Alfredo Dabancens

Intraepithelial cervical neoplasia in women using intrauterine devices and long-acting injectable progestogens as contraceptives

Abstract Between 1965 and 1967, Papanicolaou smears were obtained before admission in 2,409 women accepted for intrauterine contraceptive devices (IUDs) and 2,684 women for long-acting injectable progestogens (LAP) contraception (chlormadinone acetate and medroxyprogesterone acetate). These were repeated yearly since then, with accumulated woman years of 3,269 for the IUD group and 7,119 for the LAP group. Both groups were comparable in age distribution, previous pregnancies, and socioeconomic level. The diagnosis was based on repeated cytology, colpomicroscopy, and histology of the biopsy or conization. Statistical analysis shows that women who requested LAP had a significantly higher prevalence rate of histologically confirmed lesions than those applying for IUDs. However, the incidence rate of new lesions appearing during the use of these contraceptive methods was the same for both groups. It is concluded that the risk of developing cervical carcinoma in patients using LAP is not significantly different from women using IUDs.

Quinacrine and copper, compounds with anticonceptive and antineoplastic activity

Changes in the evolution of a malignant transplantable tumor in mice to whom quinacrine, copper and zinc were supplied in drinking water are reported. Male AJ mice were inoculated in the right thigh with 1,000,000 TA3 or TA3 MTXR tumoral cells. Three experiments were designed with different types of tumors and different schedules of quinacrine and cations administered in drinking water. The animals that received quinacrine or quinacrine plus copper in drinking water had significantly smaller tumors, and some groups had a high rate of complete tumor regression (up to 60%). Quinacrine and copper have synergistic antineoplastic activity. Zinc salts do not improve the antitumoral effect of quinacrine. The relevant fact of this experiment lies in the fact that a large number of women using IUDs with copper could occasionally be treated with quinacrine.

Effects of betamethasone, sulindac and quinacrine drugs on the inflammatory neoangiogenesis response induced by polyurethane sponge implanted in mouse

In this study, we showed the effect of the betamethasone, sulindac and quinacrine alone or combined, on the inflammatory angiogenesis promoted by polyurethane sponge on mice. The main finding reported here is that the formation of new blood vessels was strongly inhibited by low concentration of betamethasone, sulindac or quinacrine, whether alone or in combination. It is known that steroidal anti-inflammatory drugs inhibit the enzymes required for the production of prostaglandins through a nuclear glucocorticoid receptor (GR) mediated mechanism. This mechanism may occur in endothelial cells as well. Considering that activity of cyclo-oxigenases 1 and 2 is inhibited by sulindac, and that these enzymes are located in the stromal tissue, we propose that the anti-angiogenic effect of these agents may occur via inhibition of both COX isoforms. On the other hand, quinacrine inhibited PLA2 activity, and we propose here that the anti-angiogenic effect occurs via inhibition of the enzyme PLA2. The potentiated effect of the association of betamethasone, sulindac and quinacrine may have some therapeutic benefit in the control of pathological angiogenesis. Further studies are required to validate these propositions.

Effects of Steroidal and Non Steroidal Drugs on the Neovascularization Response Induced by Tumoral TA3 Supernatant on CAM from Chick Embryo

Angiogenesis, the development of new blood vessels from the existing vascular network, may result as a consequence of the increase or decrease of proangiogenic or antiangiogenic factors, respectively. The tumor itself could up-regulate the production of angiogenic factors. Recently, we established that the steroidal drug betamethasone in low concentration inhibit the neovascularization promoted by TA3 Ts on CAM of chick embryos. We describe here the effects of the non-steroidal drug ketoprofen, alone or in association with betamethasone, on the angiogenesis promoted by TA3 Ts on CAM. The main finding reported here is that the formation of new blood vessels is strongly inhibited by low concentrations of ketoprofen. The association of both drugs produced a synergistic effect, significantly decreasing tumoral supernatant angiogenesis. It is known that steroidal anti-inflammatory drugs inhibit the enzymes required for the production of prostaglandins through a nuclear GR mediated mechanism. This may operate as a general mechanism in endothelial cells as well. Considering that the induction of COX 1 and COX2 are inhibited by ketoprofen, and that these enzymes are located in the stromal compartment of the CAM, we propose that its antiangiogenic effect may occur via inhibition of the two COX isoforms. In fact, we found that ketoprofen induced apoptosis in both the stromal fibroblast and endothelial cells. The potentiated effect of the combination of betamethasone and ketoprofen may have some therapeutic projections in the control of pathological angiogenesis.

Induction of Ovulation with Synthetic Gonadotrophin-Releasing Hormone in Women with Constant Anovulation Induced by Contraceptive Steroids

The ovarian response to stimulation with follicle-stimulating hormone/luteinizing hormone-releasing hormone (FSH/LH-RH) was studied in young, healthy, and fertile women with constant iatrogenic anovulation caused by depot medroxyprogesterone acetate or depot chlormadinone acetate injected for contraceptive purposes. Results were compared with those in unstimulated controls. The response was observed directly on the ovaries at laparotomy performed after treatment with FSH/LH-RH. A wedge biopsy provided ovarian tissue for histological and histochemical studies of steroid dehydrogenase activity. Treatment with FSH/LH-RH caused a trophic effect on the ovaries, with evidence of follicular development; ovulation occurred in two out of 16 treated women. Preovulatory mature follicles were found in three others. Clearly the FSH/LH-RH-induced release of FSH and LH caused follicular growth up to Graafian follicles, mature preovulatory follicles, and ovulation. Mitosis in granulosa and theca cells was also observed. A wide individual variation in gonadal response to hypothalamic FSH/LH-RH was evident, however. Nonetheless, our data support the possibility that treatment with FSH/LH-RH may prove valuable in patients with anovulatory sterility of hypothalamic origin.

