Depletion of suppressor-cytotoxic T-lymphocytes by administration of a murine monoclonal antibody.

We administered anti-Leu 2a, a murine monoclonal antibody to the human suppressor-cytotoxic T-cell subset, to 20 patients with advanced cancer to determine the toxicity and its ability to deplete circulating Leu 2(+) lymphocytes. Four doses were tested, 1, 5, 25, and 100 mg, and the infusion rate varied from 2 to 24 h. Administration of anti-Leu 2a produced rapid (within 4 h) depletion of circulating Leu 2(+) lymphocytes, the magnitude and duration of which were dose dependent: the 1-mg dose caused a less than 50% fall in circulating Leu 2(+) lymphocytes, while the higher doses caused 75-98% depletion of those cells in 10 of 17 patients so treated. The duration of depletion of Leu 2(+) cells was 1-2 days after 5 mg of anti-Leu 2a, 3-4 days after 25 mg, and 4-30+ days after 100 mg. In seven patients (3-5, 3-25, and 1-100 mg), there was persistence of variable numbers of circulating mouse Ig-coated Leu 2(+) cells, possibly indicating impaired capacity to clear these cells. Modulation of the Leu 2a antigen after antibody treatment was not observed. Peak serum levels of anti-Leu 2a were (medians): 5-mg dose = 350 ng/ml, 25-mg dose = 5500 ng/ml, and 100-mg dose = 48,000 ng/ml; murine antibody was detectable in the serum for 7-14 days after the 100-mg dose. All patients had increased titers of antimouse antibody following treatment with peak titers on day 14. The most common toxicity was shaking chills. This occurred within 1.5 h of beginning the infusion, lasted for no more than 30 min, and did not require cessation of the treatment. Anti-Leu 2a administration caused a clinically unimportant, but statistically significant fall in hematocrit (mean = -7%) and platelet (mean = -23%) count and a transient (less than 1 day duration) fall in the total lymphocyte count. Thus, infusion of murine monoclonal anti-Leu 2a can cause substantial depletion of the suppressor-cytotoxic T-cell subset with modest toxicity.

Antitumor effects of SMANCS on rat mammary tumor induced by 7,12-dimethylbenz[a]anthracene.

We previously found that a high-molecular-weight anticancer agent, polystyrene-co-maleic acid conjugated neocarzinostatin (SMANCS), in which two chains of styrene/maleic acid copolymer are conjugated to the anticancer protein neocarzinostatin (NCS), accumulated more selectively in tumor tissue than in normal tissue and was more stable than NCS in blood. These results indicate that SMANCS should have less systemic toxicity and a better therapeutic effect than NCS. In this study, the antitumor activity and adverse effects of SMANCS were compared with those of NCS by using rat mammary tumor induced by 7,12-dimethylbenz[a]anthracene. When tumors of rats, that had received 7,12-dimethylbenz[a]anthracene (20 mg/kg, one dose, p.o. in oily formulation), became palpable usually after 4-20 weeks, SMANCS treatment was initiated. Thirty days after i.v. administration of SMANCS (0.1 mg/kg 3 times and 0.3 mg/kg 3 times), tumors had shrunk in 35 of 37 rats (a mean weight was about 10% of control value; or decreased to about 30% of the value of before treatment in tumor weight); tumor size had not changed in 1 rat, and in the remaining 1 rat the tumor had enlarged. Thirty days after i.v. administration of NCS, tumors had shrunk in 8 of 14 rats, but the tumor size was unchanged in 1 rat and was enlarged in 5. In the control group, all tumors had enlarged. Development of new tumors was completely prevented by the administration of SMANCS. Histological examination of sequential slices of tumor revealed clear finding of degeneration and tumor encapsulation at 30 days after initial administration of SMANCS, with an accompanying fatty degeneration, but these effects were not observed for tumors treated with NCS. Although red blood cell counts and hemoglobin amounts decreased significantly in rats receiving NCS, no such effects were apparent in the SMANCS group.

