Sentinel lymph node mapping in gynecologic malignancies.

Lymph node status is the most important prognostic factor for women with vulvar, cervical and endometrial carcinoma and complete lymph node dissection has historically been an integral part of the surgical treatment of these diseases. Lymphadenectomy can be morbid for patients, who may experience wound breakdown, lymphocyst formation or chronic lymphedema, among other problems. Sentinel lymph node mapping is a newer technology that allows selective removal of the first node draining a tumor thereby allowing a potentially less aggressive procedure to be performed. Sentinel node mapping is well accepted for the management of breast carcinoma and cutaneous melanoma, and has resulted in reduced morbidity without adversely affecting survival. Sentinel node mapping is currently being investigated for treatment of gynecologic cancers. Recent studies show promise for incorporating the sentinel node mapping technique for treatment of several gynecologic malignancies.

Inhibition of AKT survival pathway by a small molecule inhibitor in human endometrial cancer cells.

The PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumour suppressor is mutated in 40-50% of human endometrial cancers. PTEN exerts its effects in part via inhibition of the antiapoptotic protein AKT. We demonstrate that two endometrial cancer cell lines that harbour PTEN mutations, Ishikawa and RL95-2, have high levels of phosphorylated AKT and high AKT kinase activity. Two additional endometrial cancer cell lines that express wild-type PTEN, Hec1A and KLE, have little phosphorylated AKT and minimal demonstrable AKT kinase activity. We tested a potential inhibitor of the AKT pathway, API-59CJ-OMe, in these four cell lines. We found that API-59CJ-OMe inhibits AKT kinase activity and induces apoptosis in the Ishikawa and RL95-2 cell lines with high AKT activity, but has little effect on Hec1A and KLE cells without AKT activity. API-59CJ-OMe may therefore have therapeutic potential for those endometrial cancers that harbour PTEN mutations and AKT activation.

Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells.

Signal transducers and activators of transcription (STATs) are transcription factors activated in response to cytokines and growth factors. Constitutively active Stat3 has been shown to mediate oncogenic transformation in cultured cells and induce tumor formation in mice. An increasing number of tumor-derived cell lines as well as samples from human cancer have been reported to express constitutively active Stat3 protein. We previously demonstrated that ovarian cancer cell lines express high levels of constitutively active Stat3. In this study, we show that inhibition of the Stat3 signaling pathway using the Janus Kinase-selective inhibitor, AG490, and a dominant negative Stat3 (Stat3beta) significantly suppresses the growth of ovarian and breast cancer cell lines harboring constitutively active Stat3. In the ovarian cancer cell lines, AG490 also diminished the phosphorylation of Stat3, Stat3 DNA binding activity, and the expression of Bcl-x(L). Further, AG490 induced significant apoptosis in ovarian and breast cancer cell lines expressing high levels of constitutively active Stat3 but had a less profound effect on normal cells lacking constitutively active Stat3. AG490 also enhanced apoptosis induced by cisplatin in ovarian cancer cells. These results suggest that inhibition of Stat3 signaling may provide a potential therapeutic approach for treating ovarian and breast cancers.

Growth suppression activity of the PTEN tumor suppressor gene in human endometrial cancer cells.

The AKT proteins are constitutively activated in several types of human cancers, which may play a role in carcinogenesis. In this study, we examined the activation of AKT in a panel of human endometrial cancer cell lines and tumor samples in this study. Two endometrial cancer cell lines, Ishikawa (ISK) and RL-95 and several tumor samples showed elevated levels of phosphorylated AKT PTEN, which is mutated in 45% of endometrial cancers, is a negative regulator of AKT. We examined the growth suppression activity of PTEN in ISK and KLE endometrial cancer cells. Expression of PTEN significantly suppressed the growth of both cell clines. In primary rat embryo fibroblasts, PTEN also inhibited malignant transformation mediated by ras and c-myc oncogenes. These two oncogenes are commonly mutated or amplified in endometrial cancer. These results suggest that PTEN may be a potent therapeutic agent for endometrial cancer.

A modified p53 overcomes mdm2-mediated oncogenic transformation: a potential cancer therapeutic agent.

