithelial ovarian cancers as compared to normal ovarian surface epithelial (NOSE) cells and to determine if subcellular localization of p27(Kip1) was an important feature. METHODS: Thirteen tumor samples (1 Stage IC [early] and 12 Stage III/IV [advanced]) from patients with epithelial ovarian cancer and five NOSE samples were evaluated. Samples were surgically dissected to obtain an enriched population (90%) of cancer cells. The level of p27(Kip1) protein expression was determined by Western blot analysis. Actin was used as a loading control, and results were quantified by scanning densitometry using the ratio of the p27(Kip1) signal to the actin signal for comparison. To evaluate the subcellular localization of p27(Kip1), immunocytochemical staining was performed. Clinical pathological parameters were correlated to nuclear p27(Kip1) staining to establish if any association existed. RESULTS: When comparing the expression of p27(Kip1) between NOSE and ovarian cancer samples, only 2 of 13 ovarian cancer samples had altered p27(Kip1) expression. No correlation was found between the expression level of p27(Kip1) on Western blot and clinical pathological correlates. While no correlation between expression level of p27(Kip1) and subcellular localization was found, decreased nuclear staining (1+) was associated with shorter survivals using the log-rank test (P < 0.001). More importantly, in all tumor samples examined under the microscope, no nuclear p27(Kip1) staining was noted in cells that were undergoing mitosis. CONCLUSIONS: p27(Kip1) protein degradation may not be modified in ovarian cancer cells undergoing mitosis. Altered expression of p27(Kip1) is not an overwhelming feature in certain epithelial ovarian cancers. Decreased nuclear staining of p27(Kip1) is associated with poor survival in some epithelial ovarian cancers.

DNA methylation and ovarian cancer. I. Analysis of CpG island hypermethylation in human ovarian cancer using differential methylation hybridization.

OBJECTIVE: The aim of this study was to examine CpG island methylation patterns in ovarian cancer and determine whether epigenetic information can be related to clinical data of patients. CpG island (CpGI) hypermethylation is commonly associated with cancer progression, but little is currently known about the role of methylation in ovarian cancer. METHODS: Differential methylation hybridization (DMH) analysis at 742 loci was performed to determine methylation signatures for 20 primary epithelial ovarian carcinomas (Stages II, III, and IV adenocarcinomas, serous papillary), 6 ovarian cancer cell lines, and normal ovarian surface epithelial cells. RESULTS: Between 23 and 108 methylated CpGIs were seen in the ovarian carcinomas. Fewer (P < 0.05) methylated CpGIs were observed in the ovarian cancer cell lines; however, a number of CpGIs were commonly hypermethylated in both the cell lines and the tumor samples. A methylation signature, consisting of frequently (P < 0.05) methylated CpGIs, was determined for the samples. The observed pattern of methylation in ovarian cancers included several (11) CpGI tags that were previously reported to be hypermethylated in human breast cancer. CONCLUSIONS: Epigenetic signatures in ovarian cancer were determined using DMH. This proof-of-concept study lays the foundation for genome-wide screening of methylation to examine epigenotype-phenotype relationships in ovarian cancer.

DNA methylation in ovarian cancer. II. Expression of DNA methyltransferases in ovarian cancer cell lines and normal ovarian epithelial cells.