Effect of sulfated β-cyclodextrin, a water soluble cycloamylose, on the promotion and/or inhibition of angiogenesis

Previous studies have reported that sulfated β-cyclodextrin, a naturally occurring cycloamylose built up from six to eight glucopyranose units, when administered alone promotes angiogenesis, but administered with an angiostatic steroid inhibits angiogenesis in the cick embryo bioassay. In our experiments sulfated β-cyclodextrin has been shown to posses many properties unrelated to its classical functions in the promotion and inhibition of angiogenesis that were not previously described. We studied the angiogenic and angiostatic properties of β-cyclodextrin in a subcutaneosus plastic sponge model in mice. We realized two set of experiments. In each set mice were randomized into five groups (n= 5 mice). The first group was treated with sulfated β-cyclodextrin (200 ng), the second group was treated with sulfated β-cyclodextrin (2000 ng), the third group received unsubstituted β-cyclodextrin (2000 ng), the fourth group was treated with sulfated β-cyclodextrin (20 000 ng) and the last group was used as a control group. In all groups compounds were administered intraperitonally 4 days after subcutaneous implantation of a sterile polyvinyl sponge on day 0, controls were not treated. Cyclodextrin administered alone at low drug concentration (200 ng) promoted angiogenesis and increased the development of venules in the sponge matrix. However, cyclodextrin administered at high drug concentration (2000 and 20 000 ng) reduced the vessel index in the sponge and areas of microhemorraghes were observed. From our results we propose that β-cyclodextrin contains both a promoter and an inhibitor of angiogenesis and that the activation of both is drug concentration dependent.

Antiangiogenic effect of betamethasone on the chick cam stimulated by TA3 tumor supernatant

Tumor growth is the result of combined cell proliferation overwhelming cell death and neoangiogenesis. This report shows CAM angiogenesis promoted by TA3 tumor supernatant with or without low dosis of betamethasone (Minimal antiangiogenic concentration: beta-MAAC). Methylcellulose discs instilled with 10 microliters of beta-MAAC (0.08 microgram/ml), 10 microliters of tumor supernatant (TA3ts), 5 microliters beta-MAAC + 5 microliters TA3ts, and 10 microliters of PBS as control were implanted in host chick eggs. On day 12, the grafts were removed, photographed and fixed. Sections were stained in parallel, one and three with hematoxylin-eosin, and section two by the Tunel method. The number of vessels was evaluated in a microscopic field of the CAM (2250 micron 2). The results show that beta-MAAC produced a significant inhibition of neovascularization in comparison to that observed in controls (P < 0.0025; Student t-Test). Discs instilled with TA3ts produced an intense stimulation of angiogenesis in contrast, when discs were instilled with 5 microliters of beta-MAAC + 5 microliters of TA3ts the angiogenesis was significantly inhibited (P < 0.001). The results show that effective antiangiogenic doses of betamethasone are in the range of 10(-7) M, (probably a genomic mediated action) and that this effect of low concentration may have clinical applications.

Quinacrine: sclerosing agent of the utero-tubal junction in women, with anticarcinogenic actions in transplanted tumors in mice.

Quinacrine, an acridine derivative that was in widespread use as an anti‐malarial, has been shown to have both sclerosant and anticarcinogenic actions. The sclerosant action of quinacrine has been used to produce occlusion of Fallopian tube in both experimental animals and women, and several clinical studies are reviewed. Both actions of quinacrine are potentiated by steroidal and non‐steroidal antiprostaglandins as well as by ionic copper. Combinations of quinacrine with antiprostaglandin drugs, and also with copper, improved the efficacy of quinacrine when used for female sterilization and reduced side effects. A review of the experimental and epidemiological evidence suggests that quinacrine has no carcinogenic effects.

MAMMARY GLAND NODULES IN WOMEN UNDER CONTINUOUS EXPOSURE TO PROGESTAGENS

A prospective study of the mammary gland was performed in 3,350 women receiving medroxyprogesterone or chlormadinone acetate for contraception. The exposure to the progestagens was from one to seven years duration. Ten nodules were detected. Two were carcinomas. Since a control group of comparable age and parity, never exposed to progestin or estrogen steroids, is not yet available, the possible significance of these findings is questionable.

Contraceptive efficacy of two different metals using a modified seven vector.

Medel, M., Zipper, J., Dabancens, A. and Thomas, M. (Dept. of Physiology & Biophysics, School of Medicine, University of Chile, Santiago, and Dept. of Obstetrics & Gynecology, Sotero del Rio Hospital, Puente Alto, Chile, and International Fertility Research program, Research Triangle Park, North Carolina 27709, USA). Contraceptive efficacy of two different metals using a modified seven vector.