Phase I and clinical pharmacological evaluation of pirozantrone hydrochloride (oxantrazole).

Pirozantrone hydrochloride, an anthrapyrazole analogue, was selected for clinical evaluation based on broad antitumor activity against murine tumor systems and on potentially less cardiotoxicity when compared to anthracyclines. This anthrapyrazole analogue is currently under clinical evaluation, and we now report results on a Phase I clinical trial incorporating a pharmacologically guided dose-escalation scheme. Dose escalation was designed to proceed by factors of 2 until the patient drug exposure (concentration x time) was 40% of the murine exposure at the LD10 dose (90 mg/m2). Thereafter, more moderate dose escalations were employed. The target concentration x time value (59 micrograms-min/ml) derived from preclinical pharmacology data was exceeded in all three patients at a dose of 90 mg/m2. A dose of 160 mg/m2 was found to reproducibly result in appropriate myelosuppression. This dose is recommended for further testing in Phase II studies. Nonhematological toxicities encountered in this trial were mild, the most notable being phlebitis at the infusion site. Objective responses were observed in two patients, one with metastatic breast cancer and another with metastatic melanoma. Following a 60-min infusion, pirozantrone hydrochloride plasma elimination was monoexponential, with a half-life of approximately 30 min, mean total body clearance of 1.29 liters/min/m2, and mean steady state volume of distribution of 29 liters/m2.

Protective effects of tumor necrosis factor on murine hematopoiesis during cycle-specific cytotoxic chemotherapy.

Tumor necrosis factor (TNF) is a pleiotropic cytokine which exerts a wide range of effects when administered in vivo. Using a murine model, we have investigated the effect of pretreatment with 1 microgram (2.6 x 10(4) units) per mouse of recombinant murine TNF-alpha on hematopoietic recovery following administration of cyclophosphamide, 5-fluorouracil, methotrexate, or vinblastine. TNF pretreatment results in enhanced regeneration of circulating neutrophils and hematopoietic progenitors, as measured by in vivo and in vitro assays, in animals given cycle-specific chemotherapeutic agents. The results may suggest that TNF affects cycle kinetics in hematopoietic progenitor cell populations, thus making these cells less prone to the cytocidal effects of the chemotherapeutic agents. As myeloablation is a frequent and often critical side effect following cancer treatment, these findings may have clinical implications.

Continuous infusion of low-dose 5-Aza-2'-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome.

There is no standard therapy for elderly patients with high-risk myelodysplastic syndrome (MDS). The treatment options of low-dose Ara-C and haematopoietic growth factors are disappointing in regard to response rate or response duration. We tested the treatment with a 72-h continuous infusion of low-dose 5-Aza-2'-deoxycytidine (DAC) in a group of 29 elderly patients with high-risk MDS. In 15 patients (54%) we observed a response. Eight complete responses were reached, even among patients with bad prognostic cytogenetic findings. The actuarial median survival from the start of the therapy was 46 weeks. The only (and major) toxicity was myelosuppression, leading to a prolonged cytopenic period and thus leading to five toxic deaths (17%) in this high-risk patient group. We conclude that DAC is an effective drug in the treatment of MDS patients and that it probably works via its cytotoxic activity. Myelotoxicity is its major adverse effect.

Lifetime treatment of mice with azidothymidine (AZT) produces myelodysplasia.

