Tolerance to Pituitary-Adrenal Axis Activation by Anticancer Drugs in Normal and Tumour-Bearing Rats
M. Vacca and P. Preziosi
Department of Pharmacology, Medical Faculty of the Catholic University of the Sacred Heart, Largo F. Vito 1, 00168 Rome, Italy
Abstract. Cisplatinum given intravenously (i.v.), hydroxyurea given orally (os), procarbazine (os) and L-asparaginase (i.v.), on a decreasing scale, produce significant (p < 0.01) adrenocortical activation over 4-h period at a single dose per kg 10 times higher than those employed in human therapy. Only hydroxyurea retained this activity after a 5-day treatment both in normal and Walker carcinosarcoma-bearing rats. Adrenocortical activation depends on the presence of pituitary ACTH both after single or repeated treatments.
Key words: L-Asparaginase - Cisplatinum - Hydroxyurea - Procarbazine - ACTH - Hypothalamus-hypophyseal-adrenal axis - Adrenal cortex - Cancer chemotherapy - Drug effects - Tolerance - Walter carcinosar- coma
Introduction
The possible induction of tolerance of the adrenocortical activation seen after a single injection of antitumour drugs (Vacca et al. 1982), the target endocrine structure involved in such an activation and drugs displaying no tolerance as regards adrenocortical activation have been investigated. The possible persis- tence of this in tumour-bearing rats as well as the possible appearance of such an activation for drugs unable to retain this activation following repeated treatment has also been studied.
Materials and Methods
Animals (¿ Wistar rats, 200-250 g), housing, blood analysis (plasma corticosterone, plasma B) as previously (Preziosi and Vacca 1982). The rats were hypophysectomized by transauricular approach and employed not less than five
days after the intervention. Walker carcinosarcomas were grafted according to Preziosi and Marmo (1960) and the animals employed after 25 days bearing a non-ulcered neoplastic mass of approximately the same size. The rats were sacrificed by decapitation 2-4 h after administration of the drugs. To prevent stress in the remaining rats sampling was performed in an area adjacent to the rat holding room.
Drugs. The drugs were given by the intravenous (i.v.) or oral (os) route according to the recommended route in human therapy (Salmon 1980). The volume used was 1-5 ml/kg body weight. The following drugs, found able, after a single administration at doses per kg 10 times higher than those employed in the human (10 x human therapeutic dose, Htd) (Salmon 1980), to elicit a significant (p < 0.01) adrenocortical activation over a period of 4 h (Vacca et al. 1982) were given daily for 5 days (doses in mg if not otherwise indicated):
Dose/kg × 5 days
L-asparaginase (Asp) (i.v.) (Crasnitin, 10,000 U/10 ml ampoul)
5,140 U
Hydroxyurea (HYD) (os) (Oncocarbide, 500 mg/capsule) 800
Procarbazine (PRC) (os) (Natulan, 50 mg/capsule) 28
Because of the toxicity on repeated treatment with 10 Htd (18 mg/kg), cis-platinum (cP) was given at a dose of 0.5 mg/k/day equivalent to that recommended for protocols providing daily instead of single-dose schedule in humans (Salmon 1980). Drugs able to elicit an adrenocortical activation after a single administration were also given for 5-day treatment to hypophysectomized rats. ACTH1-24 [Synachten, 0.25 mg (25 UI)/ampoul] was given to the hypophysectomized rats by the intramuscular route at a dose of 700 mU/kg either as a single dose or repeated doses over 5 days.
All the results are expressed as group arithmetic means and standard error of the means (SE). Analysis of variance and Student-Newmann-Keul’s test for multiple comparison among groups were used to analyze the data. Differences between group means were considered significant if p < 0.05.
Results and Discussion
After repeated treatment, adrenocortical activation continued only with HYD (Table 1). A weak, not statistically significant adrenal activation was observed for cP given because of its high toxicity at a dose of 0.5 mg per kg/day; this corresponds to the dose employed in the repeated treatment schedule in cancer chemotherapy; it is lower than that (18 mg/kg) capable of eliciting a strong adrenocortical activation after a single i.v. injection (Vacca et al. 1982).
The adrenocortical activation seen 2 and 4 h after the 5th daily HYD administration is more evident in Walker carcinosarcoma-bearing rats (Fig. 1). PRC is unable to elicit a significant adrenocortical activation after a 5-day treatment either in intact or tumour-bearing rats.
The adrenocortical response to Asp, cP and PRC seems to depend on the presence of pituitary ACTH since it does not occur after single and repeated