Stimulation of malignant growth in rodents by antidepressant drugs at clinically relevant doses.

Tricyclic antidepressants, such as amitriptyline (Elavil), and the nontricyclic agent, fluoxetine (Prozac), bind to growth-regulatory intracellular histamine receptors, associated with anti-estrogen binding sites in microsomes and nuclei. The prototype anti-estrogen binding site/intracellular histamine receptor ligand, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl, inhibits normal cell proliferation in vitro but stimulates tumor growth in vivo. Because of their structural similarity to N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl, we carried out studies to determine whether amitriptyline and fluoxetine stimulate tumor growth and/or development in rodents at concentrations relevant to the treatment of human depression (equivalent human dose range, approximately 100-150 mg/day for amitriptyline and approximately 20-80 mg/day for fluoxetine). All experiments were performed blinded. In studies of growth stimulation of transplantable syngeneic tumors, groups of mice were inoculated s.c. with C-3 fibrosarcoma cells or given i.v. or s.c. injections of B16f10 melanoma cells, followed 24 h later by daily i.p. injections of saline, amitriptyline, or fluoxetine. Tumor latency (fibrosarcoma), aggregate tumor weight (s.c. injected melanoma), or time to death from pulmonary metastasis (i.v. injected melanoma) was determined; drug-induced stimulation of DNA synthesis in C-3 fibrosarcoma cells in vitro was correlated with tumor growth acceleration in vivo. In a mammary carcinogenesis model, the effects of chronic saline, amitriptyline, or fluoxetine administration on the rate and frequency of development of mammary tumors in rats fed dimethylbenzanthracene (DMBA) were compared. Eight of 20 amitriptyline- or fluoxetine-treated mice developed fibrosarcoma tumors by day 5, as compared to none of 20 saline controls (P less than 0.002). Similarly, 20 of 21 DMBA-treated rats receiving the antidepressant drugs developed 33 mammary tumors by week 15 as compared to 5 tumors in 4 of 7 DMBA-treated rats receiving saline (P less than 0.001). For both models, tumor latency decreased 30-40% and, in the DMBA model, tumor frequency increased greater than 2-fold in the antidepressant-treated rats as compared to controls. Stimulation of fibrosarcoma growth in vivo correlated with a corresponding bell-shaped drug-induced increase in DNA synthesis in vitro. While the median time to death from pulmonary metastases did not differ among groups given i.v. injections of melanoma cells, a significant (P less than 0.01) stimulation of growth of s.c. injected melanoma was observed in mice receiving the antidepressants.(ABSTRACT TRUNCATED AT 400 WORDS)

Stimulation of in vivo tumor growth and phorbol ester-induced inflammation by N,N-diethyl-2-[4-(phenylmethyl)phenoxy] ethanamine HCl, a potent ligand for intracellular histamine receptors.

We have implicated histamine as a mediator of proliferation through its binding to novel intracellular receptors (HIC), closely associated with antiestrogen binding sites (AEBS) in microsomes and nuclei. N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl (DPPE), is a potent ligand for AEBS/HIC. We now demonstrate that DPPE stimulates in vivo tumor growth (DMBA-induced mammary cancer in Sprague-Dawley rats and L5178Y leukemia in DBA/2 mice) and synergizes with phorbol-12-myristate-13-acetate (PMA) to induce inflammation and mitotic activity in mouse epidermis. Thus, ligands for intracellular histamine receptors may represent a new class of tumor promoting agents; this finding lends new credence to an important role for histamine in growth.

Study of the in-vivo antioestrogenic action of N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl (DPPE), a novel intracellular histamine antagonist and antioestrogen binding site ligand.

N,N-Diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl (DPPE) binds with high affinity to the antioestrogen binding site (AEBS), but not to the oestrogen receptor. There is an association of AEBS with a novel intracellular histamine receptor (H1C) of micromolar affinity through which histamine acts as a second messenger. An optimal dose of 4 mg DPPE/kg antagonized the uterine growth-stimulating effects of oestradiol in immature oophorectomized rats. Unlike tamoxifen, DPPE alone was not a partial agonist, but decreased uterine size and weight below control values at concentrations between 0.1 and 75 mg/kg. DPPE also antagonized oestradiol-stimulated uterine growth at 72 h; the inhibition observed was not significantly different from that seen with tamoxifen. Oestradiol-treated animals receiving the combination of DPPE (4 mg/kg) + low dose tamoxifen (0.04 mg/kg) for 72 h had significantly smaller uteri than did those receiving the same dose of DPPE or tamoxifen alone. Histologically, either DPPE or tamoxifen antagonized oestradiol stimulation of eosinophil migration and glandular epithelial proliferation; the latter inhibition was significantly greater for DPPE + tamoxifen (0.04 mg/kg) than for the same dose of DPPE or tamoxifen alone. Unlike tamoxifen, DPPE did not antagonize oestradiol stimulation of luminal epithelial proliferation, but in the presence of oestradiol, DPPE significantly decreased tamoxifen (0.65 mg/kg)-induced hypertrophy of the luminal epithelium. Based on these findings, we suggest that binding to the AEBS/intracellular histamine receptor is important to the action of antioestrogens.