The antiproliferative activities of wild-type (wt) p53 are inhibited by mdm2 (murine double minute2) oncogene product. We tested growth suppression activity of p53 14/19, an engineered p53 variant, which does not bind mdm2 and is completely resistant to the inhibition by mdm2. p53 14/19, unlike wt p53, suppressed the growth of cancer cells that contain amplified mdm2 oncogene efficiently by direct DNA transfection or adenovirus-mediated gene transfer. In addition, p53 14/19 also inhibited the growth of several different cancer cell lines expressing low levels of mdm2 oncogene product as efficiently as wt p53. We further examined the antioncogenic potencies of p53 14/19 in the rat embryo fibroblast cotransformation assay. Addition of wt p53 failed to cause any significant decrease in ras plus mdm2 foci counts. In contrast, cotransfection of p53 14/19 with ras and mdm2 significantly reduced foci number. In similar experiments, cotransfection of wt p53 or 14/19 p53 resulted in significant inhibition of oncogenic transformation in rat embryo fibroblast mediated by an activated ras plus c-myc, adenovirus E1A, or human papillomavirus E7 oncogenes. Therefore, these results suggest that p53 14/19 modified tumor suppressor gene may be a promising therapeutic agent for human cancers that express abnormally high levels of mdm2 oncogene product.

Constitutive activation of stat 3 oncogene product in human ovarian carcinoma cells.

OBJECTIVE: Stat 3 functions in transducing signals from the cell's surface to its nucleus and activation of gene transcription. Aberrations of Stat 3 in breast cancer have raised the possibility of its contribution to oncogenesis. Our goal was to examine ovarian cancer cell lines to determine whether Stat 3 plays a relevant role in ovarian carcinogenesis. METHODS: Protein lysates were extracted from normal ovarian surface epithelial cells and malignant cells. Western blotting techniques were performed with phosphorylation-independent or phosphorylation-specific Stat 3 (tyrosine 705) antibody. Confirmation of Stat 3 activation was determined by a luciferase reporter driven by a promoter containing Stat 3-specific binding sites. Bcl-x(L) and cyclin D(1) were also analyzed by Western blotting. RESULTS: MDAH 2774, OV-1063, Caov-3, and O.C. 22819 expressed high levels of phosphorylated Stat 3. In contrast, A2780 and normal ovarian surface epithelial cells had little Stat 3 phosphorylation recognized. Confirmation of persistent activation of Stat 3 activity was shown by transfection of cells with a Stat 3 luciferase reporter. Potential downstream mediators of Stat 3 including Bcl-x(L) and cyclin D(1) were also evaluated. In cells expressing activated Stat 3, high levels of both Bcl-x(L) and cyclin D(1) were detected, whereas in A2780 cells, which did not express activated Stat 3, only low levels of Bcl-x(L) and cyclin D(1) were expressed. CONCLUSIONS: Constitutive activation of Stat 3 is present in ovarian cancer lines but not in normal ovarian surface epithelial cells. Activation of Stat 3 is a common event during oncogenic transformation upstream to both Bcl-x(L) and cyclin D(1). The relationship of this aberrancy of ovarian carcinoma harboring activated Stat 3 deserves further investigation.

Elevated phosphorylation of AKT and Stat3 in prostate, breast, and cervical cancer cells.

We examined whether the persistent activation of AKT or Stat3 oncogene product is present in prostate, breast, and cervical cancer cells. We found that some prostate and breast cancer cell lines express high levels of phosphorylated AKT. Interestingly, the cancer cells, which only express low levels of phosphorylated AKT express high levels of phosphorylated Stat3. AKT or Stat3 is also highly phosphorylated in human papilloma virus-negative cervical cancer cells. Therefore, these results indicate that AKT and Stat3 are highly phosphorylated in some breast, prostate and cervical cancer cells, which may play a role in tumorigenesis of these cancers.

Prevention of cervix cancer.

Cervix carcinoma is an important health problem world-wide, being the second most common cancer among women, ranking first in many developing countries. A number of important epidemiological risk factors have been identified as contributing to the development of CIN and invasive cervix carcinoma. Of key importance is infection with human papillomavirus (HPV), which is the primary risk factor. There are evolving primary and secondary preventive strategies that could further reduce the burden from cervical carcinoma. The possible primary preventive strategies include risk reduction, diet or dietary supplements, HPV vaccines, and other chemopreventive agents. The possible advances in secondary preventive strategies include new technologies for Pap smears, HPV typing triage, and other adjuvant screening procedures. The impact of these strategies will depend upon evidence to support their use along with the characteristics of the population and environment in which they are used.

