Cryofragility and other membrane characteristics of solid mouse tumors

The membrane fragility of Ridgway osteogenic sarcoma (ROS) was compared with that of other solid tumors in an attempt to explain its sensitivity to chemotherapeutic agents. The sensitivity of ROS to freezing, hypotonicity, and to the mechanical insult of homogenization was determined by bioassay. The results were compared with those obtained with an ROS subline resistant to cyclophosphamide (ROS/CPA), with melanoma B16 and the recently induced sarcoma S1976, the latter two being relatively drug-resistant tumors. Representative values of the viability as expressed by percent of tumor takes were: (a) after storage at ?78 °C for 24 hr in Earle's balanced salt solution without DMSO, for ROS 0%, ROS/CPA 11%, B16 82%, and S1976 100%; (b) after incubation at 37 °C for 2 hr in distilled water, for ROS 0%, ROS/CPA 0%, B16 42%, and S1976 80%; (c) after mechanical dispersion in a tissue grinder, for ROS 17%, ROS/CPA 28%, B16 100%, and S1976 100%. Relevant therapeutic indices for ROS, B16, and S1976 were: for single doses of cyclophosphamide 12, 3.1, 3.5, melphalan 3.5, 1.5, 1.5, medphalan 4.2, 1.5, 1.2 and for 6 daily doses of 5-fluorouracil 1.5, <1.0, <1.0, and 6-mercaptopurine 5.9, 1.4, 1.6. The marked membrane fragility of ROS may be related to its sensitivity to chemotherapeutic agents.     

Notes on type specimens of European Miocene Talpidae and a tentative classification of old world Tertiary Talpidae (Insectivora: Mammalia)

Survey of the type of the Miocene Talpidae of Europe results in the allocation of several of the types to new or different genera. Three genera and one species previously referred to the family do not belong there. The diversity of Miocene talpids indicates an influx of generic stocks into Western Europe in the early Miocene, probably from Asia. New data provide a basis for a tentative phylogeny and classification of the European genera.     

In vitro potency and selectivity of the non-steroidal androgen aromatase inhibitor CGS 16949A compared to steroidal inhibitors in the brain.

A sensitive in vitro 3H2O microassay for aromatase activity was used to evaluate the potency and selectivity of three aromatase inhibitors in mammalian (gerbil) and avian (ring dove) hypothalamus. The steroidal inhibitors, 1,4,6-androstatrien-3,17-dione (ATD) and 4-hydroxy-androstenedione (4-OH-A) were compared with a new non-steroidal imidazole inhibitor, CGS 16949A [4-(5,6,7,8-tetrahydroimidazo-[1,5-a]-pyridin-5-yl)benzonitrile HCl]. Adult male dove hypothalamic aromatase is highly active [Vmax = 5.3 pmol testosterone (T) converted/h/mg protein], has high substrate binding affinity (Km = 4.0 nM), and direct involvement in control of sexual behaviour. With [1 beta-3H]T or [1 beta-3H]A as substrate, male dove preoptic aromatase activity was inhibited more effectively and selectively by CGS 16949A. Thus, Kis and IC50s for aromatization were approximately 50 times lower for the non-steroidal inhibitor, and inhibition of the other major androgen-metabolizing enzymes (5 alpha/beta-reductase) occurred at concentrations at least one order of magnitude greater than for ATD and 4-OH-A. Neonatal male gerbil hypothalamic aromatase activity (Vmax = 1.3 pmol T converted/h/mg protein) was lower than in the dove. Aromatase inhibition by CGS 16949A is more potent in the neonatal gerbil than in the dove (Kis of 0.03 and 0.60 nM, respectively, with A as substrate). We conclude that the imidazole is an effective aromatase inhibitor in both the adult and developing brain.     

Pharmacological studies on the behavioral thermoregulation in the salamander necturus maculosus

The aquatic salamander Necturus maculosus was tested as a model for investigations of behavioral thermoregulatory responses to drugs which modify thermoregulation in endotherms. Animals were acclimatized to 15°C and an LD 12:12 photoperiod and placed in linear thermal gradients (5° to 30–35°C). Drugs were given each day for two days and deep body temperature monitored with trailing thermocouples. Prostaglandin E₁ produced a pronounced long-lasting behavioral hyperthermia. Melatonin and chlorpromazine caused significant falls in mean selected temperature (MST). Oxotremorine and ethanol were without effect on MST, while scopolamine treatment resulted in decreased MST on Day 1 and a increase on Day 2. Neurotensin produced hyperthermia on Day 2, but not on Day 1, an effect opposite that found with mammals. Capsaicin caused a pronounced decreased in MST on Day 1, followed by hyperthermia on Day 2, a response similar to that observed in mammals. The use of ectothermic animal models for investigation of behavioral thermal responses to those pharmacological agents which influence thermoregulation in endotherms may lead to a better understanding of the evolution of vertebrate temperature regulation.