Kelly H. Clifton

The Survival of Thyroid Cells: In Vivo Irradiation and in Situ Repair

The survival of rat thyroid cells irradiated in vivo and removed immediately for transplantation survival assay was compared with results obtained previously for thyroid cells irradiated in vitro and with the survival of thyroid cells irradiated and left in situ for 24 hr before transplantation survival assay. The Do for thyroid cells irradiated in vivo and removed immediately for assay is 195 rad; N is 4 and Dq is 270 rad. These parameters are not significantly different from those obtained when thyroid cells are irradiated in vitro. When these parameters are compared to those of thyroid cells irradiated and left in situ for 24 hr, the latter have a greater N and Dq, but there is no significant difference in Do. These data provide further evidence for a form of repair of potentially lethal damage which is dependent on the tissue environment (in situ repair, ISR) as previously described for ir

Evidence for a Unique in Situ Component of the Repair of Radiation Damage

The survival of rat mammary gland cells irradiated in situ and allowed to remain in situ for 24 hr before assay by an in vivo transplantation method was assayed. The D/sub 0/ was 122 rad, the N value was 23, and the D/sub q/ was 383 rad. When these parameters are compared to those of tissue that was removed immediately after irradiation, the former has a greater N and D/sub q/ but no significant difference in D/sub 0/. Evidence is presented that these differences are due to a unique in situ form of th repair of potentially lethal radiation damage that we have termed in situ repair.

Mammary carcinoma cell population growth in preirradiated and unirradiated transplant sites. Viable tumor growth, vascularity, and the tumor-bed effect.

Although preirradiation of the transplant site profoundly depresses growth of subsequently grafted carcinomas, the potential rate of tumor cell population growth was very similar within the viable regions of large and small tumors grafted in preirradiated or unirradiated sites. The vascular space per unit of viable tumor mass has previously been shown to be constant in such viable tumor tissue. It is concluded that the tumor-bed effect is due to suppression of vascular growth capability. Insofar as therapeutic procedures depend on relative functional vascular space, the sensitivity per unit mass of viable tissue would be expected to be very similar in large and small tumors growing in unirradiated or preirradiated sites.

Relation of mammary tumors to mammotropes. III. Hormone responsiveness of transplanted mammary tumors.

Summary 1. Hormone dependence of original (spontaneous, radiation- and 3-methyl-cholanthrene induced) mammary tumors were compared with first and second generation grafts of the same tumor in fully histocompatible inbred strains of rats. 2. Almost all tumors, (carcinomas and fibroadenomas) were autonomous in that they grew in normal hosts of both sexes, but most of them were hormone responsive. 3. A fair index of responsiveness is the degree of preferential growth of tumors in females. 4. Growth is retarded by ovariectomy and hypophysectomy and is resumed upon subsequent grafts of mammotropic tumors (administered to supply mammary gland stimulating hormones). 5. Progression appears invariable in the course of transplantations in the strains studied, but hormonal responsiveness in the first passages was almost identical with that of primary tumors. 6. Malignancy, hormone responsiveness, and growth rate vary independently. A slow growing fibroadenoma can be hormone independent and rapidly growing, while a carcinoma can be highly hormone responsive. These experiments support the hypothesis which considers the mammotrope of the pituitary and its hormones to be the main direct stimulant of the mammary gland and its tumors.

Hormonal Influences on Growth and Somatotropic Actions of Autonomous Mammotropes.

Summary and Conclusions 1. The role of gonadal, adrenal, and hypophyseal hormones on growth and somatotropic actions of a transplantable, functional mammotropic pituitary tumor (MtT) was studied in rats. 2. Although this tumor is autonomous (in that it grows in normal rats of both sexes) it is highly responsive to estrogen, the rate of tumor growth and body growth of the host being roughly proportional to the quantity of estrogen administered. Hormones of mammotropes stimulate body growth and growth of many organs. Somatotropic and mammotropic effects are marked in hypophysectomized rats bearing mammotropic tumors; thus they are independent of other pituitary factors.