Transforming growth factor-alpha and insulin-like growth factor-I, but not epidermal growth factor, elicit autocrine stimulation of mitogenesis in endometrial cancer cell lines.

OBJECTIVES: Endometrial carcinoma cell lines were evaluated for epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), and insulin-like growth factor I (IGF-1) production and for autocrine stimulation. METHODS: Conditioned, serum-free media (CM) from cell lines RL95-2, KLE, HEC, and Ishikawa (ISH) were concentrated radioimmunoassayed (RIA). Samples for the IGF-1 assay were extracted with acid-ethanol to remove IGF-1 binding protein. Polymerase chain reaction (PCR) was used to validate the presence of mRNA for growth factors and receptors. Cells were incubated with Ab528, an antibody blocking EGF receptors, and alphaIR3, an antibody blocking IGF-1 receptors. Proliferation was quantified using [3H]thymidine incorporation. RESULTS: TGF-alpha was detected in CM: RL95-2 (0.4 +/- 0.001 ng/ml), KLE (0.7 +/- 0.003 ng/ml), HEC (0.8 +/- 0.01 ng/ml), ISH (1.2 +/- 0.05 ng/ml). No EGF was detected in CM. In extracted samples, IGF-1 was detected in CM: RL95-2 (0.8 +/- 0. 03 ng/ml), KLE (1.25 +/- 0.02 ng/ml), HEC (1.6 +/- 0.01 ng/ml), ISH (1.6 +/- 0.08 ng/ml). Unconditioned media served as the control. EGF, TGF-alpha, and IGF-1 mRNA was identified in all cell lines, as was the mRNA for EGF and IGF-1 receptors. Incubation with Ab528 or alphaIR3 resulted in significant inhibition of DNA synthesis in HEC 1A, KLE, and ISH. No inhibition was detected in the RL95-2 cell line. A control antibody did not inhibit the cell lines. CONCLUSION: Autocrine production and stimulation of endometrial carcinoma cell lines by TGF-alpha and IGF-1 are demonstrated in three of four endometrial cancer cell lines. No measurable EGF was produced by any of the cell lines.

The practice of surgical staging and its impact on adjuvant treatment recommendations in patients with stage I endometrial carcinoma.

A survey of American gynecologic oncologists was undertaken to assess their compliance with current surgical staging criteria in patients with early endometrial carcinoma. One hundred forty-four members of the Society of Gynecologic Oncologists responded to the survey. Respondents treated an average of 22 new cases annually. Tumor grade and intraoperative determination of depth of myometrial invasion were demonstrated to influence the frequency of lymphatic dissection. In grade 1, 2, and 3 lesions, 76, 60, and 34% of responders, respectively, indicated that depth of invasion influenced their decision to perform lymphadenectomy. In addition, depth of invasion was important in determining type and extent of lymphatic resection. Further, the impact of pathologic lymph node status on postoperative adjuvant radiation therapy recommendations was evaluated for various stratifications of endometrial adenocarcinoma confined to the corpus. The greatest differences in treatment recommendations were noted in the 50-66% invasion category. For grade 1 and 2 cancers, adjuvant therapy recommendations were reduced by 23 and 16% respectively when comparing pelvic and combined therapy versus none and vaginal therapy. The effect of surgical staging data on clinical decisions is clearly evident. The knowledge of pathologically negative lymph node status reduces the recommendation for postoperative adjuvant radiotherapy in patients with adenocarcinoma otherwise confined to the uterine corpus.

Cultured endometrial cancer cells exhibit autocrine growth factor stimulation that is not observed in cultured normal endometrial cells.

