Parathyroid hormone-related protein regulates the growth of orthotopic human lung tumors in athymic mice.

BACKGROUND: Parathyroid hormone-related protein (PTHrP) has growth regulatory effects for many malignant cells and may influence the progression of carcinomas of the breast, prostate, and lung. In the current study, the authors investigated the in vivo and in vitro effects of PTHrP neutralizing antibody and PTHrP treatment on the growth of BEN cells, a human lung squamous cell carcinoma line that expresses PTHrP and its receptor. METHODS: Orthotopic lung tumors were produced in 20 athymic mice with BEN-GFP cells (a clonal line that stably expresses green fluorescent protein [GFP]) by instilling suspensions of 3 x 10(6) cells per mouse into the lungs of anesthetized animals. The mice were divided into 2 groups receiving either subcutaneous mouse antihuman PTHrP antibodies or irrelevant mouse immunoglobulin (Ig) G (150 microg) twice weekly. RESULTS: After 30 days, 6 of 10 mice receiving anti-PTHrP antibodies had lung tumors visible on macroscopic inspection, but only 1 of the 10 mice treated with irrelevant IgG had a lung tumor that was of that size (P < 0.01). GFP fluorescence was significantly greater in lung homogenates of the PTHrP antibody-treated mice than in the mice treated with IgG (6006 +/- 411 vs. 2907 +/- 282 relative fluorescent units, respectively; P < 0.001). Although neutralizing antibodies stimulated BEN cell lung tumor growth, exogenous PTHrP 1-34 treatment (0.01-1 nM) inhibited the growth of cultured BEN cells by approximately 40%. CONCLUSIONS: Although PTHrP expression has been reported to be associated with more aggressive malignancies, the data from the current study suggest that PTHrP 1-34 was a paracrine growth inhibitor in BEN human lung carcinoma cells. The growth-related effects of PTHrP are complex, and can be both stimulatory and inhibitory.

Parathyroid hormone-related protein induces interleukin 8 production by prostate cancer cells via a novel intracrine mechanism not mediated by its classical nuclear localization sequence.

PTHrP (parathyroid hormone-related protein) overexpression by prostate carcinoma cells has been implicated in tumor progression. Although the biological effects of PTHrP can be mediated by the G-protein-coupled PTH/PTHrP receptor, PTHrP also has intracrine actions mediated by a nuclear localization sequence at residues 87-107. We investigated the effect of PTHrP transfection and treatment on production by prostate carcinoma cells of IL (interleukin)-8, which can regulate prostate cancer growth by angiogenic activity and growth-promoting effects. Six prostate cancer cell lines exhibited constitutive expression of PTHrP and IL-8 that were significantly correlated (r = 0.93; P < 0.01). We transfected wild-type and mutant PTHrP into these cells. Wild-type PTHrP1-173 and PTHrP33-173 lacking the PTH/PTHrP receptor-binding domain induced a 3-fold stimulation of IL-8 production but not production of another angiogenic factor, vascular endothelial growth factor. Transfection of the COOH-terminal truncation mutant PTHrP1-87 induced a 5-fold simulation of IL-8 and a 3-fold increase in IL-8 mRNA. Cells transfected with PTHrP1-87 and 1-173 also showed increased cell proliferation. In contrast, exogenous PTHrP1-34 and 1-86 peptides did not significantly affect IL-8 production; moreover, PTHrP-neutralizing antibodies did not inhibit the production of IL-8 by transfected PTHrP. Additional transfection studies with progressively COOH-terminally truncated PTHrP1-87 defined a 23-amino acid sequence, PTHrP65-87, required for PTHrP1-87 to robustly stimulate IL-8 in prostate cancer cells. Confocal microscopy and immunoassay demonstrated PTHrP1-87 nuclear localization. Our results demonstrate that PTHrP acts to induce IL-8 production in prostate cancer cells via an intracrine pathway independent of its classical nuclear localization sequence. This novel pathway could mediate the effects of PTHrP on the progression of prostate cancer.

Experience in laparoscopic hysterectomy: analysis of three hundred cases.

A personal experience with 300 cases of laparoscopic hysterectomy was analysed and its merits and demerits were discussed. The demographic features, indications, feasibility, complications, operating time, blood loss, hospital stay, cost effectiveness and its outcome were reviewed. The indications were uterine fibroid (40%), adenomyosis, dysfunctional uterine bleeding and pelvic inflammatory disease (36%), fibroid uterus with endometriosis (17.5%), postmenopausal bleeding (3%), ovarian neoplasm (2.1%) and fibroid uterus with ovarian cyst (1.4%). Two uterine malignancies and one case of potentially malignant ovarian neoplasm, were also encountered in our series. Assessibility score of above 20 was present in 55%. Haemorrhage was prevented intraoperatively by securing the large pedicles with electrocoagulation as well as large titanium clips (LT-400). Retrograde ureteric catheterisation was not necessary. Overall morbidity was present only in 10.62%. Intraoperative bladder injury was encountered in 1%, urinary fistula in 0.66%, primary and secondary haemorrhage in 0.33% respectively, and minor febrile morbidity in 4.66%. Conversion to conventional abdominal hysterectomy occurred in 0.66% of the cases. The average operating time was 141.99 +/- 31.678 min, the estimated blood loss was 237.07 +/- 76.76 ml and average hospitalisation was 3.37 +/- 0.66 days. The cost of laparoscopic hysterectomy was found similar to abdominal hysterectomy. Higher operating fee, operating theatre and anaesthesia charges did not affect the overall cost of laparoscopic hysterectomy because of shorter hospital stay. It is concluded that laparoscopic hysterectomy has definite role in gynaecological surgery.

Association of hypomagnesemia with diabetic retinopathy.

Serum magnesium was measured in 100 patients of type II diabetes mellitus (40 without retinopathy, 40 with non-proliferative and 20 with proliferative retinopathy) without malnutrition, hepatic or renal disease or albuminuria and in 100 age and sex matched controls. The serum magnesium levels were lower in diabetics than in controls (P less than 0.001), and the levels in diabetics with non-proliferative and proliferative retinopathy were significantly lower than in those without retinopathy (P less than 0.001). These data seem to point towards an association between hypomagnesemia and diabetic retinopathy.