Sensitivity to radiation of human normal, hyperthyroid, and neoplastic thyroid epithelial cells in primary culture

Samples of thyroid tissue removed surgically from 63 patients were cultured in vitro and exposed to X irradiation to investigate the radiosensitivities of various types of thyroid epithelial cells. A total of 76 samples were obtained, including neoplastic cells from patients with papillary carcinoma (PC) or follicular adenoma (FA), cells from hyperthyroidism (HY) patients, and normal cells from the surgical margins of PC and FA patients. Culturing of the cells was performed in a manner which has been shown to yield a predominance of epithelial cells. Results of colony formation assays indicated that cells from HY and FA patients were the least radiosensitive: when adjusted to the overall geometric mean plating efficiency of 5.5%, the average mean lethal dose Do was 97.6 cGy for HY cells and 96.7 and 94.3 cGy, respectively for neoplastic and normal cells from FA patients. Cells from PC patients were more radiosensitive, normal cells having an adjusted average Do of 85.0 cGy and PC cells a significantly (P = 0.05) lower average Do of 74.4 cGy. After allowing for this variation by cell type, in vitro radiosensitivity was not significantly related to age at surgery (P = 0.82) or sex (P = 0.10). These results suggest that malignant thyroid cells may be especially radiosensitive.

Rat mammary-cell survival following irradiation with 14. 3-MeV neutrons

The survival of rat mammary gland cells irradiated in situ with either single or split doses of 14.3-MeV neutrons was determined by an in vivo transplantation assay. The single-dose data are best fit to the multitarget single-hit model by the parameters D/sub 0/ = 97 cGy and n = 0.6 while the split-dose data are best fit by the parameters D/sub 0/ = 100 cGy and n = 1.2. Analysis of the combined data sets suggests that the two survival curves are not identical. Comparison of these data with previously published results following irradiation with 250-kVp x-rays is reported.

Prolactin and thyrotrophin content of functional transplantable pituitary tumors.

Summary The prolactin and thyrotrophin content of various transplantable pituitary tumors was studied. 1. Prolactin was found in stilbestrol induced and stilbestrol dependent rat pituitary tumor and also in an autonomous mammotrophic mouse tumor in concentrations only 10% or less that found in bovine pituitaries. These tumors contained little or no thyrotrophin. 2. Two autonomous adrenotrophic tumors contained no detectable prolactin or thyrotrophin. 3. Two dependent thyrotrophic tumors contained no detectable prolactin while the thyrotrophin concentration was ten times that of bovine pituitaries. A five gram thyrotrophic tumor contains 5,000 times more thyrotrophin than one mouse pituitary. Blood levels of thyrotrophin were 2,000 times normal.

SCREENING TECHNIQUES AND PROBLEMS OF HORMONE‐RESPONSIVE TUMORS

In introducing Part V on screening substances of potential value in control of tumors related to endocrine systems, we are not so much reporters of work done as mere theoreticians. There is little to report; the only extensive study in this area is that of Huggins et u Z . ’ ~ with mammary fibroadenomas of the rat. For a comprehensive survey of what is known on hormonal regulation of tumor growth we must turn to the recent reviews of Noble: Kirschbaum,6 Huggins,6 and Currie and Illingworth? A systematic study of potential inhibitors of endocrines and endocrinedependent tumors is long overdue. Currently, experimental chemotherapy aims a t interference with growth of cells in general in hope of finding substances that selectively inhibit neoplastic cells. This will remain an arduous task until the basic difference between neoplastic and normal cells is known. Only then will it be possible to design rational experiments in the search for tumor inhibitors. The work itself with inhibitors of nucleoprotein synthesis and growth in general, using neoplastic and normal cells, can yield information on the fundamental difference between the two cell types. As to the results, witness the control of chorioepithelioma obtained recently by Hertz8 with folic acid antagonist. In the field of endocrines, however, specific stimulants and inhibitors of cells are known. Some endocrines and their target organs, such as the breast and prostate, are not essential for life, so that their complete destruction or inhibition is without serious consequence. In other situations compensation can be attained by hormonal therapy. The influential substances are not species-specific, and the information obtained in animals is likely to be valid in man. Most, if not all, current screening presupposes that the point of attack should be the neoplastic cell. Research in the domain of endocrines clearly indicates that neoplasms can arise by mere derangement of physiological forces that regulate the numbers of each cell type a t an approximate level, without any extrinsic carcinogens or a virus. The growth of the tumors so induced is a t first dependent on the persistence of the disturbance that created it. FIGURE 1 is an oversimplified schematic presentation of the maintenance of the numbers of a cell type by a feedback mechanism of stimulating and restraining forces. Depression of one leads to hyperfunction of the other.