OBJECTIVE: To evaluate the autocrine stimulation hypothesis, primary cultures of malignant and normal endometrium were assayed for differences in response to growth factors (GF) GF and receptor blocking antibodies. METHODS: Thirteen normal and 10 malignant endometrial samples were collected. Cells were enzymatically dispersed and maintained in serum-free medium. They were incubated with epidermal GF (EGF), transforming GF-alpha (TGF-alpha), insulin-like GF-I (IGF-1), anti-EGF receptor antibody (Ab528), and anti-IGF-1 receptor antibody (alpha IR3) at physiologic concentrations. Tritiated thymidine incorporation was measured. RESULTS: Malignant endometrial cells increased thymidine incorporation when incubated with EGF (20.75%), TGF-alpha (19.8%), or IGF-1 (32.8%) compared to untreated control cells. When incubated with Ab528 or alpha IR3 antibodies alone, proliferation of malignant cells was inhibited (-12.4 and -23%, respectively, P < 0.003). Normal endometrial cells were inhibited by EGF (-24.9%), TGF-alpha (-25.6%), and IGF-1 (31.9%). Incubation of normal cells with Ab528 and alpha IR3 antibodies stimulated growth (125 and 115%, respectively, P < 0.02). CONCLUSIONS: These data are consistent with the autocrine stimulation hypothesis for neoplastic endometrium and illustrate differences compared to nonneoplastic endometrial growth factor-mediated proliferation.

Absence of cumulative bone marrow suppression in heavily pretreated ovarian cancer patients undergoing salvage chemotherapy with paclitaxel.

This retrospective study was undertaken to investigate whether paclitaxel was associated with cumulative bone marrow toxicity in patients undergoing salvage chemotherapy for refractory ovarian cancer. Seventy-seven patients were treated with paclitaxel 135 mg/m2 every 21 days, with granulocyte-colony-stimulating factor (G-CSF) support as necessary according to standard criteria. The mean white blood cell nadir was significantly higher and the incidence of severe leukopenia (Gynecologic Oncology Group grade 3-4) significantly lower after ten cycles than after the first cycle for the entire study population (3.4 vs. 1.6 x 10(3)/mm3 and 29 vs. 77%, respectively) and the patients who received G-CSF (3.5 vs. 1.4 x 10(3)/mm3 and 33 vs. 89%, respectively), but did not differ significantly for the patients who did not require G-CSF (2.9 vs. 2.5 x 10(3)/mm3 and 40 vs. 59%, respectively). The mean hematocrit and platelet nadirs, as well as the incidence of severe anemia and thrombocytopenia, did not differ significantly after ten cycles from those after the first cycle for the entire study population and both subgroups. Thirty-two (42%) patients received G-CSF, each initiated within four cycles. The indications for initiating G-CSF support were febrile leukopenia (53%) and treatment delay (47%). The average duration of G-CSF support was 4.6 days, and did not increase significantly as the number of paclitaxel cycles increased. We conclude that paclitaxel was not associated with cumulative bone marrow toxicity in patients undergoing salvage chemotherapy for refractory ovarian cancer.

Treatment of refractory ovarian carcinoma with paclitaxel and cisplatin after treatment failure with single-agent paclitaxel.

The clinical response to paclitaxel and cisplatin was evaluated in fifteen patients with refractory epithelial ovarian cancer who failed to respond to treatment with single agent paclitaxel. Patients received combination chemotherapy every 3 weeks with both 135 mg/m2 (9) or 175 mg/m2 (6) of paclitaxel and 50 mg/m2 (2), 75 mg/m2 (4) or 100 mg/m2 (9) of cisplatin. There was 1 complete clinical response, with 2 partial clinical responses for an overall response rate of 20%. The progression free interval was 6+ months for the complete responder and 9.5+ months for the partial responders. Overall five (33%) patients experienced an improvement in clinical response over that seen with paclitaxel alone, and 5 patients have died. Improvement in clinical response with combination chemotherapy compared to paclitaxel alone was positively associated with the cisplatin dose; while disease progression and death were inversely associated with the paclitaxel dose. Addition of cisplatin to paclitaxel may be useful in the treatment of patients who fail to respond to paclitaxel alone.

Exponential regression of CA 125 during salvage treatment of ovarian cancer with taxol.

The role of serum CA 125 in monitoring the response of epithelial ovarian cancer to treatment has been extensively investigated. The exponential regression curve [1n(CA 125) = i+s (days after initiation of treatment)] has been reported to describe the rate of change of serum CA 125 during treatment. In this model, the y-axis intercept (i) represents the initial CA 125-secreting tumor burden, while the slope (s) is determined by the response to treatment. The exponential regression curve was calculated for 66 patients undergoing salvage chemotherapy with taxol. At a mean follow-up of 121 days, 50 (75%) patients had progressed and 35 (53%) had died. Stratification of the patients by stage, grade, or histology did not reveal any significant differences in the regression rate. When the patients were stratified by response, the mean regression rate was 0.0157 +/- 0.011 for patients with progressive disease (N = 19) vs -0.0250 +/- 0.031 for those with stable disease (N = 25) and -0.0250 +/- 0.015 for those with a partial response (N = 22) (P < 0.0001). The regression rate did not correlate with progression-free interval or survival (P > 0.05). We conclude that changes in serum CA 125 levels follow an exponential regression curve in patients undergoing salvage chemotherapy with taxol for progressive or recurrent ovarian cancer. A positive regression rate may predict which patients will progress prior to the time progression becomes clinically evident. However, a negative rate fails to provide discriminatory utility in predicting progression-free interval or survival.