OBJECTIVE: The aim of this study was to investigate whether expression of the enzymes that catalyze cytosine CpG island methylation, DNA methyltransferases, DNMT1, DNMT3a, and DNMT3b is altered in human ovarian cancer. Aberrations in DNA methylation are common in cancer and have important roles in tumor initiation and progression. Tumors that display frequent and concurrent inactivation of multiple genes by methylation are designated as having a CpG Island methylator phenotype, or CIMP. To date, colon, gastric, and most recently ovarian cancers meet the CIMP criteria for cancer. We hypothesized that altered expression of DNA methyltransferases can result in hypermethylation events seen in CIMP cancers. METHODS: DNMT1, DNMT3a, and DNMT3b mRNA levels in eight ovarian cancer cells lines (Hey, HeyA8, HeyC2, OVCAR-3, SK-OV-3, PA-1, A2780, and A2780-P5) were compared to DNMT expression in normal ovarian surface epithelial cells using semi-quantitative reverse transcription-polymerase chain reaction. RESULTS: In HeyA8 and HeyC2 ovarian cancer cells, DNMT1 expression levels were up to threefold higher (P < 0.05) than in normal ovarian surface epithelial cells. SK-OV-3 and PA-1 displayed increased DNMT3b expression (P < 0.05) compared to normal ovarian surface epithelial cells. Transcript levels for DNMT3a, however, were similar in cancer and normal ovarian cells. CONCLUSIONS: We observed differential expression of the DNMT genes in some ovarian cancer cell lines and conclude that alterations in DNMT expression might contribute to the CIMP phenotype in ovarian cancer. However, based on the lack of aberrant DNMT expression in some of the cancer cell lines examined, we further suggest that another mechanism(s), in addition to DNMT overexpression, accounts for methylation anomalies commonly observed in ovarian cancer.

Evaluation of recombinant human interleukin-12 in patients with recurrent or refractory ovarian cancer: a gynecologic oncology group study.

Objective. The goal of this study was to estimate the antitumor activity and toxicity of recombinant human interleukin-12 (rhIL-12) in patients with recurrent or refractory epithelial ovarian cancer. Methods. From December 1997 to March 1999, patients with recurrent or refractory epithelial ovarian cancer were entered on a Gynecologic Oncology Group phase II study of intravenous rhIL-12. All patients had measurable disease, had a performance status of 0-2, and had failed first-line platinum-based chemotherapy regimen. Eligible patients received rhIL-12, 250 ng/kg IV bolus, as a single dose on Day 1 followed by a 2-week rest period, with subsequent cycles administered daily for 5 days followed by a 16-day rest period per cycle, until disease progression or adverse effects prohibited further therapy. Results. Twenty-eight patients were entered and evaluable for toxicity, while 26 were evaluable for response. The median age was 59.5 years (range: 45-77). The median number of cycles was 2 (range: 1-9). There were no complete responders; however, one patient (3.8%) was a partial responder and 13 patients (50%) had stable disease. Grade 4 myelotoxicity occurred in 21% of patients. Two patients experienced capillary leak syndrome: one grade 2 and one grade 4. Conclusion. As a single agent, rhIL-12 is tolerable and shows a low response rate in recurrent epithelial cancer with measurable disease.

A phase II trial of pyrazoloacridine (PZA) in squamous carcinoma of the cervix--a Gynecologic Oncology Group Study.

PURPOSE: The Gynecologic Oncology Group performed a Phase II study to determine the response rate of Pyrazoloacridine (PZA) in patients with advanced, persistent or recurrent squamous carcinoma of the cervix. METHODS: PZA was administered at a dose of 750 mg/m2 intravenously over three hours every three weeks. RESULTS: Among 21 evaluable patients, there were no complete and one (4.2%) partial response. The major toxicities were hematologic. CONCLUSION: PZA at the dose and schedule employed has insignificant activity in this population.

Location of the ureters in relation to the uterine cervix by computed tomography.

OBJECTIVE: Our aim was to determine the distance of the ureter from the cervix and the influence of age and weight on this distance. STUDY DESIGN: The distance of the ureter from the uterine cervix was determined by evaluating the computed pelvic tomograms from 52 women. Age and body mass index were compared to this distance by means of regression analysis. RESULTS: At the most dorsal reflection of the ureter, the average distance from ureter to cervical margin was 2.3 +/- 0.8 cm (range, 0.1-5.3 cm). There was no relationship to age, but there was a linear relationship between this distance and body mass index (R2 = 0.075; P = .049); thus the ureter was slightly more proximal to the cervical margin in heavier women. CONCLUSIONS: In women with apparently normal pelvic anatomy, the average distance between the ureter and cervix is >2 cm. The finding that this distance is <0.5 cm in 12% of the women studied may explain the relatively common occurrence of ureteral injury during hysterectomy. The relationship between body mass index and location is clinically insignificant.

