Stimulation of apoptosis by sulindac and piroxicam.

1.Sulindac, cis-5-fluoro-2-methyl-1-(p-methylsulphinylbenzylidene)indene-3-ace tic acid, inhibits growth of colon polyps and cancers. This effect has been attributed to inhibition of prostaglandin synthesis but more recent observations indicate that, in vitro, cells that do not have cyclo-oxygenase nor RNA for synthesis of such enzymes are affected by sulindac. Therefore the presumptive effect is probably not correct.2.It has also been found that sulindac stimulates apoptosis. It is herein postulated that in tumour cells such effects may be due to interaction of the anionic form of the drug with protons in the intermembrane space of mitochondria to disrupt the potential across the inner mitochondrial membrane and thereby initiate apoptosis. Normal cells are not affected.

Desquamative interstitial pneumonitis and diffuse alveolar damage in textile workers. Potential role of mycotoxins.

Five of 88 workers at a textile plant developed interstitial lung disease. Biopsy specimens from the three initial cases demonstrated desquamative interstitial pneumonitis and diffuse alveolar damage. Two of these patients developed hypoxemic respiratory failure despite high-dose corticosteroid therapy. A survey of the remaining textile workers (questionnaires, chest radiographs, and pulmonary function tests) revealed one new case. This patient, and one other with a compatible presentation, improved clinically upon leaving the workplace and did not require therapy. A comprehensive assessment of the work environment was performed in search of potentially toxic respirable agents. We propose that these cases represent desquamative interstitial pneumonitis-like reactions, occupationally related to aflatoxin inhalation.

Adenomatous polyposis coli, protein kinases, protein tyrosine phosphatase: the effect of sulindac.

A putative explanation of the effect of sulindac on adenomatous colon and duodenal polyps from clinical observations and related in vitro experiments is presented. In cells with mutant APC genes, persistent high prostaglandin content of polyps leads to desensitization, downregulation of adenylate cyclase, uncoupling of cAMP synthesis from prostaglandin, and inactivation of protein kinase A (PKA). It is suggested that in normal cells, (APC) protein binds to catenins and microtubules to maintain structure and contribute to cell-cell communication, adherence, and the dephosphorylated state, a necessary condition for such functions. Cells with mutant APC product become isolated, deprived of communication and adhesion to other epithelial cells, overphosphorylated, and without corrective capability. The latter is largely due to downregulation of cAMP synthesis and protein kinase A activity secondary to high prostaglandin. Three main biochemical defects ensue: (1) the restrictive influence of PKA catalyzed phosphorylation of Raf-1 kinase and resultant effects on the MAP kinase cascade and transcription is lost, (2) the transcription of immediate early genes, including cyclooxygenase is stimulated, and (3) the stimulation of protein tyrosine phosphatase (PTPase) by PKA is in abeyance. These putative abnormalities are reversed by inhibition of cyclooxygenase-1 by sulindac. cAMP synthesis and PKA activity return to normal. PKA catalyzed phosphorylations block Raf-1 kinase at the confluence of the Ras and protein kinase C pathways. The MAP kinase cascade is inhibited as is transcription of immediate early genes. At the same time PKA stimulates PTPase, which dephosphorylates the cytoskeleton and restores cell-cell communication, adherence, and structure. The transformed phenotype is circumvented by adjustment of the phosphorylation state and mutant cells rejoin the epithelial community. The redox state of cytoplasm in mutant cells may be shifted toward reduction.

The effect of sulindac on colon polyps: circumvention of a transformed phenotype--a hypothesis.

Sulindac suppresses the growth of colon polyps in Gardner syndrome and familial adenomatous polyposis. The mechanism of action is not known. The problems are to ascertain the significance of high prostaglandin concentrations in transformed cells, colon polyps and cancers and to explain how sulindac restores normal growth patterns. A few clinical observations and an abundance of experimental data can be integrated to produce a reasonable model based on current biochemical and physiologic concepts. A fundamental defect in the formation of colon polyps is mutation of the APC (adenomatous polyposis coli) gene that leads to inadequate suppression of proliferation. There is high PGE2 content in colon polyps and cancers, presumably the result of stimulation by protein kinase C (PKC). In small quantities it stimulates cyclic AMP production but with persistent high concentrations it desensitizes and down-regulates specific PG receptors and inactivates adenylate cyclase, cAMP synthesis, and the cAMP-dependent mechanism for control of proliferation. The PKC pathway is thereby unopposed. It is hypothesized that restriction of PG synthesis by sulindac is accompanied by resensitization of PG receptors, and reactivation of the cAMP-dependent pathway for control of cell growth. It is further postulated that restoration of cAMP synthesis and protein kinase A activity converts a functionally inadequate mutant APC suppressor gene to one sufficient to inhibit colon polyp formation.

Tremorgenic encephalopathy: a role of mycotoxins in the production of CNS disease in humans?

We describe a young man who, shortly after exposure to moldy silage, developed a neurological syndrome consisting of dementia and a remarkable tremor which was precipitated by movement. All symptoms resolved within one week. Despite investigation, no definitive diagnosis was reached. We propose that this patient's illness may have resulted from inhalation exposure to a tremorgenic mycotoxin.

Testolactone, sulindac, warfarin, and vitamin K1 for unresectable desmoid tumors.