AZT has induced a macrocytic anemia in AIDS patients on long term AZT therapy. It is generally assumed that DNA elongation is stopped by the insertion of AZT into the chain in place of thymidine thus preventing the phosphate hydroxyl linkages and therefore suppresses hemopoietic progenitor cell proliferation in an early stage of differentiation. CBA/Ca male mice started on AZT 0.75 mg/ml H2O at 84 days of age and kept on it for 687 days when dosage reduced to 0.5 mg/ml H2O for a group, another group removed from AZT to see recovery, and third group remained on 0.75 mg. At 687 days mice that had been on 0.75 mg had average platelet counts of 2.5 x 10(6). Histological examination on 9 of 10 mice with such thrombocytopenia showed changes compatible with myelodysplastic syndrome (MDS). A variety of histological patterns was observed. There were two cases of hypocellular myelodysplasia, two cases of hypersegmented myelodysplastic granulocytosis, two cases of hypercellular marrow with abnormal megakaryocytes with bizarre nuclei, one case of megakaryocytic myelosis associated with a hyperplastic marrow, dysmyelopoiesis and a hypocellular marrow and two cases of myelodysplasia with dyserythropoiesis, hemosiderosis and a hypocellular marrow. Above mentioned AZT incorporation may have induced an ineffective hemopoiesis in the primitive hemopoietic progenitor cells, which is known to be seen commonly in the myelodysplastic syndrome.

Acute inhalation exposure to isobutyl nitrite causes nonspecific blood cell destruction.

Abuse of nitrite inhalants is widespread among male homosexuals and has been epidemiologically correlated with seropositivity to human immunodeficiency virus (HIV) and to Kaposi's sarcoma. These drugs may act as cofactors in AIDS if they compromise the ability to resist infection or tumor growth. We have previously reported that 14 daily 45-minute exposure to 900 ppm isobutyl nitrite in an inhalation chamber did compromise the immunocompetence of mice. We now report that a single 45-minute exposure produced a transient anemia. Erythrocyte counts, hemoglobin, and hematocrit levels were reduced by 7% but rebounded to above-normal levels 24 hours later. In vitro exposure of blood to isobutyl nitrite vapors did not lyse the cells but did induce Heinz body formation and increase their binding to macrophages. Thus, it is likely that the red cells were removed by phagocytic clearance not by direct lysis. Blood leukocyte numbers were also reduced following a single exposure to the inhalant, but the cell loss was delayed until 24 hours after exposure. Recovery of peripheral blood leukocytes 72 hours after exposure coincided with a reduction in spleen cellularity, suggesting that spleen cells were mobilized to replace lost blood leukocytes.

The hematopoietic stem cell compartments in mice during and after long-term inhalation of three doses of benzene.

Female BDF1 mice were exposed for 16 weeks to airborne concentrations of 100, 300, and 900 ppm of benzene, 6 h per day, 5 days per week. Bone marrow hemopoietic stem cell compartments and peripheral blood cell counts were studied using clonal assays and standard methods. Dose-dependent depressive effects were observed on all stem cell compartments. Only the erythroid colony-forming units (CFU-E) compartment was depressed during exposures to 100 ppm; CFU-E were more sensitive than the erythroid burst-forming units (BFU-E), spleen CFU (CFU-S), or G-M CFU (CFU-C) during exposure to 300 ppm or 900 ppm. Lymphocytopenia was observed in the peripheral blood. After benzene-free intervals, a regeneration of lymphocyte numbers and slow normalization of stem cell numbers was seen. Complete recovery from the 16 weeks exposure to 300 ppm was seen between 73 and 185 days.

Transforming growth factor beta 1 systemically modulates granuloid, erythroid, lymphoid, and thrombocytic cells in mice.

Transforming growth factor beta 1 (TGF-beta 1) has been shown to inhibit the development of most early hemopoietic progenitors in vitro. The present series of in vivo experiments show that TGF-beta 1 can simultaneously augment and suppress distinct cell lineages in peripheral and central hemopoietic compartments. Mice treated daily for 7-14 days with s.c. injections of TGF-beta 1 exhibited up to a 95% reduction in circulating platelets and a 50% reduction in red cell counts, whereas a 50%-400% increase occurred in circulating white cells with the morphology of small lymphocytes. Decreased erythrocytes were also evident in the splenic red pulp and bone marrow sinusoids. A dramatic increase in granulopoiesis occurred in the spleen and bone marrow, followed by a peripheral neutrophilia 1 week after treatments ceased. All effects were completely reversible, with normal histologic and hematologic profiles evident 2 weeks after cessation of treatments. Thus, TGF-beta 1 can differentially regulate multiple hemopoietic pathways in a systemic, reversible, and dose-dependent fashion. These actions may be mediated by the direct effects of TGF-beta 1 or through modulation of secondary cytokines and receptors.

