Intrathecal ACNU against experimental leptomeningeal tumors

Therapeutic efficacy and cell kinetics of intrathecal ACNU, 3-(4-amino-2-methyl-5-pyrimidinyl) methyl-1-(2-chloroethyl)-1-nitrosourea, were investigated in experimental meningeal carcinomatosis rats. Therapeutic effect of intrathecal ACNU (IT ACNU) against meningeal carcinomatosis model was evaluated in rats induced by intracisternal inoculation of Walker 256 carcinosarcoma cells. The median survival time of the rats treated with IT ACNU 1.5 mg/kg on day 5 after tumor inoculation was significantly increased by 145% as compared with that of non-treatment rats. The cell kinetics was studied immunohistochemically using indirect immunoperoxidase method with bromodeoxyuridine (BrdU) and anti-BrdU monoclonal antibody (Becton-Dickinson). The meningeal carcinomatosis rats were treated with IT ACNU (1.5 mg/kg) on the fifth day after tumor inoculation. Before and 12, 24, 48, 96 or 144 hours after treatment, the rats received intravenous BrdU (200 mg/kg) injection. Thirty minutes later, the rats were sacrificed and the brains were removed. Brain sections were stained immunohistochemically with anti-BrdU monoclonal antibody. Labeling index (LI) which represented the percentage of tumor cells in synthetic phase was obtained by counting immunoreactive cells under the microscope. Before treatment, LI was around 34% on day 5 after tumor inoculation and dropped to below 20% 12 to 48 hours after IT ACNU. However, it increased to around 36% on day 4 after IT ACNU. The antineoplastic effect of IT ACNU against meningeal carcinomatosis rats might be expected in the early stage of intrathecal administration.     

The breast cancer screening controversy and the National Institutes of Health Consensus Development Conference on Breast Cancer Screening for Women Ages 40-49

PURPOSE: Unaccustomed exercise is associated with an elevated plasma creatine kinase (CK), myofibrillar inflammation, and delayed onset muscle soreness (DOMS). Nonsteroidal antiinflammatory drugs (NSAID) may attenuate DOMS and indirect indices of inflammation in humans. METHODS: We studied the effects of an NSAID (naproxen sodium (500 mg, 2 times a day for 48 h)) taken before and after resistance exercise in eight healthy, moderately trained men in a randomized, double-blind trial. The exercise consisted of unilateral knee concentric/eccentric weight lifting with 6 sets x 10 repetitions at 80-85% of the 1 repetition maximal contraction. Muscle biopsies of each vastus lateralis (EX = exercised/REST = control) were taken 24 h after exercise for immunohistochemical staining of inflammatory cells (leukocyte common antigen). At 24 and 48 h postexercise, we also determined DOMS, plasma CK activity, and knee extensor muscle torque. RESULTS: Exercise resulted in an increased CK activity at +24 and +48 h (vs preexercise: P < 0.01), with no treatment effect. There were no treatment effects for any of the measured variables except for a return of voluntary knee extension torque to baseline by +48 h postexercise for NSAID treatment (P < 0.05). CONCLUSIONS: NSAID administration did not alter CK rise, muscle force deficit at 24 h postexercise, nor perceived muscle pain. In addition, the increased CK at 24 h postexercise was not associated with an acute myofibrillar inflammatory cell infiltrate in moderately trained men after resistance exercise.     

Inhibitory effects of oral administration of ginsenoside Rh2 on tumor growth in nude mice bearing serous cyst adenocarcinoma of the human ovary

