Artificial capillaries perfused with culture medium provide a matrix in which cells can attain tissue-like densities in vitro. Products secreted into the medium can be measured as indicators of cell function or may be recovered for other purposes without disturbing the culture.

It is hypothesized that cells exposed to LCFA have increased membrane microviscosity with a consequent decrease in their ability to respond to ACHI. This decrease in trophic support may contribute to the adrenal insufficiency and atrophy in patients with ALD.

Medical treatment of metastatic adrenal cancer is largely unsuccessful and has considerable toxicity. We previously demonstrated the activity of the plant toxin gossypol against human adrenal cancers in nude mice. We therefore examined the efficacy and toxicity of oral gossypol as a treatment for adrenal cancer in humans. Twenty-one patients with metastatic adrenal cancer received oral gossypol at doses of 30-70 mg/day. Patients were monitored for side effects of gossypol, changes in hormone secretion, and tumor response. Eighteen patients completed at least 6 weeks of gossypol treatment. Three of these patients, whose tumors were refractory to other chemotherapeutic agents, had partial tumor responses (> or = 50% decrease in tumor volume) that lasted from several months to over 1 yr. One patient had a minor response followed by resection of her remaining disease, 1 patient had stable disease, and 13 patients had disease progression. Three patients died of their disease without receiving sufficient gossypol to achieve detectable drug levels, and were eliminated from the final analysis. The side effects of gossypol were generally well tolerated; the only serious side effect was abdominal ileus that resolved when the drug was temporarily withheld and restarted at a lower dose. We conclude that oral gossypol can be used relatively safely on an outpatient basis for the treatment of metastatic adrenal cancer. The response rate is similar to the other agents currently available for adrenal cancer, and responses were seen in patients who had failed other chemotherapeutic regimens. This study provides the first indication that gossypol may have activity against cancer in humans, suggesting the need for further investigation of gossypol as an antitumor agent.

A B S T R A C T Adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) are related X-linked disorders characterized by adrenal, gonadal, and nervous system dysfunction. While the pathologic finding common to these tissues appears to be the accumulation of excessive amounts of very long chain fatty acids, the mechanism leading to functional impairment in these tissues is unclear.Measurements of fluorescence polarization (P), using the lipid probe diphenylhexatriene, demonstrate a highly significant increase in the microviscosity of erythrocyte membranes in affected patients (P = 0.286±0.012) vs. normals (P = 0.239±0.020). Analyses of these membranes by gas-liquid chromatography revealed 1.9-, 1.6-, and 1.3-fold increases above normal values in the C25:0, C26:0, and C27:0 fatty acids, respectively.These observations are compatible with previously obtained data in animals that correlate membrane microviscosity with the number of hormone receptors in target tissues. The present data support the thesis that a decrease in responsiveness to trophic hormones in ALD and AMN is secondary to changes in the membrane microviscosity of the target tissues and suggest a mechanism by which adrenal and gonadal failure occur in such patients.

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Studies using cultured human adrenocortical cells were performed to determine if the immune modulation of glucocorticoid production previously described in animal studies also occurs in humans. Human monocytes significantly increased (P less than 0.001) cortisol production from adrenocortical cells after 24, 48, and 72 h of culture. This stimulation was not CRH dependent, and the presence of CRH alone did not augment cortisol production. The active factor was soluble, since supernatants of monocyte cultures stimulated cortisol production by adrenocortical cells; ACTH levels in these supernatants were undetectable by RIA. While interleukin-1 also stimulated cortisol production by adrenal cells, the degree of stimulation was only 30% of that in the monocyte experiments. In contrast to previous animal studies, we found that human monocytes stimulate cortisol production by human adrenocortical cells by a factor that is neither CRH dependent nor mediated by immunoreactive ACTH-(1-24) or ACTH-(1-39).

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