Liposomal encapsulation of 3'-azido-3'-deoxythymidine (AZT) results in decreased bone marrow toxicity and enhanced activity against murine AIDS-induced immunosuppression.

The effect of liposome encapsulation on the bone marrow toxicity and antiviral activity of AZT in C57BL/6 mice was determined. Liposomal encapsulation of AZT enhanced localization in the liver, spleen, and lung, and reduced localization in bone marrow. AZT administered i.v. (0.08-50 mg/kg/day) had significant bone marrow toxicity (30-50% reduction in cellularity) after five injections, maximum toxicity occurring at greater than or equal to 2 mg/kg/day. Parallel reductions in the number of erythrocytes and leukocytes were observed. AZT encapsulated in liposomes had no bone marrow toxicity at doses of 0.08-10 mg/kg/day, and erythrocyte and leukocyte numbers remained normal. Infection of C57BL/6 mice with LP-BM5 murine leukemia virus suppressed T- and B-cell mitogenic responses. Treatment of LP-BM5 retrovirus-infected mice with 2 mg/kg AZT three times weekly partially protected the mitogenic response at 4 but not at 7 weeks postinfection. Treatment with liposomal AZT resulted in normal T- and B-cell mitogenic responses at both 4 and 7 weeks postinfection.

DNA damage in mononuclear leukocytes of farmers measured using the alkaline comet assay: modifications of DNA damage levels after a one-day field spraying period with selected pesticides.

The alkaline comet assay was used to assess DNA damage in mononuclear leukocytes of farmers before and after a 1-day spraying period with selected pesticides under usual conditions. Two blood samples were collected, one in the morning of the day of spraying (S0) and the second in the morning of the day after (S1). Here, we assessed variations in DNA damage levels between these two sampling times. Four groups of farmers were formed, according to exposure to: (a) various fungicide-insecticide mixtures (including chlorothalonil; group 1, n = 8), (b) the herbicide isoproturon (group 2, n = 11), (c) fungicide triazoles (group 3, n = 14), and (d) a fungicide (chlorothalonil)-insecticide mixture (group 4, n = 8). An increase in DNA damage levels was observed at S1 for groups 1 and 4, who were exposed to similar pesticides. This increase was correlated with area sprayed between S0 and S1 and with the number of spraying tanks used over this 1-day period. No effect was observed on cell viability or on hematological parameters for these two groups. No statistically significant modification of DNA damage level was observed the day after spraying for groups 2 and 3, when each was observed as a whole. However, some farmers presented significantly more DNA damage after exposure, and others presented less damage. In these two groups, a significant decrease of neutrophils was observed at S1, and a decrease of red blood cells was observed in group 3. In parallel, a significant loss of lymphocyte viability was observed in these two groups. A 1-day spraying period seems to be sufficient to significantly modify DNA damage levels in mononuclear leukocytes, but the correlation of this change with pesticide-related exposure parameters depends on the kind of pesticide concerned.

Phase I study of low-dose zidovudine and acyclovir in asymptomatic human immunodeficiency virus seropositive individuals.

