Amifostine inhibits hematopoietic progenitor cell apoptosis by activating NF-kappaB/Rel transcription factors.

We investigated the involvement of NF-kappaB/Rel transcription factors that reportedly can inhibit apoptosis in various cell types in the antiapoptotic mechanism of the cytoprotectant amifostine. In the nontumorigenic murine myeloid progenitor 32D cells incubated with amifostine, we detected a reduction of the IkappaBalpha cytoplasmic levels by Western blotting and a raising of nuclear NF-kappaB/Rel complexes by electrophoretic mobility shift assay. Amifostine inhibited by more than 30% the growth factor deprivation-induced apoptosis, whereas its effect failed when we blocked the NF-kappaB/Rel activity with an NF-kappaB/Rel-binding phosphorothioate decoy oligodeoxynucleotide. In human cord blood CD34(+) cells, the NF-kappaB/Rel p65 subunit was detectable (using immunofluorescence analysis) mainly in the cytoplasm in the absence of amifostine, whereas its presence was appreciable in the nuclei of cells incubated with the cytoprotectant. In 4 CD34(+) samples incubated for 3 days in cytokine-deficient conditions, cell apoptosis was reduced by more than 30% in the presence of amifostine (or amifostine plus a control oligo); the effect of amifostine was abolished in cultures with the decoy oligo. These findings indicate that the inhibition of hematopoietic progenitor cell apoptosis by amifostine requires the induction of NF-kappaB/Rel factors and that the latter can therefore exert an antiapoptotic activity in the hematopoietic progenitor cell compartment. Furthermore, the identification of this specific mechanism underlying the survival-promoting activity of amifostine lends support to the possible use of this agent in apoptosis-related pathologies, such as myelodysplasias.

Differential regulation of the expression of interleukin-2 receptor gamma-chain during the in vitro differentiation of human myeloid cells.

The common gamma-chain (gamma c) is a shared component of cell-surface receptors for the interleukins- 2, -4 and -7, and possibly others. We studied its expression in cells and cell lines of myeloid origin and found ubiquitous presence of gamma c mRNA in all cells examined. Differential regulation of gamma c expression was observed in myeloid cell lines induced to differentiate in vitro. In K-562 erythromyeloid cells, a sharp rise in the levels of gamma c mRNA and protein accompanied megakaryocytic, but not erythroid, differentiation. Surface binding of interleukin-2, as well as the transcripts for cognate receptor chains, were scarcely detectable in K-562 cells, whereas a significant increase in the binding of granulocyte-macrophage colony-stimulating factor specifically occurred during their megakaryocytic maturation. Our data indicate that expression of gamma c is a common feature of human myeloid cells, and suggest that its expression may be a requirement for human myelopoiesis.

Desogestrel versus gestodene in oral contraceptives: influence on the clinical and histomorphological features of benign breast disease.

Forty-four female volunteers asking for oral contraception, affected by symptomatic benign breast disease (BBD) were evaluated to compare the effects on mastalgia and breast nodularity of two different low dose oral contraceptives (OCs), containing 20 micrograms [corrected] ethinylestradiol + 150 micrograms desogestrel (EE+D) and 30 micrograms ethinylestradiol + 75 micrograms gestodene (EE+G), respectively. Physical examination, bilateral thermography, X-ray and/or ultrasonography of breast, and needle and screw-needle biopsies of mammary tissue were performed in all patients before OCs administration and after six cycles of treatment. OCs administration caused an overall improvement of mastalgia in 53%. Breast nodularity improved only in 8% of patients in both groups. Epithelial tissue modifications in mammary biopsies were observed, with involutive and/or secretory histomorphological and ultrastructural changes, frequently coexisting in different areas of the same breast.

PIP: In Italy, researchers compared data on 22 women who used the low-dose oral contraceptive (OC) containing 20 mcg ethinyl estradiol and 150 mcg desogestrel (EE+D) with data on 22 other women who used the low-dose OC containing 30 mcg ethinyl estradiol and 75 mcg gestodene (EE+G) to determine the pharmacological effects of the 2 OCs on women affected by mastalgia and breast nodularity. Clinicians performed physical exams, bilateral thermography, X-ray and/or ultrasonography of breast and needle and screw-needle biopsies of mammary tissue before OC administration and after 6 cycles of OC treatment. An overall improvement of mastalgia and breast nodularity occurred in 53% and 8% of all patients, respectively. There were no significant differences between groups. Among EE+D treated women, a marked secretory attitude in breast epithelial cells occurred, probably due to a prominent progestin effect. Both OCs increased the number of cytoplasmatic organules and intraluminal secretory material without any apparent increase of cell proliferation. The observed involutive and/or secretory histomorphological and ultrastructural changes often occurred in different areas of the same breast. These results suggest that low dose OC use by women affected by benign breast disease improves mastalgia but not breast nodularity.

Polyamines and nucleic acids in gestational trophoblastic tumors.

To test the relationship between tumor malignancy and content and distribution of polyamines and nucleic acids, 2 forms of human gestational trophoblastic tumors were examined: the hydatidiform mole (self-limited form) and the human chorio-carcinoma (invasive form) xenografted into nude mice. The results indicate that there are 2 significant differences between the choriocarcinoma and the mole: 1) the choriocarcinoma is characterized by increased polyamine and nucleic acid levels, 2) tissues differ in their putrescine:spermidine and spermidine:spermine ratios. There is an increase in polyamines in the urine of mole-bearing patients over that of normal controls. The correlation between putrescine and spermidine with the chorionic gonadotropin indicates that these 2 polyamines reflect the biological activity of the mole.