Trisomy 21 associated with ovarian dysgerminoma.

A 13-year-old G(0)P(0) white female with trisomy 21 presented with a complex pelvic mass. She underwent resection of the mass and complete staging for what was found to be a stage IIIC completely resected dysgerminoma. She was treated with three cycles of bleomycin, etoposide, and cisplatin chemotherapy and remains free of disease 1 year later. This association is presented as a rare case that may illustrate the relative increase in germ cell neoplasms in female patients with Down's syndrome. While the association of seminoma with Down's syndrome has been documented in a number of cases in males, the female counterpart of this tumor, dysgerminoma, in trisomy 21 has been reported quite infrequently. The potential for germ cell tumors in both male and female trisomy 21 is therefore illustrated.

Transforming growth factor-beta differentially inhibits epithelial ovarian carcinoma cells from primary and metastatic isolates without up-regulation of p21WAF1.

BACKGROUND: Transforming growth factor-beta (TGF-beta) is known to inhibit primary epithelial ovarian carcinoma cells. The mechanism by which this inhibitory response is achieved is poorly understood. Furthermore, whether this response is consistent in cells from metastatic sites compared with the primary site cells is unknown. The authors wanted to determine whether TGF-beta differentially inhibited ovarian carcinoma cells from primary tumor sites compared with metastatic sites and to establish whether this response was associated with up-regulation of p21WAF1 or overexpression of p53. METHODS: Tumor cells were purified from primary and metastatic sites in five patients with advanced epithelial ovarian carcinoma. TGF-beta effect at concentrations of 10, 1, and 0.1 ng/mL was determined by tritiated thymidine incorporation assay. Expression of p21WAF1 was determined by Northern and slot blot analysis. p53 was detected by immunocytochemistry. RESULTS: Metastatic tumor isolates were more responsive to the inhibitory effect of TGF-beta compared with their corresponding primary tumor isolates at 0.1 ng/mL. Increasing TGF-beta concentration conferred no additional inhibitory effect on the metastatic isolates; however, a dose-related phenomenon was observed in primary tumor isolates. p21WAF1 mRNA was up-regulated in only 2 of 10 primary and metastatic isolates. There was no correlation between TGF-beta responsiveness, p21WAF1 up-regulation, and p53 overexpression. CONCLUSIONS: Differential inhibition was observed between primary and metastatic tumor isolates. p21WAF1 up-regulation and p53 overexpression were not major modulators in TGF-beta regulation of primary and metastatic tumor growth in early passaged ovarian carcinoma cells.

Bleomycin, etoposide, and cisplatin combination therapy of ovarian granulosa cell tumors and other stromal malignancies: A Gynecologic Oncology Group study.

OBJECTIVES: The objectives of this study were to assess efficacy and toxicity of the combination of bleomycin, etoposide, and cisplatin (BEP) in this Phase II trial as first-line therapy for ovarian stromal malignancies. METHODS: Patients with incompletely resected Stages II-IV or recurrent cancer underwent surgical debulking. There were two bleomycin-related deaths early in the trial; thus, the initial schedule of bleomycin (20 units/m2 x 9 weeks for a maximum dose of

Location of the transverse colon in relationship to the umbilicus: implications for laparoscopic techniques.

STUDY OBJECTIVE: To establish the location of the transverse colon in relationship to the umbilicus, and determine if it varies as a function of patient height or weight. DESIGN: Retrospective review of computed tomograms (CT) of the abdomen (Canadian Task Force classification II-2). SETTING: University hospital. PATIENTS: Sixty-seven women with normal abdominal anatomy. INTERVENTION: Review of abdominal CT scans. MEASUREMENTS AND MAIN RESULTS: The relative relationships of the transverse colon and umbilicus were compared with age, height, weight, and body mass index (BMI = kg/m2) using multiple regression analysis. Average location of the superior margin of the transverse colon was 4.6 cm (95% CI 3.5-5.7 cm) above the umbilicus. In nine (13%) women it was below the umbilicus. The colon was below the umbilicus in 25% of nonobese women (BMI <25 kg/m2). CONCLUSION: Because the transverse colon lies below the umbilicus in more than 10% of women, injury to it may be an uncommon yet unavoidable complication of laparoscopy.