PURPOSE: The combination of zidovudine and acyclovir has shown in vitro antiretroviral activity and led to short-term improvement in patients with symptomatic human immunodeficiency disease (HIV) disease. We performed a phase I study of zidovudine (500 mg/day) plus acyclovir (2 or 4 g/day) in asymptomatic HIV-seropositive men to investigate pharmacokinetics, safety, tolerance, and immunologic effects of the combination. SUBJECTS AND METHODS: Fifty HIV-seropositive homosexual or bisexual men from the San Francisco City Clinic Cohort Study were recruited for the study; of these, 20 met the eligibility criteria. Treatment with zidovudine and acyclovir was open label. Pharmacokinetic, virologic, immunologic, and clinical data were collected periodically over a 24-week period. RESULTS: Pharmacokinetic analysis showed no drug interaction. The combination was generally well tolerated, and hematologic parameters remained stable through 24 weeks. There were no significant changes in total lymphocytes, T4 lymphocytes, overall skin test reactivity, or ability to culture virus from peripheral blood. CONCLUSION: This combination of agents is safe in this population for at least six months. Conclusions about long-term tolerance and efficacy await the results of larger trials with longer follow-up.

Losartan, an angiotensin-II receptor antagonist, reduces hematocrits in kidney transplant recipients with posttransplant erythrocytosis.

BACKGROUND: Posttransplant erythrocytosis (PTE) occurs in 10-15% of patients with a well-functioning kidney transplant and is associated with increased morbidity. Although the mechanism of PTE is unknown, PTE responds to inhibitors of ACE (ACE-i) in most cases. ACE converts angiotensin I to angiotensin II and is a metabolizer of a number of other peptides. METHODS: Because ACE-i frequently show side effects we wanted to elucidate the pathway by which ACE-i mediate their effect in PTE. Therefore, we treated eight patients (five with newly diagnosed PTE, two with PTE unresponsive to ACE-i, and one with PTE responsive to ACE-i, which had to be withdrawn due to side effects) with 50 mg of the type 1 angiotensin II receptor antagonist losartan for at least 14 weeks. RESULTS: Hematocrit values in the two patients who were unresponsive to ACE-i did not change significantly. In contrast, hematocrits decreased in all the other six patients from 0.53+/-0.02 to 0.44+/-0.02 after 14 weeks of treatment with losartan (mean +/- SE; P<0.005, paired t test). Graft function, cyclosporine concentration, and leukocyte and platelet count remained stable. The serum potassium level rose in one patient from 6.0 to 6.8 mmol/L but remained stable in all other patients. CONCLUSIONS: We conclude that blockade of the type 1 angiotensin II receptor is safe and effective in treating PTE.

Altered patterns of organ distribution of autologous and grafted blood cells in mice treated with hydroxyurea.

Migration and distribution of lymphocytes and red blood cells were profoundly altered in C57BL/6 mice treated with the anti-mitotic drug hydroxyurea (HU). HU treatment given twice daily for four consecutive days, markedly reduced the population of nucleated cells in the spleen and bone marrow; the numbers of nucleated cells in spleen and bone marrow were reduced to 20% and 10% of normal values, respectively. Paradoxically, in the bone marrow of HU-treated mice, the numbers of mature erythrocytes were increased 8-fold, while in the spleen erythrocyte values were decreased. To explore this altered pattern of red blood cell partition, radiolabeled cells were injected and their migration traced in normal and HU-treated recipients. Both erythrocyte and leukocyte populations were observed to migrate preferentially to the bone marrow of HU-treated animals. The altered pattern of blood cell partition in the bone marrow could be explained by the induction of abnormal permeability of the bone marrow-blood barrier by the antimitotic drug. This point may be of importance when considering clinical bone marrow transplantation. It stresses the need for antimitotic treatment before grafting individuals with hemopoietic precursors.

Evaluation of toxicity of cypenhymustine, a new anticancer compound, in mice.

