RESUMEN
Endometrial hyperplasia is a precursor lesion of endometrial carcinoma. Clinical studies of endometrial hyperplasia have shown that levonorgestrel (LNG) is more therapeutically effective than medroxyprogesterone acetate (MPA). The present pharmacological in vitro study was performed to compare progestin effects on human endometrial cancer (Ishikawa) cells. Supraphysiological concentrations of progesterone (PG) and high concentrations of LNG and MPA were employed to determine the order of potency in reducing cell density. The order of potency was LNG>MPA>PG with respective 50% inhibitory concentrations (IC(50)) of 3.9+/-0.4, 30.4+/-3.4 and 45.3+/-2.7 microM. Mifepristone (MF) is a potent antiprogestin, but was unable to antagonize the PG-induced cell density reduction. For MF concentrations from 0.2 to 70 microM alone, a PG-mimetic effect was observed with an IC(50) value of 19.0+/-1.7 muM. When PG and MF were combined, a marked reinforcement of the effect was seen. These observations indicate that extranuclear initiated signaling pathways are involved in the reduction of endometrial cancer cells exposed to high concentrations of PG and MF.
Asunto(s)
Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Levonorgestrel/farmacología , Medroxiprogesterona/farmacología , Mifepristona/farmacología , Progesterona/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica , Línea Celular Tumoral , Anticonceptivos Sintéticos Orales/farmacología , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Neoplasias Endometriales/metabolismo , Femenino , Humanos , Progestinas/farmacología , Receptores de Progesterona/metabolismoRESUMEN
BACKGROUND: The search for biological markers to predict malignant disease and its recurrence, or to monitor the effectiveness of treatment is a continuous process in medicine. Several years ago, urinary excretion of cGMP in urine was found to be a sensitive predictor in the follow-up of ovarian cancer and of monitoring treatment of cancer of the uterine cervix. PATIENTS AND METHODS: In the present study, 27 patients with gynecological cancer, including cancer of the uterine cervix (n=13), cancer of the uterine corpus (n=8) and cancer of the ovaries (n=6), were monitored for 10 years. Blood and urinary samples were taken before primary treatment (baseline sample) and three months thereafter (three-month sample). The serum levels of CEA, CA-125 and PIIINP and urine excretion of cGMP and cAMP were determined. Creatinine levels in serum and urine were employed to determine renal clearance. RESULTS: After 10 years' observation of women with cancer of the uterine cervix, seven patients showed no relapse and cGMP levels in baseline samples and three-month samples were 36.8+/-4.1 and 24.9+/-4.4 nmol cGMP/micromol creatinine (mean+/-SEM, p<0.01), respectively. The levels in patients (n=6) with relapse after 10 years' observation were 32.8+/-4.0 (baseline sample) and 43.5+/-4.2 (three-month sample) nmol cGMP/micromol creatinine (mean+/-SEM, p<0.02). Among the patients treated for cancer of the uterine corpus (n=9), none showed recurrent disease within the observation period of 10 years. The cGMP levels fell from 37.9+/-6.3 (baseline sample) to 22.3+/-2.3 (three-month sample) nmol cGMP/micromol creatinine (p<0.005). In the patients with ovarian cancer (n=6), 4 patients relapsed during the observation period of 10 years. In these women the cGMP levels increased from 34.5+/-2.7 (baseline sample) to 46.3+/-4.7 nmol cGMP/micromol creatinine whilst in both patients without relapse the levels decreased from 31.8 (range: 26.5-37.1) to 27.3 (range: 25.7-28.8) nmol cGMP/micromol creatinine, respectively. The changes in levels of cAMP, CEA, CA-125 and PIINP did not show statistically significant differences. Early changes in cGMP levels appear to predict long-term prognosis in gynecological cancers.
