Effect of midbrain raphe lesion on avoidance learning in aggressive mice.

Lesion of the midbrain ventral raphe nucleus greatly improves the avoidance-learning efficiency of normal and isolated-aggressive Albino Swiss mice. Since the lesion of this brain area selectivity lowers the forebrain concentration of 5-hydroxytryptamine (5-HT), implications of the role of brain 5-HT in avoidance-learning acquisition are discussed.

Renal damage in mice after treatment with cisplatinum alone or in combination with X-irradiation.

Functional kidney damage in mice was measured (using clearance of 51Cr-EDTA) from 1 to 39 weeks after treatment with single doses of cisplatinum (c-DDP), X rays, or their combination. After c-DDP alone renal damage was observed within 1 week. From 1 to 7 weeks there was recovery of function after low drug doses but after doses in excess of 6 mg/kg some damage persisted. After irradiation alone there was no measurable change in function for 20 weeks. Beyond this time there was a dose dependent and progressive deterioration of function. c-DDP given before or after irradiation caused more damage than either agent alone. During the first 20 weeks independent toxicities accounted for most of this effect but at later times modification of radiation damage possibly contributed. The greatest enhancements were observed when c-DDP was given 1/2 hour before to 1 day after irradiation (Dose Modifying Factor, DMF, 1.3). c-DDP given 3 to 4 weeks before X rays caused only a slight enhancement of damage (DMF 1.1).

The effect of cisplatin on the repair of radiation damage in RIF1 mouse tumours in vivo.

The effect of the antitumour agent cisplatin on repair of X-ray-induced damage was studied in RIF1 mouse tumours treated in situ. The response of tumours, assessed by growth delay, to 4 fractions of X-rays given at 5-h intervals was compared with that after single doses. The displacement between the curves was taken as a measure of repair. A single dose of 6 mg.kg-1 cisplatin given 0.5 h before the first fraction resulted in no detectable inhibition of repair despite a significant growth delay caused by drug alone. A dose of 2 mg/kg cisplatin given 0.5 h before each of the X-ray fractions did, however, cause some repair inhibition; a result confirmed by tumour control experiments. The schedule dependence for repair inhibition was the same whether the irradiations were carried out on clamped (fully hypoxic) tumours or under ambient conditions. Significant enhancement of radiation damage was seen after correcting for the effects of drug alone, whether or not repair inhibition occurred. The effects of cisplatin on normal stroma within the tumour (vascular damage) was also investigated by monitoring the regrowth rates of recurrent tumours. In contrast to the effects on tumour cells, no enhancement of damage or inhibition of repair was seen for this assay in the combined treatment schedules.

Consideration of the use of 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5- alpha-androstan-3-one (4MA), a 5 alpha-reductase inhibitor, in prostate cancer therapy.

We investigated the effect of 17 beta-N,N-diethylcarbamoyl-4-methyl-4aza- 5 alpha-androstan-3-one (4MA), a 5 alpha-reductase inhibitor, on growth inhibition of androgen-sensitive rat prostatic tumour (R3327-H) and correlated it with changes in weight of normal androgen target tissues and with levels of androgens. Groups of male Copenhagen rats were treated for 28 days with a daily injection of various, increasing doses of 4MA (0.01-4.0 mg/day) and the results were compared with control (vehicle-treated) and with castrated animals. 4MA decreased tumour growth rate in a dose-dependent manner, which was reflected in a decreased incorporation of BrdUrd in DNA of glandular epithelial cells in the tumour. Normal prostate wet weight was also decreased after high-dose 4MA treatment while serum testosterone levels were not affected by 4MA treatment. Contrary to expectations, however, tissue levels of dihydrotestosterone in tumour and ventral prostate were still considerable in 4MA-treated animals. The tumour-inhibiting action of 4MA, therefore, has to be interpreted as not being purely due to 5 alpha-reductase inhibition. On the other hand, it was not possible to demonstrate any direct tumoricidal effect of 4MA in vitro. The relevance of these findings in terms of the endocrine mechanism of action of 4MA on tumour growth is discussed.

Intratumoural administration of cisplatin in slow-release devices. I. Tumour response and toxicity.