The toxicity of cypenhymustine, a potential anticancer compound 1 (Cancer Letters, 70 (1993) 1-6), was assessed in normal as well as in Ehrlich ascites carcinoma (EAC), Sarcoma-180 (S-180) and Dalton's lymphoma (DL)-bearing Swiss male mice by measuring drug-induced changes in (1) hematological parameters and (2) femoral bone marrow cellularity on day 9 following drug treatment at the optimum dose of 3.0 mg/kg body weight from days 1 to 7. Detailed studies were also made by noting sequential changes in the above parameters in normal and EAC-bearing mice on days 12, 15, 18 and 21, respectively. The results indicate that the compound did not adversely affect hematopoiesis. From the sequential studies, it was observed that after a mild initial decrease in hematological counts, particularly in EAC-bearing treated mice, normalcy was reached within 11-14 days after termination of drug therapy. Drug induced hepatotoxicity and nephrotoxicity were also sequentially evaluated in normal and EAC-bearing mice on days 9, 12 and 15 but no such toxicities were detected. Also, body weight, skin and hair texture, and behavioural pattern (food and water intake and activity) did not reflect any toxic reaction in the host mice at this optimum dose.

The response of the pig kidney to the combined effects of cisplatin and unilateral renal irradiation.

Seven mature Large White female pigs, approximately 10 months of age received a single dose of cis-dichlorodiammineplatinum(II), c-DDP (2.5 mg/kg body weight). Prior to, and 4 weeks after c-DDP administration, individual kidney glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by [99mTc]DTPA and [131I]hippuran renography. Of the 5 pigs surviving the c-DDP treatment most exhibited a reduction in both GFR and ERPF; the mean reduction in GFR (36.2 +/- 18.9%) was more pronounced than that for ERPF (12.6 +/- 19.4%). However, the difference in the severity of the impairment in these two parameters was not significant (p greater than 0.55). Haematocrit, haemoglobin and red blood cell counts were markedly reduced 14 days after c-DDP infusion, and despite some recovery evident 21 days after treatment, all three haematological parameters were still reduced 28 days after c-DDP administration. The right kidneys of these 5 animals, plus 5 pigs which did not receive c-DDP, were irradiated with a single dose of 11.9 Gy of 60Co gamma-rays. Individual kidney GFR and ERPF was routinely measured up to 24 weeks after irradiation. Pigs in which only the right kidney was irradiated showed a marked increase in both GFR and ERPF values 2 weeks after irradiation. This was followed by a decline in function with a reduction of 50% in terms of ERPF 16 weeks after irradiation. Values then showed some evidence of a recovery in function. There was a concomitant compensatory response by the contralateral unirradiated kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of longitudinal analysis of peripheral blood counts to validate historical reconstructions of benzene exposure.

We studied over 17,000 peripheral blood counts, accumulated during hematologic surveillance from 1940 through 1975, from a cohort of 459 benzene-exposed workers. Linear regressions demonstrated significant decreases in white and red cell counts, as well as hemoglobin, for workers exposed during the 1940s, without persistent trends over the ensuing 25 years. Strongly positive correlations were observed between these blood count fluctuations and fluctuations in retrospective estimates of benzene exposures for these workers in the earlier period of surveillance (mean estimated exposure 1940 to 1948, 75 ppm), but not for later years, (mean estimated exposure 1948 to 1975, 15 to 20 ppm). These data suggest substantial limitations of hematologic examination of populations to detect abnormalities in populations currently exposed to benzene. The analysis also demonstrates a novel approach to the biological validation of exposure estimates based upon limited industrial hygiene and historical record data. The application of biologic monitoring data may be useful for assisting decisions in reconstruction of a previous exposure.

The effect of heparin on trinitrobenzene sulphonic acid-induced colitis in the rat.