Asunto(s)
Biomarcadores de Tumor/orina , GMP Cíclico/orina , Neoplasias de los Genitales Femeninos/orina , Adulto , Anciano , Biomarcadores de Tumor/sangre , Antígeno Ca-125/sangre , Antígeno Carcinoembrionario/sangre , AMP Cíclico/orina , Femenino , Estudios de Seguimiento , Neoplasias de los Genitales Femeninos/sangre , Neoplasias de los Genitales Femeninos/terapia , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/orina , Fragmentos de Péptidos/sangre , Procolágeno/sangre , Pronóstico , Sensibilidad y Especificidad , Resultado del TratamientoRESUMEN
The anti-proliferative effect of progestins was studied in human transformed cell lines from the uterine cervix (C-4I, C33A and Me-180). Progestins caused a concentration-dependent inhibition of proliferation. The maximum tested concentration (2.6-3.2 microM) inhibited C-4I cell growth by the following order of potency: progesterone (56%) > medroxyprogesterone (38%) > megestrol acetate (25%). The sensitivity, expressed as I(25) (the concentration that caused 25% inhibition of growth), showed the same order: progesterone (7.7 nM) > medroxyprogesterone (78 nM) > megestrol acetate (570 nM). The intracellular levels of cGMP and cAMP were elevated and the cellular export of these cyclic nucleotides was inhibited by a similar order of potency. The C-4I cell line was devoid of progesterone-, estrogen-, androgen- and glucocorticoid-receptors. In addition, the antiprogestins mifepristone, onapristone and ZK-112993 did not block the anti-proliferative effect of progesterone. On the other hand, antiprogestins (2.3 nM) appeared to have some progesterone-like ("mimetic") activity with inhibition of C-4I cell growth; mifepristone (11%), onapristone (12%) and ZK-112993 (16%). The observed effects of progestins and antiprogestins on C-4I cells were also presented in C33A cells (16% androgen receptor positive) and Me-180 cells (22% progesterone receptor positive, 9% androgen receptor positive and 17% glucocorticoid receptor positive). This study suggests that a non-genomic mechanism contributes to the anti-proliferative effect of progestins.
Asunto(s)
AMP Cíclico/química , GMP Cíclico/química , Mifepristona/análogos & derivados , Progestinas/antagonistas & inhibidores , Progestinas/metabolismo , Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Línea Celular Transformada , Relación Dosis-Respuesta a Droga , Gonanos/farmacología , Antagonistas de Hormonas/farmacología , Humanos , Mifepristona/farmacología , Radioinmunoensayo , Receptores de Esteroides , Factores de TiempoRESUMEN
The efflux pump for cGMP has been shown to be an ATP-energized multiorganic anion transporter. The present study was performed to extend the knowledge of the pharmacological characteristics of this efflux pump. Inside-out vesicles prepared from fresh blood were incubated with [3H]-cGMP (1 microM) with or without various concentrations of competitors for 120min at 37 degrees. The tested compounds could be divided in four groups: one with high affinity (K(i) < 5 microM), a second with moderate affinity (K(i): 5-50 microM), a third with low affinity (K(i): 0.1-5mM) and the fourth with extremely low or no affinity at all. With the mean K(i)-values given in parenthesis, the high affinity group consisted of mifepristone (0.2 microM), zaprinast (0.35 microM), dipyridamole (0.35 microM), estradiol 3-beta-glucuronide (0.42 microM), genistein (0.43 microM), estradiol 17-beta-glucuronide (0.47 microM), onapristone (1.3 microM), progesterone (1.7 microM) and sildenafil (3.6 microM). The inhibitors with medium affinity were estradiol (8 microM), sulfinpyrazone (13 microM), daunorubicin (23 microM), megestrol acetate (26 microM), doxorubicin (28 microM), 6-thioguanine (28 microM) and 6-thioguanosine-5'-monophosphate (32 microM). The low affinity group comprised 6-TIMP (220 microM), 6-methylmercaptopurine (MMP) (220 microM), vincristine (270 microM), medroxyprogesterone (680 microM), para-aminohippurate (PAH) (1.9mM) and taurocholate (2.2mM). No or minimal effect was seen in the presence of 6-mercaptopurine (6-MP), methotrexate, 9-(2-phosphonylmethoxyethyl)adenine and mitoxantrone. The cGMP transporter had a unique pharmacological profile, different from that of MRP1, but with some characteristics in common with MRP4 and MRP5.