A matched study of surgically treated stage IB adenosquamous carcinoma and adenocarcinoma of the uterine cervix.

Thirty-eight patients with surgically treated stage IB adenosquamous carcinoma of the uterine cervix (AS) have been matched with patients with other histologic subtypes of adenocarcinoma (A) for stage, lesion size, node status, grade of adenocarcinoma and age at diagnosis. An additional six patients with AS were unable to be matched. Overall 5-year survival and disease-free survival for the matched AS and A were not significantly different, 83 vs. 90%, and 78 vs. 81% nor were the number of recurrences, 8/38 AS vs. 6/38 A, but the mean time to recurrence was significantly shorter in the AS group: 11 vs. 32 months (P = 0.003). A subgroup of AS with a high risk of a poor outcome can be identified based on either lesion size >/= 4 cm, depth of invasion >/= 10 mm or plevic lymph node metastasis. These patients may be suitable candidates for adjuvant therapy before or after surgical treatment.

Combined carboplatin and cisplatin. Limited prospects for dose intensification.

BACKGROUND: The relative lack of overlapping toxicities and less-than-complete cross-resistance of tumors treated with both carboplatin and cisplatin may allow these two analogues to be given in combination to exploit platinum dose intensity therapeutics. Early experience with combined platinum regimens, however, found myelosuppression, particularly severe thrombocytopenia, to be dose-limiting. It was postulated that a 2-day interval between carboplatin and cisplatin would allow for near complete clearance of the former before cisplatin administration and a potential gain in dose intensity. METHODS: Other carboplatin-cisplatin regimens produced Grade 3-4 toxicity in 20% of patients. By defining 95% confidence limits around this observed rate of Grade 3-4 toxicity, the accrual needs of this study were determined in a two-stage process. Sixteen patients with advanced malignancies were entered onto a trial of 300 mg/m2 of carboplatin on day 1, followed by 125 mg/m2 of cisplatin on day 3 every 28 days. Hematologic and nonhematologic toxicity was closely monitored, including the use of serial audiograms, to allow appropriate dose modification. RESULTS: A total of 40 courses of combination platinum therapy was administered to 15 patients who were evaluable for toxicity. Higher-than-anticipated ototoxicity and neurosensory toxicity was observed. WHO Grade 3 ototoxicity (hearing loss) was documented in 12 of 15 patients (80.0%, 95% confidence interval [CI]: 52.0-97.0%) and emerged as the dose-limiting side effect of this regimen. High-frequency hearing loss, as demonstrated by conventional audiograms, was universal among all 12 patients who received at least 2 courses of combination platinum therapy (100%, 95% CI: 73.5-100%). Grade 2 or 3 neurosensory toxicity also was observed in 4 of 15 patients. Hematologic toxicity was manageable. WHO Grade 3-4 neutropenia or thrombocytopenia occurred in only 14% and 11%, respectively, of 40 courses. There was no evidence of cumulative marrow toxicity. Calculated dose intensities (mg/m2/week) were 94 +/- 26.0 for carboplatin, 39.3 +/- 12.4 for cisplatin, and 64.0 +/- 19.2 for the combination (expressed as cisplatin equivalents). Objective responses (complete response+partial response) occurred in 8 of 16 subjects (50.0%, 95% CI: 24.7-75.4%), with 1 patient achieving a complete response of 14+months. CONCLUSIONS: The schedule of day 1 carboplatin plus day 3 cisplatin every 4 weeks appeared to allow a higher platinum dose intensity with less myelotoxicity than previously reported schedules combining these two analogues. Ototoxicity, however, was unexpectedly severe and limits future prospects for the use of combined platinum analogues to achieve dose intensification.

Characterization of epidermal growth factor receptor in normal and neoplastic human endometrium.