We examined the inhibitory effect of the oral administration of ginsenoside Rh2 (Rh2) on tumor growth in nude mice bearing human ovarian cancer cells (HRA). In the first experiment, it was revealed that daily administration of 30 microM Rh2 significantly inhibited tumor growth. In the second experiment, therefore, various concentration of Rh2 (1, 15, 30, 60, 120 microM) were administered every day for 91 days, beginning the day after tumor inoculation. Treatment with Rh2 resulted in a remarkable retardation of the HRA cell tumor growth. In particular, tumor growth in mice treated with 15, 30 and 120 microM Rh2 was significantly inhibited, compared to that in CDDP treated mice as well as in untreated mice. Consequently, 50% survival in nude mice treated with 15, 30 and 120 microM Rh2 was significantly prolonged, compared to that not only in untreated mice but also in CDDP treated mice. No side effect was observed in any mice treated with Rh2. Red ginseng containing Rh2 has been used exclusively, orally administered. In the present study, we considered that oral administration of Rh2, which is a component of red ginseng, has strong inhibitory effects on human ovarian cancer cell growth in nude mice.     

Platelet-derived growth factor reverses the effects induced by NSAIDs on ulcer healing

BACKGROUND: It is known that non-steroidal anti-inflammatory drug (NSAID) use delays the healing of peptic ulcers and that growth factors play an important role in the ulcer healing process. AIM: To evaluate the effect of platelet-derived growth factor (PDGF) in healing chronic gastric ulcers in rats treated with NSAIDs. METHODS: Chronic gastric ulcers were induced with acetic acid in male Wistar rats and then treated with either aspirin (100 mg/kg/day), indomethacin (2 mg/kg/day), PDGF-BB (0.1 nM/kg/day) or combinations. Gastric secretion and ulcer size, wound contraction, mucosal regeneration and cell proliferation were assessed in histological specimens. RESULTS: Both aspirin and indomethacin delayed the healing rate of gastric ulcers and reduced ulcer contraction, mucosal regeneration and cell proliferation. All these effects were completely reversed by oral treatment with PDGF-BB without affecting gastric acid secretion. CONCLUSION: Oral administration of PDGF accelerates ulcer healing and reverses the effects induced by NSAIDs on ulcer healing without affecting gastric secretion.     

Surgery for asymptomatic carotid stenosis: a study of three patient subgroups

Increasing evidence suggests that non-steroidal anti-inflammatory drugs (NSAID) differ in gastrotoxicity. This study aimed to compare the effects of a short-acting NSAID, tiaprofenic acid, with indomethacin on experimental gastric ulcer healing in a rat model. Similar anti-inflammatory and prostaglandin-inhibitory doses of indomethacin (1 mg/kg) and tiaprofenic acid (2 mg/kg) were administered to rats with acetic acid-induced ulcers. After 2 weeks treatment, rats were killed and ulcer size determined. In addition, histological sections of ulcers were assessed for ulcer contraction and mucosal regeneration. The degree of inhibition of prostaglandin E2 (PGE2) synthesis was 72% at 2 h after tiaprofenic acid and 64% at 2 h after indomethacin administration, respectively. Rats treated with indomethacin for 2 weeks had significantly larger ulcers, both macroscopically and microscopically, than controls. Rats treated with tiaprofenic acid for 2 weeks had ulcers of a similar size to those of controls. Indomethacin-treated ulcers showed a failure in mucosal regeneration. Tiaprofenic acid-treated ulcers had significantly more regeneration than indomethacin-treated ulcers. We conclude that tiaprofenic acid inhibits mucosal prostaglandin levels but does not inhibit experimental gastric ulcer healing. These findings suggest that inhibition of PGE2 synthesis is not the only factor in generating gastrotoxicity and that a shift to low gastrotoxic NSAID may be clinically worthwhile.     

