estramustine and nornitrogen-mustard

To further clarify the mode of action of estramustine, the influence on macromolecular synthesis in the human prostatic tumour cell line 1013L was investigated. Cell treatment with estramustine, nor-nitrogen mustard and tauromustine, followed by radioactive nucleotide and leucine incorporations, as a measure of RNA, DNA and protein labelling, were carried out. The initial effect of estramustine clearly differed from that obtained after treatment with nor-nitrogen mustard and tauromustine. No inhibition of DNA synthesis was found whereas an inhibition of overall RNA synthesis was predominant. Adaption of an established RNA separation method was used in an indepth study of RNA labelling after estramustine treatment. An inhibition of 29S, 18S and 4-7S RNA was found after estramustine treatment, indicating disturbances in either RNA processing or RNA transport. The lack of 45S RNA labelling additionally indicates pre-ribosomal inhibition.

Topics: Affinity Labels; Biological Transport; Cell Survival; DNA, Neoplasm; Estramustine; Humans; Leucine; Macromolecular Substances; Male; Nitrogen Mustard Compounds; Nitrosourea Compounds; Nucleotides; Prostatic Neoplasms; RNA, Neoplasm; Taurine; Tumor Cells, Cultured

In growth proliferation experiments on two human prostatic carcinoma cell lines, DU 145 cells were found to be more sensitive to the cytotoxic effect of estramustine and nor-nitrogen mustard than PC-3 cells. Estramustine was, however, much more cytotoxic in both cell lines than nor-nitrogen mustard. Cytogenetic experiments revealed that estramustine produced a drastic increase of the mitotic index in both these cell lines. This increase could be accounted for by the arrest of cells in their first treatment-metaphase. The arrested metaphases exhibited all the characteristics commonly found for stathmokinetic agents such as colchicine and vinca-analogues. No mitotic arrest was found for nor-nitrogen mustard but chromosomal aberrations were found at toxic concentrations. Estradiol exhibited minimal toxicity and caused no mitotic arrest in these cell lines. The mitotic arrest induced by estramustine was found to be reversible on removal of the drug.

Topics: Carcinoma; Cell Line; Cell Survival; Cells, Cultured; Drug Evaluation, Preclinical; Estramustine; Humans; In Vitro Techniques; Karyotyping; Male; Mitosis; Nitrogen Mustard Compounds; Prostatic Neoplasms; Time Factors

Estramustine at concentrations ranging from 3-40 x 10(-6) M inhibited the cell growth and clonogenic survival of a human prostatic carcinoma cell line (DU 145). This cell line was found to be unresponsive to estradiol and testosterone at concentrations ranging from 10(-9) M to 5 x 10(-5) M. Metabolism studies with estramustine showed that only a few per cent of the ester linkage was cleaved during the exposure period. This small amount of metabolism could possibly lead to the release of nor-nitrogen mustard, which was however found not to be as inhibitory as estramustine in this cell line. The results indicate that estramustine per se causes the cell death of hormone unresponsive human prostatic carcinoma cells in cell culture.

Topics: Carcinoma; Cell Line; Cell Survival; Cells, Cultured; Estradiol; Estramustine; Humans; In Vitro Techniques; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Testosterone