In vivo and in vitro enhanced antitumor effects by pentoxifylline in human cancer cells treated with thiotepa

Methylxanthines enhance lethality of alkylating agents in human cancer cells, a phenomenon attributed to the prevention of DNA repair. Pentoxifylline is a nontoxic methylxanthine, used clinically for claudication. Using human cancer cells in culture or in a mouse xenograft model, we studied combination treatments with alkylating agents and pentoxifylline or other methylxanthines. With human bladder cancer cells in culture, cytotoxicity of thiotepa was increased up to 10-fold (P less than 0.01) by posttreatment with pentoxifylline, with a major clinical metabolite of pentoxifylline, or with caffeine; the pentoxifylline concentrations required (0.4-1.0 mM) are clinically achievable in the bladder after nontoxic p.o. doses. With human bladder or breast cancer xenografts in a modified subrenal capsule assay, enhancement of thiotepa was also observed by in vivo posttreatment with pentoxifylline. In contrast, these combinations produced no increased toxicity to normal tissues in these animals, measured by weight, lethality, or histological changes of the normal bladder urothelium. These results provide evidence for a novel approach to improve the therapeutic index of thiotepa and other alkylators, used for topical therapy of bladder cancer and, possibly, systemic therapy of other malignancies.     

Evidence for prostanoid biosynthesis as a biochemical feature of certain subclasses of non-small cell carcinomas of the lung as determined in established cell lines derived from human lung tumors

Detectable levels (greater than or equal to 0.2 pmol/10(6) cells) of one or more prostanoid species resultant to calcium ionophore A23187-induced biosynthesis from endogenous arachidonic acid were distributed in 28 cell lines derived from different histological classes of lung tumors as follows: large cell undifferentiated carcinoma (3 of 3 cell lines); adenosquamous carcinoma (1 of 2 cell lines); squamous cell carcinoma (0 of 2 cell lines); adenocarcinoma (9 of 10 cell lines); bronchioloalveolar cell carcinoma (2 of 2 cell lines); and small cell carcinoma (1 of 9 cell lines). Using the mean levels of 9 alpha,11 beta-prostaglandin F2, prostaglandin F2 alpha, prostaglandin D2, prostaglandin E2, thromboxane B2 and 6-keto-prostaglandin F1 alpha as an index of prostaglandin H (PGH) synthase activity, the distribution in cell lines representative of the different histological classes of human lung tumors exhibiting PGH synthase activity exceeding mean values greater than or equal to 2 pmol/10(6) cells was as follows: large cell undifferentiated carcinoma (3 of 3 cell lines), adenosquamous carcinoma (1 of 2 cell lines), adenocarcinoma (8 of 10) cell lines), bronchioloalveolar cell carcinoma (2 of 2 cell lines) and small cell carcinoma (0 of 9 cell lines). Three different prostanoid species accumulated to mean levels greater than or equal to 2 pmol/10(6) cells. Prostaglandin E2 levels exceeded 2 pmol/10(6) cells in 14 of the 16 cell lines in which this prostanoid accumulated to detectable levels. Cumulative levels of prostaglandin F2 alpha exceeded 2 pmol/10(6) cells in 9 of the 15 cell lines in which prostaglandin F2 alpha reached detectable levels. Detectable levels of thromboxane B2 were observed in five cell lines with thromboxane B2 accumulation exceeding 2 pmol/10(6) cells in two of the five cell lines. 9 alpha,11 beta-prostaglandin F2 and 6-keto-prostaglandin F1 alpha accumulated to detectable levels in the culture medium of one cell line, while prostaglandin D2 accumulation to detectable levels was observed in two cell lines. Stimulation of cultured human lung tumor cells exhibiting PGH synthase activity greater than or equal to 2 pmol/10(6) cells in the presence of 10(-5) M exogenous arachidonic acid resulted in a 2- to 4-fold increase in the accumulation of individual prostanoids, while the inclusion of a 10(-5) M exogenous concentration of arachidonic acid failed to stimulate detectable prostanoid production in human lung tumor cells in which PGH synthase activity was not previously expressed.(ABSTRACT TRUNCATED AT 400 WORDS)     