Physical and chemical properties of DMP 504, a polyalkylammonium-based bile acid sequestrant

In an open, controlled, multi-centre clinical field trial, seven 'naturally occurring' outbreaks of acute febrile (rectal temperature > or = 39.5 degrees C) respiratory disease in housed calves were treated with a single antimicrobial agent, and either the non-steroidal anti-inflammatory drug (NSAID) carprofen (n = 95) or flunixin meglumine (n = 92) on an alternate basis. Carprofen was administered as a single subcutaneous injection at a mean dosage of 1.4 mg kg-1 (range 1.2 to 1.9 mg kg-1) body weight on the first day and flunixin meglumine by intravenous injection at a mean dosage of 2.0 mg kg-1 (range 1.2 to 2.6 mg kg-1) body weight on the first 3 consecutive days. All calves were examined clinically immediately prior to initial treatment and on three occasions up to 1 week after the end of treatment. There were no statically significant differences between NSAID groups in reduction of clinical parameters between examinations, or in overall efficacy. This trial demonstrated that a single dose of carprofen was equally effective as three daily doses of flunixin meglumine as adjunctive therapy to antimicrobial treatment in acute respiratory disease in calves.     

Effect of intracerebral administration of Corynebacterium parvum on the growth of brain tumors in mice

The effect of intracerebral administration of Corynebacterium parvum (C. parvum) on the growth of syngeneic brain tumors in C57BL/6 mice and the mechanism of its action were investigated. Mice were inoculated with 10(4) malignant glioma cells intracerebrally, and treated with various doses of C parvum on day 6 after tumor inoculation. The growth of tumors was significantly inhibited in proportion ot the dose of C. parvum. The cytotoxic activity of effector cells was enhanced when C. parvum was administered at the site of tumor inoculation. Significant cytotoxic activity was observed in the adherent cell fraction of brain mononuclear cells, while less cytotoxic activity was observed in the nonadherent cell fraction. These results indicate that activated intracranial macrophages may participate in the tumoricidal effect of intracerebral C. parvum administration.     

Effect of the NSAID flurbiprofen on remodelling after periodontal surgery

The aim of the present experiment was to assess the effect of the administration of the NSAID flurbiprofen (Froben) on tissue healing after periodontal surgery. Sites from patients with the same treatment modality (modified Widman flap) but receiving a placebo drug and sites within each patient not exposed to surgery served as controls. Nineteen patients suffering from moderate to severe periodontal disease were recruited and they signed informed consent forms. These patients required periodontal surgery as assessed at the periodontal re-evaluation. The sites chosen for the study were all diagnosed with PPD > or = 5 mm and were bleeding on probing. During the healing phase 10 patients received 50 mg Froben 3 times per day for 30 d whereas 9 patients received a placebo drug. Two sites with PPD > or = 5 mm after initial therapy and bleeding on probing served as surgical sites, whereas 2 similar sites were not exposed to surgery. The study design was set up double-blind. The radiographic examination consisted of 2-4 standardized vertical bitewings obtained at the periodontal re-evaluation (BL) at 1, 3 and 6 months post-surgically for digital subtraction and computer assisted densitometric image analysis (CADIA). The regions of interest analysed were mesial or distal crestal sites. Minimal remodelling activity was observed radiographically after periodontal surgery in both patient groups. There were no statistically significant differences between the four groups of sites regarding the mean changes in density when analysing the pairs of radiographs 0-1, 0-3, 0-6 months. A frequency analysis was performed to list the number of sites with different ranges of density change. No differences in the distributions of the numbers of sites were observed when comparing the 4 site groups (Kolmogorov-Smirnov, p > 0.05). A significant reduction of the probing pocket depth and a significant amount of clinical attachment gain was noted at the surgically treated sites irrespective of whether the patients had used flurbiprofen or placebo. Whereas the pathways leading to bone resorption in periodontally diseased sites have been shown, in other studies, to be influenced by NSAID, the results of the present study could not justify general administration of Froben for the purpose of reduction of bone resorption after periodontal surgical procedures in patients with adult periodontitis.     

Brief social work intervention in the hospice setting: person-centred work and crisis intervention synthesized and distilled

We analysed the effects of strychnopentamine, an alkaloid isolated from Strychnos usambarensis, on an Ehrlich ascites tumor growing in the mouse after inoculation. Four subcutaneous injections of 1.5 mg strychnopentamine (1 per day) induce a significant decrease of the number of tumor cells and a significant increase of the survival of the treated mice. Observed side effects are partial haemolysis and some liver damage.     

