Angiotensin I‐converting enzyme (ACE) has been shown to be involved in the catabolism of the tetrapeptide acetyl‐Ser–Asp–Lys–Pro (AcSDKP). As AcSDKP is a physiological inhibitor of haematopoietic stem cell proliferation, we investigated the in vitro and in vivo effects of captopril, one of the specific inhibitors of ACE, on the proliferation of primitive haematopoietic cells. Regenerating bone marrow cells obtained from mice given one injection of cytosine arabinoside (100 mg/kg) as well as SA2 myeloid leukaemia cells were incubated in vitro for 24 h with 10−6 m captopril. Captopril significantly reduced the proportion of high proliferative potential colony‐forming cells (HPP‐CFC‐1) in S‐phase, whereas it had no effect on the proportion of SA2 leukaemic colony‐forming cells in S‐phase. When given in vivo to mice 1 h after 2 Gy γ‐irradiation or cytosine arabinoside (AraC) injection, captopril (100 mg/kg) was shown to prevent HPP‐CFC‐1 entry into S‐phase induced by these cytotoxic treatments. The observed effects correlated with a reduction in ACE degradative activity and an increase in the level of endogenous AcSDKP both in the supernatants of captopril‐treated bone marrow cells and in plasma of treated animals. The present findings suggest that AcSDKP might mediate the observed in vitro and in vivo inhibitory effects of captopril on primitive haematopoietic cell proliferation.
Neoplastic transformation induced by ionizing radiation was studied using a human retinal pigment epithelial cell line immortalized by telomerase. Radiation-transformed cell clones were tumorigenic in athymic mice and were analyzed by G-banding and comparative genomic hybridization (CGH). Radiation-transformed cloned cell lines and cell lines derived from tumors produced in athymic nude mice following transplantation exhibited a recurrent karyotype:45,XX,der(10),-13. CGH showed an amplification of 10p11.2 and a deletion of the remaining 10p. Positional cloning of the amplified region by FISH analysis and subsequent sequence analysis of BAC clones showing amplified FISH signals identified the candidate gene PARD3. This gene also was found to be transcriptionally expressed at an increased level. The findings indicate that PARD3 may play an important role in radiation-induced carcinogenesis of RPE cells. This is the first evidence for PARD3 amplification in human cancer cells.
Evidence from clinical and laboratory studies suggests that angiogenesis is important in the progression of solid tumours and hematologic malignancies. We have shown that the naturally occurring tetrapeptide Acetyl-Ser-Asp-Lys-Pro (AcSDKP) is a potent angiogenic factor normally present at nanomolar concentrations in the blood. A murine leukemia model was used to assess whether there was a correlation between levels of endogenous AcSDKP and the development of disease. Levels of AcSDKP in the plasma and bone marrow (BM) cells from mice bearing an acute myeloid leukemia (AML) were five- to ten-fold greater than those in non-leukemic mice. Furthermore, a strong correlation between the concentration of endogenous AcSDKP and the progression of AML was demonstrated. These results are consistent with the marked increase in BM vascularity observed in leukemic mice. The physiologic relevance of these findings awaits further studies and the contribution of AcSDKP to the pathogenesis of leukemia is under investigation.
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