Tumor blood flow and the cytotoxic effects of estramustine and its constituents in a rat glioma model.
OBJECTIVE
Estramustine (EaM) is a conjugate of nor-nitrogen mustard (NNM) and 17 beta-estradiol (E2) that has cytotoxic and radiosensitizing effects on experimental malignant glioma. Its mechanism of action is only partly understood. To further investigate the mechanism in vivo, the effects on tumor blood flow (TBF) and tumor growth were analyzed.


METHODS
TBF was measured by radioactive microspheres, and tumor growth was measured by weight. Apoptosis was evaluated by in situ end labeling and gel electrophoresis. The effects of the constituents NNM and E2 were also evaluated.


RESULTS
EaM increased TBF to 153.8 ml/100 g/min after 3 days and to 153.9 ml/100 g/min after 10 days of treatment, compared with 94.0 ml/100 g/min in untreated controls. Cerebral blood flow did not change after EaM treatment. NNM increased TBF but also showed a tendency to increase cerebral blood flow. E2 increased TBF, whereas cerebral blood flow was unchanged. EaM resulted in a rapid reduction in tumor weight from 230 mg in untreated animals to 146 mg after 3 days of treatment. EaM induced an early transient fragmentation of deoxyribonucleic acid in glioma but not in the normal brain. Neither NNM nor E2 affected tumor weight.


CONCLUSIONS
EaM increases TBF in the BT4C rat glioma model with a concomitant rapid antitumoral effect. The increase in TBF could partially be induced by an estrogen-like action of EaM, but the rapid cytotoxic effect of the drug is obviously attributed to the intact EaM compound. This cytotoxic effect might be attributable to the induction of programmed cell death.
Johansson
M
M
Department of Oncology, University Hospital, Umeå, Sweden.
Bergenheim
A T
AT
Henriksson
R
R
Koskinen
L O
LO
Vallbo
C
C
Widmark
A
A
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001783:Blood Flow Velocity / Q000187:drug effects; D001932:Brain Neoplasms / Q000098:blood supply* / Q000473:pathology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D004961:Estramustine / Q000494:pharmacology*; D005260:Female; D005910:Glioma / Q000098:blood supply* / Q000473:pathology; D008297:Male; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology*; D051381:Rats; D011919:Rats, Inbred Strains
D018906:Antineoplastic Agents, Alkylating; D004961:Estramustine