Clinical assessment of the activity of tumor necrosis factor (TNF) against human cancer has been limited by a dose-dependent cardiovascular toxicity, most frequently hypotension. TNF is also thought to mediate the vascular collapse resulting from bacterial endotoxin. The present studies address the mechanism by which TNF causes hypotension and provide evidence for elevated production of nitric oxide, a potent vasodilator initially characterized as endotheliumderived relaxing factor. Nitric oxide is synthesized by several cell types, including endothelial cells and macrophages, from the guanidino nitrogen of L-arginine; the enzymatic pathway is competitively inhibited by -me yl-L-arginine. We found that hypotension induced in pentobarbital-anesthetized dogs by TNF (10 ,ug/kg, i.v., resulting in a fall in mean systemic arterial pressure from 124.7 ± 7 to 62.0 ± 22.9 mmHg; 1 mmHg = 133 Pa) was completely reversed within 2 min following administration ofNG-methyl-L-arginine (4.4 mg/kg, i.v.). In contrast, NG-methyl-L-arginine failed to reverse the hypotensive response to an equivalent depressor dose of nitroglycerin, a compound that acts by forming nitric oxide by a nonenzymatic, arginine-independent mechanism. The effect of NG-methyl-L-arginine on TNF-induced hypotension was antagonized, and the hypotension restored, by administration of excess L-arginine (100 mg/kg, i.v.). Our rmdings suggest that excessive nitric oxide production mediates the hypotensive effect of TNF.Tumor necrosis factor (TNF) is a cytotoxic protein produced by macrophages upon activation by bacterial endotoxin (1, 2). In addition to a spectrum of cytotoxic and immunologic actions, TNF causes marked hypotension in mammals (1, 3). The observations that bacterial endotoxin elicits TNF production (4, 5) and that pretreatment of animals with anti-TNF antibodies abolishes the hypotensive action of endotoxin (6) suggest that TNF is the key mediator of endotoxic shock in vivo. Although TNF is known to promote hemorrhagic necrosis of some animal tumors (7), its clinical promise as an antineoplastic agent is limited by severe dose-dependent side effects, predominantly hypotension (8, 9). Despite the clinical importance of TNF-induced hypotension, its mechanism is unknown.The present study addresses the possibility that increased nitric oxide production accounts for TNF-induced hypotension. Earlier studies established that endothelium-derived nitric oxide is a labile modulator of vascular tone (10, 11). Originally termed endothelium-derived relaxing factor (EDRF, ref. 12), nitric oxide is responsible for the vascular smooth muscle relaxation elicited by acetylcholine, bradykinin, and many other endogenous vasorelaxants. L-Arginine is the biosynthetic precursor of endothelium-derived nitric oxide (13)(14)(15)(16), and NG-methyl-L-arginine (L-MeArg) is a competitive inhibitor of this pathway (14, 15). The finding that administration of L-MeArg causes a moderate increase in blood pressure by an arginine-reversible mechanism in the anesthetized guine...

To evaluate the relative efficacy of cisplatin, cyclophosphamide, and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) (CISCA) versus methotrexate, vinblastine, Adriamycin, and cisplatin (MVAC), a prospective randomized trial was performed in patients with advanced metastatic urothelial tumors. Patients were stratified by histologic disease type and degree of tumor dissemination. Equal distribution of the clinical characteristics was achieved. One hundred ten patients with metastatic disease of the urinary tract (86 bladder, 16 renal pelvis, seven ureter, one prostatic urethra) met eligibility criteria and were enrolled on study. These represented 82% of the total patients seen during the study period in the Section of Genitourinary Oncology who met the eligibility criteria. The combined complete and partial response rate was significantly higher for patients treated with MVAC than for those treated with CISCA (65% v 46%; P less than .05). The survival duration of MVAC-treated patients was significantly longer than that of CISCA-treated patients (mean, 62.6 weeks; median, 48.3; range, 5.0+ to 162.3+ v mean, 40.4 weeks; median, 36.1; range, 7+ to 147.1+). We conclude that MVAC chemotherapy is superior to CISCA chemotherapy, achieving a higher response rate and a longer survival for equivalent patients with metastatic urothelial tumors.

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Clinical studies using biological response modifiers in cancer therapy have shown that the major dose-limiting toxic effects are hypotension and diffuse microvascular leakage. The cause and pathophysiology of this hypotension remains unknown. Previous experiments have demonstrated that a number of cell types, including endothelial cells, neutrophils, and macrophages, can secrete a potent hypotensive agent--endothelium-derived relaxing factor, which has recently been identified as nitric oxide. In this study, we tested interferon gamma, tumor necrosis factor, interleukin-1, interleukin-2, muramyl dipeptide, and endotoxin for their effects on production of nitrogen oxides by endothelial cells. Interferon gamma, in combination with tumor necrosis factor, interleukin-1 (IL-1), or endotoxin, induced murine brain endothelial cells to secrete nitrites (20-45 microM within 48 hr), which are breakdown products of nitric oxide. Nitrite production was blocked by incubation of endothelial cells in medium without L-arginine, a substrate for nitric-oxide synthase. Accumulation of nitrites was also inhibited by addition of NG-monomethyl-L-arginine (L-NMMA), which acts as a competitive inhibitor of this enzyme. The inhibitory effects of L-NMMA were reversed by addition of excess L-arginine. These results suggest (a) that endothelial cells produce nitric oxide in response to immunomodulators and (b) that endothelial cell-derived nitric oxide plays a role in the development of hypotension in patients treated with tumor necrosis factor or interleukins. Furthermore, administration of substrate analogues such as L-NMMA may favorably alter the toxicity associated with these immunomodulators and result in a higher maximum tolerated dose, with subsequent improvement in the antitumor activity.

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