Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice.

Phosphorylation of tyrosine residues on the epidermal growth factor (EGF) receptor (EGFr) is an important early event in signal transduction, leading to cell replication for major human carcinomas. CP-358,774 is a potent and selective inhibitor of the EGFr tyrosine kinase and produces selective inhibition of EGF-mediated tumor cell mitogenesis. To assess the pharmacodynamic aspects of EGFr inhibition, we devised an ex vivo enzyme-linked immunosorbent assay for quantification of EGFr-specific tyrosine phosphorylation in human tumor tissue specimens obtained from xenografts growing s.c. in athymic mice. When coupled with pharmacokinetic analyses, this measurement can be used to describe the extent and duration of kinase inhibition in vivo. CP-358,774 is an effective, orally active inhibitor of EGFr-specific tyrosine phosphorylation (ED(50) = 10 mg/kg, single dose). It has a significant duration of action, producing, on average, a 70% reduction in EGFr-associated phosphotyrosine over a 24-h period after a single 100 mg/kg dose. Inhibition of EGFr phosphotyrosine in an ex vivo assay format effectively estimates the potency and degree of inhibition of EGFr-dependent human LICR-LON-HN5 head and neck carcinoma tumor growth. Substantial growth inhibition of human tumor xenografts was achieved with p.o. doses of the compound (ED(50) = 10 mg/kg q.d. for 20 days). Combination chemotherapy with cisplatin produced a significant response above that of cisplatin alone with no detectable effects on body weight or lethal toxicity. Taken together, these observations suggest that CP-358,774 may be useful for the treatment of EGFr-driven human carcinomas.

Quantitative structure-activity relationships of antitumor guanidinothiazolecarboxamides with survival enhancement for therapy in the 3LL Lewis lung carcinoma model.

Guanidinothiazolecarboxamides (GTCs) are a novel class of antitumor agents found to be systemically active against experimental pulmonary metastases of 3LL Lewis lung carcinoma. A series of substituted benzothiazole GTCs were found to produce enhancement of survival in this model by using 8 days of intraperitoneal dosing initiated 2 days after intravenous tumor challenge. Quantitative structure-activity relationships have been discovered in the GTC series with survival enhancement correlated to substituent parameters. Optimal correlations were found between the probit transform of the drug-induced increased lifespan (ILS) and field and pi parameters. Among the most effective analogues in this series was N-(5-fluorobenzothiazol-2-yl)-2-guanidinothiazole-4-carboxam ide.

Nephrotic syndrome in two patients with cured Hodgkin's disease.

Two cases of lipoid nephrosis (minimal change glomerulonephritis) in patients cured of Hodgkin's disease are reported and the literature is reviewed. Cases reported to date have shown a close temporal relationship between this renal lesion and the presence of Hodgkin's disease. The patients reported are 11 and 9 years without evidence of active malignancy after successful treatment for Hodgkin's disease. Each had abnormal immunologic parameters, depressed T4 (helper) cells and increased T8 (suppressor) cells, which may predispose to the development of the nephrotic syndrome. However, the advent of this complication is not necessarily a harbinger of recurrent lymphoma.

Albumin excretion by the kidney: the effects of volume expansion.

With the use of a highly sensitive radioimmunoassay for rat albumin, urine albumin excretion rate (UalbV) was measured under baseline conditions and following saline-induced volume expansion. Volume expansion was associated with a significant increase in glomerular filtration rate (GFR), urine volume (V), fractional excretion of sodium (FEna), and UalbV (p less than 0.002). The increase in UalbV correlated far better with the increase in GFR than the increase in F and FEna, which suggests that volume expansion results in an increased albumin filtration with saturation of the tubular reabsorptive capacity.