cortodoxone and Lung-Neoplasms

Adrenocortical carcinoma is a rare malignancy in children, with a high mortality. Little is known about long-term outcome, especially in infants treated with mitotane. We report the successful long-term outcome of a case of metastatic adrenocortical carcinoma presenting in infancy treated with surgical resection and mitotane. The patient presented at 2 months of age with Cushing's syndrome, a large adrenal mass, and elevated adrenal steroid levels. The tumor was removed surgically. Intraoperative findings included an adrenal tumor (confirmed malignant pathologically) invading the adrenal vein and vena cava. After surgery he was treated with mitotane at a dose of 2 g/d. Six months after surgery 11-deoxycortisol levels increased, and a computed tomography scan showed a pulmonary metastasis. Mitotane was increased to 2.5 g/d, and the metastasis was removed surgically. Plasma mitotane levels ranged 10-15 micro g/ml. Tumor markers remained normal, and mitotane was discontinued at 18 months. During therapy the patient's somatic growth was poor. His motor and speech development was delayed. After mitotane was discontinued he demonstrated catch-up growth. This case shows successful long-term outcome and recovery from the toxic effects of mitotane.

Topics: Adrenal Cortex Neoplasms; Antineoplastic Agents, Hormonal; Carcinoma; Cortodoxone; Growth Disorders; Humans; Infant; Lung Neoplasms; Male; Mitotane; Neoplasm Metastasis; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography

Inhibitors of angiogenesis hold potential in the treatment of cancer and other diseases where the disease is caused or maintained by the inappropriate growth of blood vessels. In the present study, a novel inhibitor of angiogenesis was synthesized by covalently linking a nonanticoagulating derivative of heparin, heparin adipic hydrazide (HAH), by an acid-labile bond to the antiangiogenic steroid, cortisol. The rationale was that the heparin derivative, which binds to sulfated polyanion receptors on endothelial cells, should concentrate the steroid on the surface of vascular endothelial cells. Endocytosis of the conjugate and decomposition of the acid-labile linkage inside lysosomes and other acidic intracellular compartments should then lead to release of the cortisol and expression of its antiproliferative activity. Analysis of the stability of HAH-cortisol showed that it was stable at pH 7.4 and broke down rapidly (t1/2 15 min) at pH 4.8 at 37 degrees C. Treatment of murine pulmonary capillary endothelial cells with HAH-cortisol at 10(-5) M (with respect to cortisol) suppressed their DNA synthesis by 50% and inhibited their migration into wounded areas of confluent monolayers. HAH-cortisol at 10(-4) M (with respect to cortisol) did not suppress the DNA synthesis of Lewis lung carcinoma cells. Daily i.p. injections of HAH-cortisol into mice bearing s.c. sponge implants retarded vascularization of the sponge, and injections directly into the sponge abolished vascularization for as long as the injections were continued. Daily i.v. injections of HAH-cortisol at doses causing no apparent toxicity retarded the growth of solid s.c. Lewis lung carcinomas in mice by up to 65%. In all of these assays, equivalent treatments with a mixture of the HAH plus cortisol was significantly less effective. The antiproliferative effect of HAH-cortisol on endothelial cells appeared independent of the glucocorticoid activity of the steroid since HAH conjugated to 5 beta-pregnane-3 alpha,17 alpha,21-triol-20-one, a steroid lacking glucocorticoid or mineralocorticoid activity, was even more effective at inhibiting DNA synthesis by murine pulmonary capillary endothelial cells than was HAH-cortisol. In conclusion, HAH-cortisol represents the prototype of a new class of angiogenesis inhibitors for the treatment of cancer and other angiogenic diseases.

Topics: Animals; Anticoagulants; Antineoplastic Agents; Cell Division; Cells, Cultured; Cortodoxone; DNA, Neoplasm; Drug Stability; Endothelium, Vascular; Heparin; Hydrocortisone; Hydrogen-Ion Concentration; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Neovascularization, Pathologic; Swine

An in vivo model of tumor-induced angiogenesis was used to monitor two known inhibitors of angiogenesis, protamine sulfate and the steroid tetrahydro S. Tumor cells entrapped in alginate beads were injected s.c. into mice. Blood vessel induction was measured by two quantitative methods: measurement of hemoglobin at the alginate pellet site, and pooling of radiolabeled RBC to the alginate pellet site. The two methods gave parallel results. Tetrahydro S with or without heparin inhibited blood vessel growth by 50%, and protamine sulfate inhibited blood vessel growth by 85%. These results were supported by gross morphology and histological analysis of the alginate pellet site.

Topics: Animals; Cortodoxone; Disease Models, Animal; Drug Synergism; Female; Heparin; Lung Neoplasms; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Protamines

The effect of angiostatic steroids on pulmonary metastasis was investigated using mice treated with such a steroid before or after intravenous inoculation with Lewis lung carcinoma; cortisone acetate and tetrahydro S, of which the former possesses glucocorticoid activity, and the latter lacks it, were used as the angiostatic steroids. In the presence of heparin, both types of steroids prevented angiogenesis in chick embryo and also pulmonary metastasis in mice when the administration started after cell lodgement. On the other hand, one-shot cortisone treatment before cell inoculation increased the weight of lung colonies to twice that seen in the controls, while tetrahydro S pretreatment did not enhance metastasis. These results revealed that both angiostatic steroids with and without glucocorticoid activity in the presence of heparin inhibited tumor growth in the lungs, and further indicated that cortisone acetate affected the steps of metastasis after the invasion of tumor cells into the blood stream until angiogenesis in the secondary foci, and consequently promoted metastasis, whereas tetrahydro S (which has no glucocorticoid activity) did not affect the steps before angiogenesis. It was thus indicated that the inhibitory effect of angiostatic steroids against tumor growth due to an anti-angiogenic activity was not dependent at all on the metastasis promotion by these steroids having glucocorticoid activity.

Topics: Allantois; Animals; Chick Embryo; Cortisone; Cortodoxone; Glucocorticoids; Heparin; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neovascularization, Pathologic; Structure-Activity Relationship

A 64-year-old man with an asymptomatic pulmonary mass discovered on routine chest roentgenography was found to have substantial bilateral adrenal enlargement by abdominal computed tomography. Percutaneous adrenal aspiration biopsy showed cytologically normal adrenal glands. A diagnosis of subclinical 21-hydroxylase deficiency was established by stimulation testing with adrenocorticotropic hormone. The adrenal size and appearance by computed tomographic scanning in congenital adrenal hyperplasia and particularly in its subclinical form have not been well defined. This case demonstrates that marked adrenal enlargement can occur and may provide the only clue to the diagnosis in an asymptomatic patient without other clinical stigmata of adrenal hyperplasia.

Topics: 17-alpha-Hydroxyprogesterone; Adenocarcinoma; Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Carcinoma, Squamous Cell; Cortodoxone; Humans; Hydroxyprogesterones; Lung Neoplasms; Male; Middle Aged; Steroid Hydroxylases; Syndrome