In this study we investigated the effect of the incorporation of cisplatin in slow-release systems on tumour response and animal toxicity after intratumoural (i.t.) administration. Solid slow-release rods with incorporated cisplatin were prepared either from starch or from three different polyether-hydrogel formulations. In vitro release rates from these rods were widely different. With the starch system, approximately 100% release was obtained in 2 h. For the hydrogel formulations, release was approximately 100% in 1 day for a formulation with 40% water uptake (T3), 45% within 4 days for a formulation with 14% water uptake (T2) and 8% within 4 days for a formulation with 4% water uptake (T1). The slow-release rods containing graded amounts of cisplatin were implanted i.t. in s.c. RIF1 murine tumours. The i.t. administration of cisplatin in starch rods did not reduce animal toxicity or increase tumour response relative to i.t. injections of cisplatin in solution. For the hydrogel rods, the tumour response and animal toxicity for a given dose of cisplatin decreased with decreasing release rate. Higher doses of cisplatin could therefore be delivered with the slower-releasing hydrogel formulations. The slowest-release hydrogel rods (T1) had very little effect on either tumour (growth delay) or host (animal weight loss), even at cisplatin doses 8 times that tolerated as an i.p. injection. The fast (T3)- and intermediate (T2)-release hydrogel rods resulted in dose dependent tumour growth delays that were longer than those obtained with i.p. or i.t. administration of cisplatin. The highest response, a tumour growth delay of 55 days, was obtained with the intermediate-release hydrogel rods (T2) at a cisplatin dose of 40 mg/kg. Analysis of tumour growth delay for a given level of toxicity indicated that the intermediate-release formulation (T2) was slightly better than the fast-release formulation (T3) and confirmed the therapeutic advantage of i.t. implants over systemic therapy.

A rapid in vivo bioassay of the ovulation hormone of Lymnaea stagnalis.

The neurosecretory caudo-dorsal cells (CDC) of the basommatopora Lymnaea stagnalis produce an ovulation hormone (CDCH), which is released at the periphery of the intercerebral commissure (COM). A rapid in vivo bioassay for CDCH has been established and is based on the dose-dependent relationship between the quantity of injected CDCH (COM-extract) and the number of snails responding with the first stages of the egg-mass production process, as determined 30 min after injection. Three types of scores can be distinguished: (1) no response (very low CDCH doses), (2) ovulation only (O), and (3) ovulation and packaging (O + P). With increasing CDCH doses the number of snails responding with O, O + P, and oviposition increases. It is shown that the O response first increases followed by a decrease, while simultaneously, the P response increases. This is caused by the fact that the packaging latency is dose dependent, i.e., at low doses it is greater than 30 min, whereas at higher doses it is less than 30 min. This agrees with the finding that at low doses the oviposition latencies are longer (ca. 20 min) than at higher doses. The size of the egg mass is not dose dependent. Several factors that influence the responses upon which the bioassay is based have been analyzed, i.e., refractory period, photoperiod, and day-to-day variability of the assay snails. Experiments relating to the development of a bioassay are reported. The half-life of injected CDCH appeared to be 30-40 min.

Effect of the photoperiod on the time schedule of egg mass production in Lymnaea stagnalis, as induced by ovulation hormone injections.

In the pulmonate snail Lymnaea stagnalis the neurosecretory caudo-dorsal cells (CDC) produce an ovulation hormone (CDCH) which is released at the periphery of the cerebral commissure (COM). Time schedules of the successive stages of the egg mass production following CDCH injection (COM extract) were determined at 20 degrees. Ovulation is performed rapidly, within 10 to 20 min. The latencies of the other stages are: egg formation, 20-30 min; egg mass formation, 60-90 min; and oviposition, about 120 min. The duration of oviposition is dependent on the size of the egg mass and varies from 5 to 20 min. At a 16-hr photoperiod all stages start 10 min earlier than at a 12-hr photoperiod. It is suggested that the effect of the photoperiod is achieved by a change of release activities of dorsal bodies and/or of CDC. The possibility that a nervous mechanism is involved in the control of the packaging of the egg cells is discussed.