Dual inhibition of the epidermal growth factor and vascular endothelial growth factor phosphorylation for antivascular therapy of human prostate cancer in the prostate of nude mice.

BACKGROUND: Androgen-independent prostate cancer (PCa) may be susceptible to modulation of the tumor microenvironment. We determined whether a dual tyrosine kinase inhibitor (AEE788) of the epidermal growth factor receptor (EGF-R) and vascular endothelial growth factor receptor (VEGF-R) combined with chemotherapy can produce therapy of human PCa in nude mice. METHODS: PC-3MM2 human PCa cells were injected into the prostate of nude mice. Three days later, the mice were randomized into four groups: saline control, paclitaxel, AEE788, and AEE788 and paclitaxel. The mice were treated for 5 weeks and necropsied. Tumor incidence, weight, and incidence of lymph node metastasis were recorded. Tumor tissue was analyzed immunohistochemically. RESULTS: Treatment of mice with AEE788 or AEE788 plus paclitaxel significantly decreased tumor incidence, total tumor weight, and incidence of lymph node metastasis. AEE788 treatment alone or in combination with paclitaxel inhibited the phosphorylation of EGF-R and VEGF-R on tumor cells and tumor-associated endothelial cells. Therapeutic efficacy correlated with an increase in apoptosis of tumor cells and tumor-associated endothelial cells. CONCLUSION: Blockade of EGF-R and VEGF-R signaling pathways coupled with chemotherapy suppressed the progressive growth and metastasis of human PCa cells growing orthotopically in nude mice.

Determining variables for repeat prostate biopsy.

During the evaluation of prostate cancer, men who have undergone transrectal ultrasound-guided biopsy with negative results present a dilemma as to what further follow-up is required. Multiple variables have been proposed throughout the literature to improve cancer detection rates not only in initial biopsy results, but also on repeat evaluation. These variables include prostate-specific antigen (PSA) velocity, PSA density, free-percent PSA, and histological findings, each of which may singly or collectively dictate the need for further biopsy. After performing a Medline literature search using specific Medical Subject Headings (prostate biopsy, repeat prostate biopsy, PSA velocity, PSA density, free-percent PSA, prostate inflammation), we critically evaluated pertinent articles. Using this accumulated data and information, we composed an algorithm to assist in the decision process for repeat biopsy.

Angiogenesis is not mediated by prostate cancer neuropeptides.

Once metastatic, prostate cancer (CaP) treatment options are limited to androgen withdrawal. In this environment, the cells often develop an androgen independent state resulting in patient demise. It has been shown that during this transition, CaP cells transdifferentiate to neuroendocrine cells, which produce neuropeptides. These neuropeptides have a mitogenic effect on surrounding CaP cells. Previous observations suggest that endothelial cells may show a similar mitogenic response to neuropeptides, implicating angiogenesis in the progression of CaP. We stimulated human umbilical endothelial cells (HUVECs) with the neuropeptides bombesin and neurotensin and measured proliferation, migration, cell tube formation, and tyrosine kinase activation. In our studies, neurotensin and bombesin did not stimulate HUVEC proliferation, migration, nor tube formation. Although HUVECs express the non-receptor tyrosine kinases Fak, Src, and Etk which mediate neuropeptide signaling in CaP, they are not activated by neuropeptides in HUVECs.

The effect of nicotine on in vitro sperm motion characteristics.

UNLABELLED: PURPOSE AND STUDY PLAN: Men who are habitual smokers tend to have poor semen quality. We studied the effect of nicotine on sperm motility in vitro. Spermatozoa from 13 normal fertile nonsmoking donors, washed free of seminal plasma, were treated with medium alone (control); and, 10 mM, 5 mM, 1 mM and 0.1 mM nicotine (concentrations estimated to approximate residual concentrations of nicotine in the testes of heavy smokers). Computerized sperm motion analysis (CASA) was done at 2, 4, 6 and 24 h after incubation. RESULTS: Sperm motility, beat/cross frequency, linearity and maximum anterior lateral head displacement (ALH max.) were significantly decreased across nominal dosages (P < 0.001 by repeated measures analysis of variance). Of the concentrations tested, 0.1 mM had no effect; 1 mM significantly decreased sperm motility (P = 0.003) and linearity (P = 0.02); 5 mM decreased the beat frequency (P = 0.001) and linearity (0.02); and 10 mM markedly decreased motility (P = 0.0001), beat frequency (P = 0.0002), linearity (P = 0.02) and ALH max. (P = 0.02). The interactions between dose and time were insignificant. CONCLUSION: Nicotine at concentrations of > or = 1 mM significantly decreased sperm motion characteristics after different periods of incubation, whereas 0.1 mM concentration had the least effect.