In previous studies we have shown that the gene encoding cholecystokinin (CCK) is expressed in spermatogenic cells of several mammalian species. In the present study we show that a gene homologous to the CCK-related hormone, gastrin, is expressed in the human testis. The mRNA hybridizing to a human gastrin cDNA probe in the human testis was of the same size (0.7 kb) as gastrin mRNA in the human antrum. By in situ hybridization the gastrinlike mRNA was localized to seminiferous tubules. Immunocytochemical staining of human testis revealed gastrinlike peptides in the seminiferous tubules primarily at a position corresponding to spermatids and spermatozoa. In ejaculated spermatozoa gastrinlike immunoreactivity was localized to the acrosome. Acrosomal localization could also be shown in spermatids with electron microscopy. Extracts of the human testis contained significant amounts of progastrin, but no bioactive amidated gastrins. In contrast, ejaculated sperm contained mature carboxyamidated gastrin 34 and gastrin 17. The concentration of gastrin in ejaculated human spermatozoa varied considerably between individuals. We suggest that amidated gastrin (in humans) and CCK (in other mammals) are released during the acrosome reaction and that they may be important for fertilization. (J. Clin. Invest. 1990. 86:660-669.) Key words: activation * cholecystokinin. fertilization -neuropeptide -sperm Introduction The gastrointestinal hormones gastrin and cholecystokinin (CCK)' are homologous. They share an identical carboxyl-terminus Gly-Trp-Met-Asp-Phe-NH2, which contains the active site ofboth hormones (1, 2). The active site homology explains the overlapping spectra ofactivity and suggests that gastrin and CCK are derived from a common ancestor (3). This suggestion is supported by analysis of mammalian gastrin and CCK preprohormone structures (4-9) and by the recent detection of an invertebrate hybrid of mammalian gastrin and CCK (10).

The interaction of radiation and hyperthermia was systematically studied in the Dunning R3327G prostatic adenocarcinoma, the preeminent animal model for human prostatic cancer. Subcutaneous tumors (produced by injection of 10(7) cells) were treated when they had reached a volume of about 1 cm3, which occurred about 3 weeks after implantation. With the use of a randomized complete factorial design, four factors were examined. Each agent was used at one of three dose levels. For radiation, these were 5, 15, and 25 Gy; for hyperthermia, 42 degrees C for 15 minutes, 43 degrees C for 30 minutes, and 44 degrees C for 60 minutes. Two sequences (hyperthermia plus irradiation and irradiation plus hyperthermia) and five time delays between agents (0, 12, 24, 48, and 120 hours) were used. The growth delay (the time it took for the initial tumor volume to double) of subcutaneously implanted tumor served to quantitate treatment effect. Significant (P less than .05) statistical interactions were observed for several combinations of factors and individual factors. Hyperthermia plus irradiation was more effective than irradiation plus hyperthermia except at the delay time between treatments of 0 hours. Peak growth delay occurred when the time between treatments was 0-24 hours and depended on agent doses. Many combinations produced therapeutic synergy.

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