A randomized double blind trial of verbal NSAID education compared to verbal and written education

OBJECTIVE: We performed a double blind randomized controlled trial to investigate whether patients taking nonsteroidal antiinflammatory drugs (NSAID) knew more about these drugs at followup depending on whether they were randomized to receiving or not receiving an NSAID information sheet. The patients were unaware they were in a study. METHODS: All patients received verbal education on the side effects of NSAID that was standardized and always given by the same rheumatologist. Thirty patients randomly received an NSAID information sheet and 26 patients did not. At next clinic followup, after reading a letter of explanation about the study and signing a consent form, patients completed a questionnaire asking about their knowledge of NSAID. RESULTS: Outcome variables assessed within the questionnaire included whether NSAID : (1) can decrease inflammation; (2) help with pain; (3) cause stomach upset and bleeding in the bowels. None of these variables were statistically significant. The only variable that was statistically significantly different between the groups was their report of whether they had received an information sheet about NSAID (p<0.00004). A greater proportion of patients who received the NSAID information sheet correctly reported they had received one compared to those who had not received one and who said they had not received one (85% in the former group, 70% in the latter group). The group who received the NSAID information sheet were more apt to say that NSAID can help with their pain (odds ratio 6.1, p<0.05). Education level was positively correlated with knowledge (p<0.04). However, level of education explained only 11% of the variance in overall knowledge scores (r=0.34) among all patients. CONCLUSION: An information sheet may not add educational value over verbal information by a physician in a clinic setting.     

Differential diagnosis of cervical lymphadenopathy with intranodal color Doppler flow signals in patients with oral squamous cell carcinoma

OBJECTIVE: To investigate the mechanism by which pilocarpine causes increased aqueous humor (AH) flare, hypotony, and miosis in dogs. ANIMALS: 6 dogs with normal eyes. PROCEDURE: Both eyes of each dog were treated topically with a 2% solution of pilocarpine, and 1 eye of each dog was additionally treated with commercially available ophthamic solutions. Breakdown of the blood-aqueous barrier (BAB) was quantitated in each eye, using laser flaremetry to measure AH flare. Intraocular pressure and pupil size were also measured. RESULTS: Pilocarpine caused increased flare from BAB breakdown that was inhibited by the drugs tested. Inhibition (most to least) of BAB breakdown was flurbiprofen more than diclofenac, proparacaine, or suprofen, which were more than 0.125 or 1.0% prednisolone. Inhibition appeared dose-dependent and caused consensual inhibition in the contralateral eye. Intraocular pressure was decreased only in proparacaine-treated eyes and increased in eyes treated with nonsteroidal anti-inflammatory drugs (NSAID). Flurbiprofen and proparacaine were the most effective at blocking miosis. CONCLUSIONS: Pilocarpine produced a predictable, reproducible BAB breakdown in dogs. Miosis and increased AH flare were inhibited equally by proparacaine or NSAID, suggesting that these signs were caused by neuropeptide release into the AH from antidromic stimulation, which subsequently triggers prostaglandin production. Hypotony was inhibited only by anti-inflammatory drugs. CLINICAL RELEVANCE: Proparacaine in combination with pilocarpine would be the best choice for treating dogs with acute glaucoma. Topical administration of NSAID should not be used to treat dogs with acute glaucoma, because they increase intraocular pressure and negate the effects of pilocarpine.     