Endophthalmitis due to Blastomyces dermatitidis. Case report and review of the literature.

Blastomycosis very rarely affects ocular structures other than the eyelid. It is even more unusual for involvement to occur in the absence of active widespread disease. The authors report a 71-year-old woman with unresponsive endophthalmitis of the right eye who underwent enucleation. Results of microscopic examination of the globe showed severe acute and chronic granulomatous and nongranulomatous endophthalmitis as well as numerous fungi having the histologic features of Blastomyces dermatitidis. Although constitutional symptoms (weight loss, fatigue, night sweats) were noted by the patient, multiple investigations failed to disclose any evidence of systemic disease.

Malignant lymphoepithelial lesion of the submandibular salivary gland.

A case of malignant lymphoepithelial lesion (MLEL) occurring in the submandibular salivary gland of an Eskimo woman is presented. These unusual carcinomas have a striking frequency in Eskimos but are usually in the parotid gland. Cytology of fine-needle aspirated material demonstrated the cell type found by histologic examination. Electron microscopy confirmed a squamous differentiation of the malignant cells.

Chordoid sarcoma: ultrastructural evidence supporting a synovial origin.

A case of chordoid sarcoma which presented as a painful mass on the dorsum of the right hand in a 72-year-old man was studied by light and electron microscopy. The tumor was composed of lobules separated by thin connective-tissue bands. At the periphery of the lobules, the cells were epithelioid in appearacne and there were numerous nests of clear cells. From the periphery, stellate and spindle shaped cells were radially oriented and formed a loose cobweb arrangement in an abundant loose ground substance. Distinctive ultrastructural features included pseudoacinar formation, microvilli, long cytoplasmic filopodia (often with complex interdigitations), numerous desmosomes, partial basal lamina, scanty endoplasmic reticula, and numerous intracytoplasmic filaments 80--100 A in width. We believe these ultrastructural features indicate a synovial origin of this uncommon neoplasm.

The actinic cheilitis of hereditary polymorphic light eruption.

Sixty-four North American Indians with hereditary polymorphic light eruption (HPLE), or a family history of HPLE, had chronic, recurrent, exudative, and exfoliative cheilitis. Fifty-two had the cheilitis by the age of 10 years. Microscopically, the epithelium was either thickened, or thinned and covered by a thick crust. The dermis had a dense infiltration of inflammatory cells, mostly lymphocytes and plasma cells. The condition was not premalignant. The HPLE has to be differentiated from the chronic actinic cheilitis caused by long exposure to sunlight with out any element of hypersensitivity. The latter is potentially premalignant. Chronic recurrent actinic cheilitis associated with hereditary polymorphic light eruption appears to be a specific characteristic of photosensitivity occurring in American Indians. Plasma cell infiltration is not specific for either type of cheilitis.

Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons.

In a sibship of nine, six members had hereditary medullary carcinoma of the thyroid. Two of those with thyroid neoplasms and two without had numerous small papular skin lesions. These proved to be a type of pilar tumor that we named fibrofolliculoma. Further investigation of the total kindred of 70 showed no other evidence of thyroid neoplasm. Skin tumors only appeared after the age of 25 years. Fifteen of 37 members older than the age of 25 years exhibited the typical skin lesions. Obviously, the original sibship was the repository of two dominantly inherited traits. The fibrofolliculoma is characterized by abnormal hair follicles with epithelial strands extending out from the infundibulum of the hair follicle into a hyperplastic mantle of specialized firbrous tissue. Associated skin lesions in this kindred were trichodiscomas and acrochordons.

Insidious rifampin-associated renal failure with light-chain proteinuria.

A patient who was receiving rifampin treatment for tuberculosis developed heterogenous light-chain proteinuria and insidious renal failure after a period of fluid restriction. The renal damage was characterized pathologically by an interstitial nephritis with invasive tubular casts and an associated renal vein thrombosis. The possible role of the light-chain proteinuria in the pathogenesis of the renal failure is discussed.

Isolated liver nodules.

Thirteen examples of isolated liver nodules were examined in 7 persons, 4 with single nodules and 3 with multiple nodules. Pathologically they present a spectrum from a solid structure that resembles liver parenchyma with varying degrees of disorganization and fibrosis to soft and fatty enough to superficially resemble a lipoma. Abnormal blood vessels were commonly found in and around the nodules, and the nodules were all ischemic compared to surrounding normal liver. The association of abnormal blood vessels and ischemia may be a cause and effect relationship. Studies by angiography might prove two things: (1) that the presence of abnormal blood vessels is constant in the lesions; (2) that the vessels, although relatively large, fail to provide adequate blood supply to the area, either by lack of branches or by some type of shunting mechanism. Review of cases of "lipoma of the liver" reported in the literature suggest that the lesions described are, in fact, the fatty type of isolated liver nodules.

Simultaneous occurrence of sarcomas in a husband and wife.

The simultaneous occurrence of sarcomas in a husband and wife is documented. The wife first presented with an undifferentiated uterine sarcoma, and within six months of the onset of her disease her husband developed an anaplastic liposarcoma. This finding is considered in the light of recent evidence suggesting a possible viral etiology for human sarcomas.