Gynecologic cancers metastatic to the breast.

BACKGROUND: We report a series of gynecologic cancers metastatic to the breast, illustrating the diagnostic and prognostic implications of this rare event. STUDY DESIGN: By reviewing the gynecologic oncology data base, we identified 10 women with gynecologic cancer metastatic to the breast who were treated at Indiana University School of Medicine between August 1978 and February 1995. Medical records were reviewed for pertinent data concerning the presentation, evaluation, and treatment of the primary gynecologic malignancy and the metastatic breast tumor. RESULTS: The mean patient age was 56.8 years (range, 30-80 years). The most common gynecologic malignancy was ovarian cancer (five patients), followed by cervical cancer (two patients) and cancers of the vagina, endometrium, or peritoneum (one patient each). A palpable solitary breast mass was found in 8 of 10 patients (80%), and the upper outer quadrant of the breast was the most common site of tumor involvement. One woman presented with examination findings resembling inflammatory breast cancer, and one patient presented with multiple firm subcutaneous nodules. Despite further treatment, which in all cases consisted of systemic chemotherapy, 83% of the patients died with a breast metastasis within 1 year of presentation. CONCLUSIONS: Secondary breast malignancy should be suspected in any patient with a breast tumor and a known history of gynecologic cancer. A breast metastasis implies widespread tumor dissemination and a poor prognosis. Radical breast surgery should be avoided.

Evaluation of cisplatin and cyclosporin A in recurrent platinum-resistant ovarian cancer: a phase II study of the gynecologic oncology group.

OBJECTIVE: The objective of this study was to study the effectiveness of cyclosporin A and cisplatin in patients with recurrent epithelial ovarian cancer. METHODS. Twenty-six patients with measurable recurrent epithelial ovarian cancer, considered to be resistant to cisplatin, received cisplatin in combination with cyclosporin A. Patients received 75 mg/m2 cisplatin every 3 weeks and two cyclosporin A injections over 2 h each, 24 h apart, at a dose of 4 mg/kg each. RESULTS: Only a single patient had a complete response, with two experiencing a partial response to cyclosporin A/cisplatin combination. Hematologic toxicity in this study was modest. No patient developed grade 4 renal toxicity. CONCLUSION: These data indicate minimal activity of the combination of cyclosporin A and cisplatin in ovarian cancer patients with recurrent measurable disease previously treated with cisplatin and thought to be resistant to this chemotherapeutic agent.

Complete hydatidiform mole coexisting with a twin live fetus: clinical course.

A 33-year-old G4P0 white female presented for a pregnancy ultrasound at 9 weeks gestation and was found to have a complete hydatidiform mole coexisting with a live twin fetus (CHTF). The beta-hCG level was 600,000 mIU/ml and the chest X ray was negative. The pregnancy was uneventfully terminated by suction curettage and oral contraceptives were prescribed. The initial beta-hCG declined appropriately; however, it subsequently rose. The metastatic workup was negative and the patient was treated with weekly intramuscular methotrexate at 30 mg/m2. The hCG levels declined appropriately and then plateaued. Salvage chemotherapy with intravenous actinomycin D at 1.25 mg/m2 every 14 days was started. The hCG level normalized after 3 cycles and the patient was free of disease at 1 year follow-up.

A prospective controlled trial of early postoperative oral intake following major abdominal gynecologic surgery.