A molecular model of myelin oligodendrocyte glycoprotein

We evaluated the mechanism of the antitumor effects of mouse rIFN-gamma-inducing factor/IL-18 protein on the growth of mouse tumor cell lines in vivo. Mice received IL-18 before or after challenge with CL8-1, a mouse melanoma cell line. Both regimens significantly suppressed tumor growth and reduced the number of mice with growth of tumor from 60% (3/5) to 20% (1/5). Furthermore, IL-18 administered before and after tumor inoculation completely abrogated the establishment of CL8-1 in all animals. IL-18 administration also significantly suppressed the growth of MCA205, a sarcoma cell line, even when treatment was delayed to 7 days following tumor inoculation. Although IL-18/IL-12 combination therapy had the most significant and immediate antitumor effects, many mice so treated succumbed with markedly elevated serum IFN-gamma levels. The antitumor effects of IL-18 were abrogated almost completely when NK cells were eliminated using anti-asialo GM1 Ab administration, but only marginally impaired in IFN-gamma or IL-12 gene-disrupted mice. Immunohistochemical staining revealed that the number of the CD8+ T cells, but not CD4+ T cells, found at the tumor site was reduced in animals treated with IL-18. These results indicate that IL-18 has potent antitumor effects mediated by CD4+ T cells and NK cells, but in IFN-gamma- and IL-12-independent pathways.     

Effects of an allicin-based product on cryptosporidiosis in neonatal calves

OBJECTIVE: To evaluate effectiveness of an allicin-based product in neonatal calves inoculated with Cryptosporidium parvum. DESIGN: Randomized controlled study. ANIMALS: 43 neonatal calves. PROCEDURE: Calves were inoculated with 1.5 x 10(8) or 7.5 x 10(5) C parvum oocysts within 2 days after birth. Calves were given an allicin-based product once after inoculation or daily for 7 days after inoculation or were not treated. Calves that developed diarrhea were treated by administration of the product. Fecal consistency scores and weight gains were statistically evaluated. RESULTS: Mean daily weight gain and severity of diarrhea in calves 4 to 21 days old were unaffected by prophylactic use of the product. However, intensive prophylactic administration may have delayed onset of C parvum-induced diarrhea in calves inoculated with the lower dose of oocysts. CLINICAL IMPLICATIONS: Administration of an allicin-based product did not alter duration of C parvum-induced diarrhea or enhance weight gain in neonatal calves. However, intensive prophylactic administration of an allicin-based product may delay onset of diarrhea in calves exposed to C parvum oocysts.     

Does the preoperative administration of ketorolac improve postoperative analgesia

AIM OF THE STUDY: 1) To verify the usefulness of ketorolac administration (30 mg i.v.) before a surgical operation in terms of postoperative analgesia improvement; 2) To evaluate the impact of preoperative ketorolac administration on perioperative renal function and on intraoperative water balance; 3) to evaluate the presence of adverse effect due to preoperative NSAID use. DESIGN: Prospective randomized trial. SETTING: University surgical department. PATIENTS AND METHODS: Forty adult patients undergoing major abdominal surgery, randomized in 2 groups: in group 1 ketorolac (30 mg i.v.) was administered immediately after the induction and, for postoperative analgesia, ketorolac (30 mg i.v.) was administered beginning at the time of skin closure; in group 2 no ketorolac was administered before the operation and postoperative treatment was the same. Buprenorphine (0.3 mg i.m.) was administered in case of unsatisfactory analgesia. Fluids infused and diuresis were measured intraoperatively. One, 6 and 24 hours after the end of operation pain was evaluated using pain intensity score and VAS. The day after the operation serum creatinine and urea were measured. RESULTS: No statistically significant differences were found between groups regarding fluids infused, intraoperative diuresis, postoperative pain, adverse effects and number of bleeding episodes. More than 50% of patients, in either groups, required opioids administration. CONCLUSIONS: Ketorolac (30 mg i.v.) administration before a major abdominal operation does not improve postoperative analgesia nor determines significant alterations in renal function or increase in the frequency of abnormal bleedings. Opiate administration is necessary in more than 50% of the patients to achieve adequate analgesia.     