The increased risk of proximal colonic cancer after cholecystectomy

In a retrospective case control review we determined the cholecystectomy frequency of 479 index cases of colonic carcinoma and 479 age, sex, and admission date matched controls. The frequency distribution patterns of cholecystectomy with reference to subsite specific cancer of the large bowel were determined. The cholecystectomy frequency in patients with proximal colonic cancer was high than those in whom cancer was present in areas other than the proximal colon (12,3 per cent vs. 6.6 per cent, P<0.02). There was a gradient of previous cholecystectomy history from the proximal colon to the rectum. The overall frequency of previous cholecystectomy in the index cases was 8.1 per cent while that in the matched control was 5.4 per cent. The difference was not statistically significant. However, the cholecystectomy frequency of the proximal colonic cancer subgroup was significantly higher than its matched control group (12.3 per cent vs. 4.6 per cent, P<0.02). The difference was greater in females with proximal colonic cancer compared with their matched controls (14.3 per cent vs. 3.6 per cent, P<0.02). Our data supported the hypothesis that either(1) altered bile salt metabolism after cholecystectomy may increase colonic cancer formation, or (2) gallbladder disease and colonic cancer may share common etiologic factors.     

Prescription drug therapy in the podiatric outpatient population: interactions and precautions

A survey of 2,000 outpatients at the clinic of the Dr. William M. Scholl College of Podiatric Medicine was conducted analyzing both medications reported by the patients at the time of treatment and drugs by the attending podiatrist. The major groups of medications already used by the patients included diuretics, vitamins and minerals, nonsteroidal antiinflammatory drugs, cardiovascular medications, insulin and oral hypoglycemics, estrogen and thyroid hormone replacement, and antibiotics. Patients with asthma, ulcers, epilepsy, affective disorders and Parkinsonism represented significant subgroups. The major drugs used by podiatrists in the outpatient clinic included analgesics and antiinflammatory agents, local anesthetics, antibiotics, sedative-hypnotics, and a variety of topical agents. These two sources of medication serve as the basis for a review of drug interactions in the podiatric outpatient population. In addition, precautions for the use of drugs commonly administered by podiatrists are reviewed.     

The mortality rate from lung metastases in animals inhaling nitrogen dioxide (NO2)

A study was carried out to determine the interrelationship between the inhalation of nitrogen dioxide (0.4 +/- 0.50 ppm), lung metastases development from circulating cancer cells, and death rate from such metastases. C57 BL/6J mice were used in these experiments. Animals were divided into control and NO2-exposed groups, and were exposed to filtered air and 0.4 ppm of NO2, respectively. Following 12 weeks of exposure, all animals were infused intravenously with syngeneic, viable B16 melanoma cells. The results indicate that a subpopulation of NO2-exposed animals showed a significant increase in mortality rate during the early part of the experiment. The interpretation is that animals especially sensitive to the NO2 insult developed extensive metastases at an early stage. The question raised is whether or not the progression of human cancer is influenced by the inhalation of noxious pollutants in the ambient atmosphere.     

Novel anticholinesterases based on the molecular skeletons of furobenzofuran and methanobenzodioxepine

Reductive cyclization of 5-hydroxy-3-methyl-3-methoxycarbonylmethylenebenzofuran-2(3H)-one (4) gave 5-hydroxy-3a-methyl-2,3,3a,8a-tatrahydrofuro[2,3-b]benzofuran (5) and the rearrangement product 7-hydroxy-4,5-dihydro-2,5-methano-1,3-benzodioxepine (6). Reaction of compounds 5 and 6 with different isocyanates provided two series novel carbamates (7-12) whose structures were confirmed by X-ray crystallography. These were assessed for anticholinesterase action against freshly prepared human enzyme and proved to be potent inhibitors of either acetyl- (AChE) or butyrylcholinesterase (BChE) with specific compounds exhibiting remarkable selectivity. Because the two series of carbamates (7-12) differ in their phenolic moieties, their respective potency and selectivity for AChE versus BChE was governed by their N-substituted groups. This same characteristic was also present in a series of physovenine analogues (1, 13, 15, 17) and physostigmine analogues (2, 14, 16, 18). These structure-activity relations proved valuable in elucidating the mechanisms underpinning the interaction between carbamate-based cholinesterase inhibitors and their enzyme target. In addition, because physostigmine analogues have demonstrated activity in lowering the Alzheimer's disease protein, amyloid precursor protein (APP), examples of the two new series of carbamates were characterized in culture assays of quantifying cell viability and synthesis of APP.