OBJECTIVE: The objective was to determine whether, when compared with traditional dietary advancement, early oral intake following major gynecologic surgery leads to a reduction in the length of hospitalization. METHODS: Patients undergoing major abdominal gynecologic surgery were invited to participate in this study. After informed consent was obtained, they were randomized to one of two groups. The control group (group 1) was treated traditionally. Oral intake was initiated only after documentation of bowel function, which was defined by two of the following three criteria: (1) bowel sounds; (2) flatus or bowel movement; and (3) subjective hunger. Those assigned to the study group (group 2) were given a clear liquid diet on postoperative day 1. Once 500 cc was tolerated, a regular diet was given. Patients were evaluated on a daily basis for bowel sounds, flatus, bowel movement, hunger, nausea, vomiting, and need for nasogastric tube decompression. The groups were compared with regard to length of hospital stay, length of postoperative ileus, and incidence of adverse effects including nausea, vomiting, and postoperative complications. Statistical analyses were performed with the Student t and chi 2 tests. RESULTS: The demographic characteristics of the control (N = 47) and study groups (N = 49) were similar, with no significant differences in underlying medical conditions, prior abdominal surgery, or diagnosis of a malignancy. The groups did not vary statistically in the number of subjects who required postoperative antiemetics or postoperative biscodyl suppository. There was a statistically significant reduction in the length of hospitalization for those patients on the early feeding regimen. The average length of stay for group 1 was 4.02 days +/- 0.30 (SEM), while that for group 2 was 3.12 days +/- 0.16 (P = 0.008). While there was a significantly higher incidence of emesis in the study population, this was not associated with any untoward outcome, and this group actually tolerated a solid diet nearly one full day earlier (2.72 days +/- 0.14 vs 1.88 days +/- 0.14, P < 0.0001). CONCLUSIONS: Early postoperative oral intake results in a decreased length of hospitalization and is well tolerated when compared with traditional dietary management in patients undergoing abdominal surgery on a university gynecologic oncology service.

Soluble interleukin-2 receptor alpha is elevated in sera of patients with benign ovarian neoplasms and epithelial ovarian cancer.

BACKGROUND: Previous studies have established that soluble interleukin-2 receptor alpha (sIL-2R alpha) levels are elevated in ascites and sera from individuals with advanced ovarian cancer (International Federation of Gynecology and Obstetrics [FIGO] Stage III/IV). This study was undertaken to evaluate sIL-2R alpha levels in individuals with benign ovarian neoplasms and early stage ovarian cancer (FIGO Stage I/II). Comparison with CA 125 levels was performed to assess screening potential. METHODS: Sera from 92 healthy individuals, 61 with benign adnexal masses, 12 patients with FIGO Stage I/II ovarian cancers, and 27 patients with FIGO Stage III/IV ovarian cancers were assayed for sIL-2R alpha by enzyme-linked immunosorbent assay and CA 125 by radioimmunoassay. RESULTS: The mean serum sIL-2R alpha levels for benign pelvic masses, and Stage I/II and Stage III/IV epithelial ovarian cancer were 1507 +/- 82, 1631 +/- 274, and 2596 +/- 384 U/ml, respectively. The difference between mean serum sIL-2R alpha levels in individuals with benign adnexal masses and Stage III/IV epithelial ovarian cancer was statistically significant (P < 0.05). In addition, of the four individuals with FIGO Stage I/II ovarian cancer who had CA125 levels below 35 U/ml, the accepted upper limit of normal, three patients had elevated serum sIL-2R alpha levels. Eleven of 12 patients (92%) with potentially curable Stage I/II disease had elevated serum levels of either sIL-2R alpha or CA125 and 8 of 12 (67%) had elevations of both sIL-2R alpha and CA125. Sensitivity and specificity of a combination of CA 125 and soluble IL-2R alpha were 88.5% and 27.1%, respectively. CONCLUSION: Soluble interleukin-2 receptor alpha levels do not appear to differentiate between benign adnexal lesions and early malignancy; however, measurement of sIL-2R alpha levels in combination with CA125 warrants further evaluation to determine if together they will identify individuals with Stages I and II ovarian cancer.