BACKGROUND: Reduced blood coagulability seems to protect against inflammatory bowel disease; pilot studies using heparin in patients with inflammatory bowel disease have reported positive results. AIM: To evaluate the effects of heparin treatment on microangiographic and on inflammatory parameters in experimental colitis, induced by trinitrobenzene sulphonic acid (TNBS)-ethanol. METHODS: Four groups of rats: (i) controls (saline enema), TNBS-induced colitis with (ii) sham treatment (saline, s.c.), (iii) dexamethasone (0.25 mg/kg/day s.c.) and (iv) heparin (500 U/kg t.d.s., s.c.). Microangiography was performed 2 and 4 days after colitis induction. Partial thromboplastin time, colonic wet weight, macroscopic damage score and mucosal myeloperoxidase (MPO) activity were determined at day 4. RESULTS: TNBS-induced colitis caused a reduction in visible bowel wall vessels, which was prevented by heparin (P < 0.05) but not by steroids. The macroscopic damage scores and colon wet weights were similar in all colitis groups. Compared to untreated colitis the MPO activity in heparin-treated animals was of borderline significance. CONCLUSIONS: Heparin treatment improved microangiographic features and reduced inflammation to a certain degree. Steroids delayed development of colon hypoperfusion, but were ineffective on MPO activity. It remains to be determined if the observed effects are due to the antithrombotic activity of heparin or to an anti-inflammatory action.

Local and systemic effects of water-soluble contrast media and barium in rats with chronic small bowel obstruction.

RATIONALE AND OBJECTIVES: The local effects on the small intestine and systemic changes produced by different contrast media in small bowel obstruction, with time courses of 4 days, were evaluated. MATERIALS AND METHODS: Four groups, each with 10 normal rats and another four groups (also each with 10 rats) that had ligation of the terminal ileum (obstructed rats) for 4 days were given 3 mL of barium, meglumine sodium diatrizoate, iohexol, or saline (control animals). Radiographs were taken immediately, 1 and 4 hours after administration of contrast media. Immediately before sacrifice, blood samples were taken to determine the hematocrit (Hct), hemoglobin (Hb), white blood cell count (WBC), red blood cell count (RBC), and serum sodium, and potassium and chloride concentrations. Specimens of small bowel were taken for histologic and morphometric analysis. RESULTS: In obstructed rats, the image quality with iohexol improved on final radiographs despite being diluted in the great intestinal contents. There was an improvement in the serum electrolyte concentrations in the obstructed animals that were given any one of the contrast media, the best improvement being in the iohexol groups. A shortening of the length of epithelial cells when any one of the contrast media was administered was observed, as was an increase in the lymphatic space area in the diatrizoate group in normal rats. In the bowel proximal to the obstruction, the lymphatic space area was increased in the diatrizoate group and the size of the epithelial cells was higher in the diatrizoate and iohexol groups compared to the barium and saline groups. CONCLUSION: Our results suggest that iohexol offers good radiologic efficacy and excellent systemic and local tolerance in small bowel obstruction.

A new anticancer drug delivery system for the management of carcinomatous peritonitis.

To develop a new drug delivery system for the treatment of carcinomatous peritonitis, we constructed 5-fluorouracil poly L-microcapsules (5Fu-mc) by the organic phase separation technique and examined their drug-releasing capacities and anticancer effects. The microcapsules consisted of in vitro dissolvable polymolecular poly L-lactic acid and 5-fluorouracil (5Fu). The 5Fu-mc was about 200 microns in diameter and had a 5Fu content of about 40% (weight/weight). 5Fu-release time from the microcapsules was about 50 hours in vitro and about 48 hours in vivo. After the release of the 5Fu, the poly L-lactic acid was metabolized very slowly in the peritoneal cavity. The 5Fu-mc caused fewer side effects than the equivalent dose of a 5Fu solution. In addition, macroscopic and microscopic examinations of various abdominal organs revealed no toxic effects from the microcapsules. After administration of 5Fu-mc into the abdominal cavity of rats with AH-130 carcinomatous peritonitis, the 5Fu concentration remained at a high level for an extended period in the ascites but fell rapidly to low levels in the plasma. In conclusion, the present studies indicated that the 5Fu-mc were much more effective in prolonging the life of tumor-bearing hosts while producing less systemic side effects than a 5Fu solution.