Influenza A virus infection increases IgE production and airway responsiveness in aerosolized antigen-exposed mice

BACKGROUND: Respiratory viral infection is known clinically to promote sensitization to antigen inhalation and the development of asthma. OBJECTIVE: The purpose of this investigation was to determine whether influenza type A virus infection enhances inhalation sensitization and increases airway responsiveness in mice. METHODS: Mice were infected by intranasal inoculation with influenza A viruses (strains: H1N1 and H3N2) or PBS. Animals were exposed to aerosols of ovalbumin on day 3. Two weeks after ovalbumin sensitization, mice were challenged with ovalbumin aerosols; 24 hours later, airway responsiveness (AR) to inhaled methacholine, levels of ovalbumin-specific IgE, and bronchoalveolar lavage fluid (BALF) were examined. RESULTS: Neither influenza A virus (H1N1 nor H3N2) alone nor ovalbumin sensitization alone caused changes in AR or IgE. However, ovalbumin sensitization after inoculation with either influenza A virus increased AR and levels of ovalbumin-specific IgE. On BALF-cell analysis, ovalbumin sensitization after inoculation with influenza virus A increased the number of lymphocytes but not the number of eosinophils. No difference in AR or IgE levels was observed between the 2 strains of influenza A viruses. Immmunostaining of BALF cells showed an increase in T cells, especially CD8(+) cells, with ovalbumin sensitization after inoculation with influenza virus A. CONCLUSION: Infection by influenza A virus enhances sensitization to inhaled antigens and airway responsiveness in mice by means of mechanisms including CD8(+) cells and antigen-specific IgE.     

Relationship between in vitro sensitivity of coliform pathogens in the udder and the outcome of treatment for clinical mastitis

The relationship between in vitro sensitivity to antimicrobials and the outcome of treatment was studied in 228 cows with coliform mastitis. All the cows were treated with a preparation containing sulphonamide and trimethoprim, and 197 of them were also treated with a non-steroidal anti-inflammatory drug (NSAID). The relationship between in vitro sensitivity to sulphonamide/trimethoprim and recovery was analysed by multivariate logistic regression. The possible confounding effects of treatment with an NSAID, days in lactation, parity, herd, and type of infecting organism were tested. Only treatment with an NSAID had a significant confounding effect and was included in the final statistical model. The recovery rate of the 165 cows infected by coliforms that were sensitive to sulphonamide/trimethoprim (89.1 per cent) was higher than that of the 63 cows infected by coliforms that were resistant to sulphonamide/trimethoprim (74.6 per cent). The odds ratio of recovery for the cases associated with organisms that were sensitive to sulphonamide/trimethoprim relative to the cases associated with organisms that were resistant to sulphonamide/trimethoprim was 2.75, with a 95 per cent confidence from 1.25 to 5.85. The odds ratio of recovery for the cases treated with an NSAID relative to the cases treated with sulphonamide/trimethoprim only was 2.76 with a 95 per cent confidence interval from 1.12 to 6.79.     

Conventionalization of germ-free rats reverses the disability of rhein anthrone to induce laxation

This study shows that rhein anthrone has no laxative potency in germ-free rats because after intracaecal administration of a dose of 50 mg/kg the large intestine transit exceeded 240 min. The time course of the laxative potency of rhein anthrone injected intracaecally was evaluated after peroral inoculation of germ-free rats with the caecal contents of conventional rats. Large intestine transit was measured at consecutive periods, on days 0, 1, 2, 3 and 5 after peroral inoculation. It appeared that 1 day after peroral inoculation the laxative potency of rhein anthrone was already established (large intestinal transit < 10 min) and laxation remained on the following days (days 2, 3 and 5). We concluded that rhein anthrone is inactive in germ-free rats and acquires laxative potency after peroral inoculation of germ-free rats with caecal contents of conventional rats.     