Chemotherapy-induced apoptosis in epithelial ovarian cancers.

OBJECTIVE: To determine whether chemotherapy drugs elicit programmed cell death (apoptosis) in ovarian cancer cells. METHODS: Monolayers of immortalized ovarian cancer cell lines and primary ovarian cancer cells obtained from ascites were grown in the presence of cisplatin, 4-hydroxyperoxy-cyclophosphamide (the active metabolite of cyclophosphamide) or paclitaxel. Next, DNA was extracted from the cells and subjected to electrophoresis to determine if DNA laddering characteristic of apoptosis was present. RESULTS: In three of six immortalized cell lines (OVCA 420, 429, and 433), apoptosis was not seen in response to any of the three drugs. In contrast, in OVCAR-3 and OVCA 432, DNA laddering consistent with apoptosis was observed in response to all three drugs. In the DOV 13 cell line, apoptosis was seen only with 4-hydroxyperoxycyclophosphamide. Among three primary ovarian cancers, cisplatin elicited apoptosis in one case. Both cell lines with mutant p53 genes (OVCAR-3 and OVCA 432) underwent apoptosis in response to all three drugs, whereas among three cell lines known to have normal p53 genes, one underwent apoptosis in response to 4-hydroxyperoxycyclophosphamide and two were unaffected. CONCLUSION: Ovarian cancer cell death in response to commonly used chemotherapeutic drugs involves the induction of a genetically programmed sequence of events (apoptosis) rather than simply necrosis.

Villoglandular adenocarcinoma of the cervix: a case report.

BACKGROUND: Villoglandular adenocarcinoma of the cervix is a rare neoplasm associated with a favorable outcome and has not been described as a complication of pregnancy. CASE: A gravida at 20 weeks' gestation was found to have a bulky stage-IB adenocarcinoma of the cervix. She was delivered at 32 weeks' gestation by cesarean, then a radical hysterectomy and pelvic and periaortic lymphadenectomies were performed. Pathology revealed a deeply invasive, grade 1 villoglandular adenocarcinoma confined to the cervix. The patient remains free of disease at 14 months follow-up. CONCLUSION: Villoglandular adenocarcinoma of the cervix has a favorable prognosis and can be managed conservatively, even when complicated by pregnancy.

Regulation of apoptosis in normal and malignant ovarian epithelial cells by transforming growth factor beta.

Previously, we found that transforming growth factor beta (TGF-beta) inhibits proliferation of normal human ovarian epithelial cells. In addition, although only 1 of 5 immortalized ovarian cancer cell lines was inhibited, TGF-beta inhibited proliferation of 19 of 20 primary epithelial ovarian cancers. In this study, we examined whether TGF-beta induces apoptosis in normal and malignant ovarian epithelial cells. Among 5 immortalized cell lines, only OVCA 420 is markedly growth inhibited by TGF-beta, and this was the only cell line in which TGF-beta elicited DNA fragmentation characteristic of apoptosis. Induction of apoptosis in OVCA 420 was time and concentration dependent and could be partially inhibited by concurrent treatment with an anti-TGF-beta mAb. Although apoptosis was not seen in normal ovarian epithelial cells (n = 7), [3H]thymidine incorporation was inhibited in all cases [mean = 61.2 +/- 7.2% (SD) of untreated control; P < 0.01]. Similarly, TGF-beta inhibited [3H]thymidine incorporation in all 10 primary ovarian cancers (mean = 40.4 +/- 7.1% of control; P < 0.01), but only 3 of 10 (30%) were found to undergo apoptosis when treated with TGF-beta. There was no relationship between p53 status of the ovarian cancers and the ability of TGF-beta to elicit apoptosis. In conclusion, TGF-beta inhibits proliferation but does not induce apoptosis in normal human ovarian epithelial cells. In contrast, some ovarian cancers that are growth inhibited by TGF-beta also undergo apoptosis. These data are consistent with the hypothesis that malignant cells are more susceptible to apoptosis than their normal nontransformed counterparts.