Ten patients with large inoperable desmoid tumors in various body locations were treated with testolactone. Four tumors (40%) responded with major regressions, i.e., more than 50% reduction in volume. Eight patients received nonsteroid anti-inflammatory drugs (indomethacin, sulindac, or sulindac with warfarin and vitamin K1 [Mephyton]) for periods of 2 to 91 months. There was one major regression, one partial regression, and three instances of tumor growth arrest over periods up to 8 years. Seven patients were treated with nonsteroid anti-inflammatory drugs concurrent with or after testolactone or tamoxifen. There were five major regressions and one partial regression with extensive central necrosis of an enormous intra-abdominal tumor. The last patient has been treated for only 12 months, with no change in tumor volume. It appears that estrogens function as growth factors for desmoid tumors, and that minimization of these effects inhibits tumor growth in some, but not all, cases. In those instances where antiestrogens were not effective as single agents, the tumors usually responded to subsequent nonsteroid anti-inflammatory drug therapy. Withdrawal of estrogen may be followed by inhibition of transcription of genes that support tumor cell proliferation, and sulindac and indomethacin may augment these effects by inhibiting prostaglandin and cyclic AMP synthesis and the activity of protein kinase C. Warfarin may function as a protonophore to acidify the cytoplasm and prevent the alkalinization that is necessary to initiate DNA synthesis and cell cycle progression, again an impairment of the transcription process.

A special scanner speeds orders for this lab and its satellites.

The authors' laboratory integrated optical mark readers with its existing mainframe computer system to streamline order processing--and improved staff morale as well.

Sulindac for polyposis of the colon.

The effect of sulindac, a nonsteroid antiinflammatory drug, on colon polyposis has been evaluated in seven patients after subtotal colectomy and ileoproctostomy and in four patients with intact colons. The patients all had Gardner's syndrome or familial polyposis coli. All polyps were eliminated, except for a few that arose in the rectal mucosa and the anal canal. No cancers developed in these patients on follow-up.

Sulindac for polyposis of the colon.

Four members of a Gardner's syndrome family had rectal and colon polyposis treated with nonsteroid anti-inflammatory drugs. Three of these patients had had subtotal colectomy and ileoproctostomy and the residual polyps arose in the rectal mucosa. The polyps almost completely disappeared when sulindac was administered. Indomethacin therapy over the course of a preceding year was ineffective in one of these patients. One patient (case 4) had diffuse polyposis in an intact colon. After sulindac therapy for a year, only three small mucosal polyps could be identified by air contrast barium enema and colonoscopic examination. These observations confirm those of Pollard and Luckert [1,2] on rats with chemically induced polyposis of the intestinal tract.

Nonsteroid antiinflammatory drugs and tamoxifen for desmoid tumors and carcinoma of the stomach.

The results of treatment of desmoid tumor patients with nonsteroid antiinflammatory drugs alone or in combination with tamoxifen are described. Tumor growth was inhibited in six of seven patients. Nonsteroid antiinflammatory drugs administered along with 5-fluorouracil and cyclophosphamide and other inhibitors of T-suppressor cells were used to treat nine patients with metastatic carcinoma of the stomach. Survival of these patients was extended so that after 12 months minimal follow-up the majority are well. A prospective controlled clinical trial is indicated.

Indomethacin and ascorbate inhibit desmoid tumors.

Administration of indomethacin caused complete resolution of a desmoid tumor after a partial response to radiation. In another patient, this drug caused an immediate response, then became ineffective. When large doses of ascorbic acid were given with indomethacin, slow resolution of the tumor began and has continued for 14 months. Treatment of a third case with indomethacin and ascorbic acid from the beginning produced shrinkage of the tumor which has continued to date.

Epithelioid sarcoma: case report with ultrastructural review, histogenetic discussion, and chemotherapeutic data.

A case of abdominal wall epithelioid sarcoma, studied by light and electron microscopy over a 3-year period, is presented. Ultrastructurally, there appear to be two types of tumor cells, light and dark, which differ by virtue of a heavier concentration of microfibrils and dilated rough endoplasmic reticulum in the dark cells. Both tumor cell types contain prominent Golgi systems, abundant free ribosomes, and numerous pinocytotic vesicles. The ultrastructural characteristics of the tumor cells resembel those of epithelioid cells of experimental human granulomas, as well as those of normal human synovium. A multifaceted relationship between histiocytes and synovial cells is demonstrated and it is concluded that the tumor is probably derived from mesenchymal reserve cells capable of differentiating a long histiocytic or synovial lines. Preliminary chemotherapeutic data are reviewed.

Treatment of intra-abdominal and abdominal wall desmoid tumors with drugs that affect the metabolism of cyclic 3',5'-adenosine monophosphate.

A female patient with Gardner's syndrome was treated with delta1-testololactone (200 mg daily) because of growth of a large desmoid tumor in the pelvis and lower abdomen and a tumor in a scar from a previous laparotomy. There was also pain and swelling of the left leg. An immediate effect of the drug therapy was complete relief of pain followed shortly thereafter by disappearance of the edema of the leg. After two months, the numerous sebaceous cysts were less prominent. The gross measurements of the diameter of the pelvic and lower abdominal tumor clearly demonstrated tumor shrinkage following therapy. Small polyps scattered over the rectal mucosa and numerous osteomata were not demonstrably affected. After one year of treatment with delta1-testololactone, a laparotomy for partial small bowel obstruction was necessary. Obstruction was caused by the involvement of small bowel mesentery and the bowel itself in a contracted residuum of dense fibrous tissue. Substitution of theophylline and chlorothiazide for the testololactone in Januray 1974 was followed by further diminution of the measurable abdominal and pelvic desmoids. All of these compounds synergize the action of 3',5'-adenosine monophosphate and at least the latter two may function by inhibiting the action of 3',5'-adenosine monophosphate diesterase.