Skin permeability and local tissue concentrations of nonsteroidal anti-inflammatory drugs after topical application

Nonsteroidal anti-inflammatory drugs (NSAIDs) are being administered increasingly by transdermal drug delivery for the treatment of local muscle inflammation. The human epidermal permeabilities of different NSAIDs (salicylic acid, diethylamine salicylate, indomethacin, naproxen, diclofenac and piroxicam) from aqueous solutions is dependent on the drug's lipophilicity. A parabolic relationship was observed when the logarithms of NSAID permeability coefficients were plotted against the logarithms of NSAID octanol-water partition coefficients (log P), the optimum log P being around 3. The local tissue concentrations of these drugs after dermal application in aqueous solutions were then determined in a rat model. The extent of local, as distinct from systemic delivery, for each NSAID was assessed by comparing the tissue concentrations obtained below a treated site to those in contralateral tissues. Local direct penetration was evident for all NSAIDs up to a depth of about 3 to 4 mm below the applied site, with distribution to deeper tissues being mainly through the systemic blood supply. A comparison of the predicted tissue concentrations of each NSAID after its application to human epidermis was then made by a convolution of the epidermal and underlying tissue concentration-time profiles. The estimated tissue concentrations after epidermal application of NSAIDs could be related to their maximal fluxes across epidermis from an applied vehicle.     

Effect of a nonsteroidal antiinflammatory drug on synovial fluid in osteoarthritis

OBJECTIVE: The use of nonsteroidal antiinflammatory drug (NSAID) therapy in osteoarthritis (OA) is controversial because of suggestions that pure analgesics can be as effective as NSAID for pain relief. In addition, there is incomplete information whether antiinflammatory effects have any longterm benefit in OA. NSAID have been known to affect synovial fluid (SF) prostaglandins in rheumatoid arthritis. We describe the first examination of the effect of an NSAID, etodolac, on SF prostaglandins, cytokines, and cells in OA. METHODS: Joint fluids were studied before and 2 weeks after initiation of therapy with etodolac 400 mg tid. Leukocyte counts, prostaglandin, interleukin 6, and tumor necrosis factor were measured. RESULTS: Pretreatment features of SF did not predict clinical response. We found no change in the relatively low leukocyte counts. However, SF prostaglandin levels and interleukin 6 levels were significantly decreased and tumor necrosis factor alpha levels were increased after therapy with NSAID. CONCLUSION: This NSAID had potentially important local effects that could be either beneficial or deleterious. Further studies on effects of this and other NSAID on a broader variety of SF and synovial cytokines may help predict longterm effects of NSAID on progression of OA.     

Sulindac enhances cell proliferation in DMH-treated mouse colonic mucosa

In a previous study we reported that the NSAID sulindac had a marked inhibitory effect on the development of colonic tumours in mice treated with the carcinogen 1,2-dimethylhydrazine (DMH). In this study we examined the effects of sulindac in respect of cell-kinetic changes in mouse colonic mucosa as determined by flash labelling with the thymidine analogue bromodeoxyuridine (BrdUrd) at varying intervals during the process of colonic carcinogenesis. We also investigated the possibility that these changes may be modulated by misoprostol a prostaglandin E1 analogue. Four groups of 36 mice each were treated for 18 weeks with the following drug/s respectively: (1) DMH; (2) DMH and sulindac; (3) DMH, sulindac and misoprostol; and (4) DMH and misoprostol. Three animals from each group were killed each week between the sixth week and the eighteenth week after the start of the experiment. A 1-h flash label technique was employed and paraffin sections of colonic mucosa were examined. For each animal a total of 50 perfect axially cut crypts were chosen and the following parameters determined: crypt length, labelling index and labelling index distribution: the data were analysed using the computer program GLIM. For each of the four groups, crypt lengths increased significantly with the duration of treatment with no significant difference between the groups. In sulindac-treated animals the labelling index for all positions increased with duration of treatment whereas for animals not treated with sulindac there was no significant difference in labelling index with respect to duration of treatment. The administration of misoprostol did not appear to significantly alter the effects of sulindac. It is postulated that the observed increase in cell proliferation could be a compensatory phenomenon occurring secondary to loss of crypt epithelial cells by apoptosis induced by sulindac. Also the finding of an increase in labelling index mediated by a chemopreventive agent indirectly questions the rationale behind the therapeutic manipulation of crypt cell proliferation in order to reduce the risk of colon cancer.