Cranial irradiation for cerebral and nasopharyngeal tumours in children: evidence for the production of a hypothalamic defect in growth hormone release

A synthetic 29-amino acid analogue of human pancreatic GH-releasing hormone (GHRH(1-29)NH2) has recently been shown to stimulate the release of GH in normal subjects. We have studied the GH response to GHRH(1-29)NH2 in nine children irradiated for brain and nasopharyngeal tumours, who were not growing and were deficient in GH as assessed by insulin-induced hypoglycaemia. Serum GH rose in response to GHRH(1-29)NH2 in all the children, and in five the peak serum GH response was greater than 20 mu./l. The data suggest that when hypothalamo-pituitary irradiation results in GH deficiency, this is due to a failure of the synthesis or delivery of endogenous GHRH from the hypothalamus to the pituitary cells. It also suggests that it may be possible to treat such children using synthetic GHRH in place of exogenous GH.     

Production of erythroid potentiating factor(s) by a human monocytic cell line

U-937 is a human monocytic cell line that has been to elaborate factors that affect normal human hematopoiesis in vitro. Studies on the effects of these factors demonstrated an erythroid potentiating factor (EPF) and a potent inhibitor of granulocyte-macrophage (CFU-GM) colony growth. The EPF was present in both serum-containing and serum-free U- 937 conditioned media, had a dose-dependent effect on erythroid colony formation and was remarkably heart stable. The CFU-GM inhibitory activity was also detected in serum-free conditioned medium, was dose- dependent, heart labile and its effect was reversed by Indomethacin. Indomethacin (Sigma, St. Louis, Mo.) did not alter the erythroid effects of the U-937 conditioned medium. No colony stimulating factor (CSF) or erythropoietin (Ep) could be detected in this medium. The existence of a human cell line capable of production EPF without simultaneous CSF production will permit further studies on the biochemical and biologic nature of these factors.     

Axillary lymph node metastases in breast cancer: preoperative detection with US

The importance of axillary node status in the prognosis of breast cancer led the authors to conduct a prospective study comparing the value of clinical examination with ultrasound (US) performed by a transpectoral approach. All 60 patients examined underwent axillary dissection. Sensitivity was 45.4% for clinical examination versus 72.7% for US. US provides valuable information for breast cancers treated solely by irradiation, after insufficient dissection, and for large tumors not amenable to primary surgery. When the nodal region is treated by surgery and/or radiotherapy, local monitoring with US appears unnecessary owing to the low incidence of nodal recurrence.     

Tiazofurin: A new antitumor agent

Summary Tiazofurin is an interesting drug now entering Phase I trials, with marked preclinical antitumor activity against P388 and L1210 leukemias, and the Lewis lung carcinoma. Schedule dependency favoring frequent administration has been noted.The drug has a novel mechanism of action, being metabolized to an inhibitory cofactor of inosine monophosphate dehydrogenase.Tiazofurin is widely distributed after i.v. administration exhibiting a triphasic pattern of plasma decay, with a terminal half-life of 3–16 h in the three species studied. Approximately 90% of the drug was excreted unchanged in the urine within 24 h. A significant potential for the slower release of intracellularly retained drug exists.Anticipated organ toxicities based on the studies described include myelotoxicity, hepatotoxicity and nephrotoxicity. These were mild and reversible at lower doses, and were not seen at levels corresponding to the starting doses in man. A potential for hyperuricemia exists; this should be easily controllable by the use of allopurinol, without compromising the drug's antitumor effect.Phase I trials under the sponsorship of the NCI are underway in a number of institutions.     

Enhanced melphalan cytotoxicity in human ovarian cancer in vitro and in tumor-bearing nude mice by buthionine sulfoximine depletion of glutathione

The development of acquired resistance to alkylating agents frequently limits the effectiveness of chemotherapy in the treatment of ovarian cancer. While the resistance to alkylating agents is multifactorial, the association of drug resistance with elevations in glutathione (GSH) is of potential clinical relevance since there exist pharmacologic means to lower intracellular GSH levels. We have used in vitro and in vivo models of human ovarian cancer to demonstrate that selective inhibition of GSH synthesis with L-buthionine-S,R-sulfoximine (L-BSO) leads to a lowering of GSH levels and an increase in cytotoxicity of the alkylating agent melphalan. In the human ovarian cancer cell line NIH:OVCAR-3, derived from a patient clinically refractory to alkylating agents, L-BSO resulted in a 3.6-fold enhancement of melphalan cytotoxicity. This cell line was also adapted for intraperitoneal growth in athymic nude mice. In this in vivo model, in which the mice die of massive ascites and intraabdominal carcinomatosis, L-BSO given orally in drinking water for 5 days decreased GSH levels in the tumor cells by 96% compared to a 79 and 86% reduction in GSH levels in the bone marrow and gastrointestinal mucosa respectively. Lowering of GSH levels with BSO was not accompanied by an increase in lethality for melphalan in non-tumored nude mice. However, in tumor-bearing nude mice, a single melphalan (5 mg/kg) treatment following GSH depletion with L-BSO was markedly superior to treatment with melphalan alone, producing a 72% increase in median survival time. Furthermore, L-BSO treatment of human bone marrow cells prior to melphalan exposure had little effect on melphalan toxicity as assessed in a CFUc-GM assay. These results suggest that treatment with the GSH synthesis inhibitor BSO may preferentially enhance the cytotoxic effects of alkylating agents against human ovarian cancer and overcome acquired resistance.