Growth factors, including epidermal growth factor (EGF), have been implicated in the growth of several types of cancer. This study compares EGF receptors in normal and neoplastic endometrium. Membrane fractions were isolated from surgical specimens. Radioreceptor assays demonstrated the presence of receptors with a dissociation constant of 0.64 nmol/l in normal endometrium. Affinity cross-linking revealed receptor molecular weight of 150 to 170 kiloDaltons (KD). A survey of samples (n = 37) revealed progressive decrease of EGF receptors in cancers of increasing grade: Grade 1-2 adenocarcinoma decreased 34% from control (n = 6, P less than 0.01), whereas Grade 3 adenocarcinoma decreased 90% (n = 7, P less than 0.01) and sarcoma decreased by 72% (n = 3, P less than 0.01). The dissociation constant and molecular weight of the receptor in neoplastic endometrium did not differ significantly from normal. The inverse relationship with grade suggests receptor alteration or down regulation by hormones and/or growth factors.

Regulation of epidermal growth factor and insulin-like growth factor I receptors by estradiol and progesterone in normal and neoplastic endometrial cell cultures.

Growth factors are polypeptides which regulate cell proliferation through binding to specific receptor proteins. Normal and neoplastic human endometrium have been shown to express epidermal growth factor (EGF) and insulin-like growth factor I (IGF-1) receptors. Endometrial cell cultures were used to test modulation of EGF and IGF-1 receptors in response to steroid hormones. Endometrial gland and stroma cells were separated by enzymatic dispersion and were incubated in medium containing estradiol (10, 100, or 1000 pg/ml) or progesterone (1, 10, or 100 ng/ml) followed by radioligand assays. Normal endometrial cultures (n = 6) treated with estradiol demonstrated 40% less EGF binding than control cultures (P less than 0.05), while IGF-1 binding was unaffected. Stromal cells treated identically decreased in only one treatment group. Progesterone treatment stimulated a significant increase in EGF and IGF-1 receptors in gland cultures. Cultures derived from adenocarcinoma (n = 2) demonstrated decreased EGF binding compared with normal endometrium (P less than 0.05). Carcinoma cells treated with progesterone resulted in a dose-dependent increase in EGF binding over control (P less than 0.05). These data illustrate effects of steroid hormones upon growth factor receptors in human endometrium, and suggest involvement of growth factors in the regulation of normal and neoplastic endometrial growth.

Insulin-like growth factor I receptors in normal and neoplastic human endometrium.

Insulin-like growth factor I (IGF-I) binding sites were characterized in normal and neoplastic endometrium. The characteristics of the endometrial IGF-I receptor are similar to those reported for other tissues. The binding of 125I-IGF-I to the endometrial membranes is saturable and time, temperature, and pH dependent. The 125I-IGF-I binding activity to the membranes obtained from differentiated and undifferentiated adenocarcinoma as well as sarcoma of the endometrium was significantly higher (P less than 0.05) when compared to the binding activity of the membranes obtained from normal endometrium. The Scatchard analysis of the competitive binding data of both normal and neoplastic endometrium revealed linear plots. This indicated a single class binding site for IGF-I with equilibrium dissociation constants (Kd) of 5.0, 6.8, 6.94, and 6.88 nM for normal, differentiated, and undifferentiated adenocarcinoma, and sarcoma of the endometrium, respectively. Therefore, the differences observed in 125I-IGF-I binding between normal and neoplastic endometrial membranes was due to an increase in the number of IGF-I binding sites and not to a change in receptor binding affinity. Autoradiograms from affinity labelling studies revealed a band corresponding to Mr 132,000 subunit of the receptor which is characteristic of the type I receptor reported for other tissues. A dimer of the alpha subunit (Mr 263,000) was also observed in all four categories of endometrial tissue. Additionally, autoradiograms obtained from sarcoma of the endometrium revealed a Mr 40,000 band that was only displaced by IGF-I and IGF-II peptides but not by the monoclonal antibody alpha IR-3 to the type I receptor. These suggest that the band is representative of the IGF-I or IGF-II binding protein. A similar band was not observed in the other tissues. The results show that the human endometrium contains high affinity IGF-I or IGF-II binding sites. The fact that IGF-I binding activity was significantly higher for neoplastic endometrium suggests that IGF-I may play an important role on supporting the growth of this neoplastic tissue.