Antischistosomal Agents Research Articles

Continuous in vitro propagation and differentiation of cultures of the intramolluscan stages of the human parasite Schistosoma mansoni.

The metazoan parasitic blood flukes, Schistosoma spp., infect over 200 million people worldwide and cause extensive human morbidity and mortality. Research strategies for development of anti-schistosomal agents are impeded by the organism's complex molluscan-mammalian life cycle, which limits experimental approaches and availability of material. We derived long-term continuously proliferative cultures of Schistosoma mansoni sporocysts capable of generating cercariae in vitro. Cultured organisms retained the ability to parasitize the host, and they exhibited developmental regulation of candidate stage-specific genes in the host-free culture system. Evidence for expression of a reverse transcriptase also was found in the cultured organisms, pointing to this activity as a possible mechanistic contributor to the dynamic relationship between the parasite and its hosts. Continuous in vitro propagation of the asexual sporocyst stage allows isolation of clonally derived parasite populations and provides a means to study schistosomal molecular genetics, metabolism, and evasion of host defenses.

Cyclosporins: Lack of Correlation between Antischistosomal Properties and Inhibition of Cyclophilin Isomerase Activity

Khattab, A., Pica-Mattoccia, L., Klinkert, M. Q., Wenger, R., and Cioli, D. 1998. Cyclosporins: Lack of correlation between antischistosomal properties and inhibition of cyclophilin isomerase activity.Experimental Parasitology90, 103–109. The immunosuppressive fungal products cyclosporin A (CsA) and FK506 bind with high affinity to intracellular receptor proteins: cyclophilin (CYP) is one of the receptors for CsA and FK506-binding protein (FKBP) is one of the receptors for FK506. These proteins catalyze thein vitroisomerization from acisto atransconformation of peptidyl-prolyl bonds in oligopeptides. The relative importance of the peptidyl-prolylcis-transisomerase (PPI ase) activity of CYP compared to FKBP in schistosomes is not known. Here, we examine the effects of CsA and FK506 and show that the former inhibits PPIase activity in schistosome extracts, whereas the latter does not. Since CsA is specific for the CYP protein, this result is indicative of the fact that the PPIase activity in the parasite is mostly attributable to CYP. The observation that CsA was significantly more effective than FK506 as an antischistosomal agent, bothin vivoandin vitroraises the possibility that killing of schistosomes is caused by the inhibition of schistosome CYP PPIase. We compared a number of Cs analogs for their antischistosomal effects and for the inhibition of CYP PPIase, but were unable to find a correlation between the two properties. We therefore conclude that the lethal effect of CsA is not directly linked to the inhibition of the enzymatic activity of schistosome CYPs.

O6-Methylguanine and O6-methylguanine-dna methyltransferase activity in tissues of BDF-1 mice treated with antiparasitic drugs

Levels of the DNA promutagenic methylation damage, O 6-methylguanuine ( O 6-MeG) and the activity of the O 6-methylguanuine-DNA methyltransferase (MGMT), the enzyme responsible for repairing O 6-MeG, were measured at various time intervals in tissues of BDF-1 mice administered a single therapeutic dose of the antischistosomal agents hycanthone, oxaminiquine and metrifonate. Hycanthone increased O 6-MeG in the liver-DNA after 6 h, then decreased by 3-fold after 48 h. Lower levels of the adduct and a slower rate of formation were found in the intestine and bladder. MGMT activities were significantly lower in the liver (74%) and bladder (25%) compared to control animals after 6 h, then restored by 48 h. Oxaminiquine increased O 6-MeG in all tissues, but spleen, after 6 h and persisted only in the bladder after 48 h. Liver and bladder tissues of these animals exhibited a pattern of alteration in the MGMT activity similar to that observed for hycanthone. Metrifonate induced a profile of O 6-MeG comparable to that of oxaminiquine but the levels of the adduct were about 2-fold lower. Hepatic MGMT in these animals was significantly lower (∼38%) than the control values after 6 h, then restored by 48 h. A significant negative correlation was obtained between O 6-MeG and MGMT activity in the liver ( r=−0.85), intestine ( r=−0.62) and bladder ( r=−0.59). These results demonstrate that treatment with antischistosomal agents may lead to the formation of promutagenic alkylation damage in the tissue DNA and alterations in the DNA repair capacity.

Oltipraz chemoprevention trial in Qidong, Jiangsu Province, People's Republic of China

Oltipraz has been used clinically in many regions of the world as an antischistosomal agent and is an effective inhibitor of aflatoxin hepatocarcinogenesis in rats. This chemopreventive action of oltipraz results primarily from an altered balance in aflatoxin metabolic activation and detoxication. In 1995, a randomized, placebo-controlled, double-blind intervention was conducted in residents of Qidong, People's Republic of China, who are at high risk for exposure to aflatoxin and development of hepatocellular carcinoma. The major study objectives were to define a dose and schedule for oltipraz that would reduce levels of aflatoxin biomarkers in biofluids of the participants, and to further characterize dose-limiting side effects. Two hundred thirty-four healthy eligible individuals, including those infected with HBV, were randomized to receive either 125 mg oltipraz daily, 500 mg oltipraz weekly, or placebo. Blood and urine specimens were collected to monitor potential toxicities and evaluate biomarkers over the 8-week intervention and subsequent 8-week follow-up periods. Overall, compliance in the intervention was excellent; approximately 85% of the participants completed the study. Objective evaluation of adverse events was greatly facilitated by inclusion of a placebo arm in the study design. A syndrome involving numbness, tingling, and pain in the fingertips was the only event that occurred more frequently among the active groups (18 and 14% of the daily 125 mg and weekly 500 mg arms, respectively) compared to placebo (3%). These symptoms were reversible and could be relieved with non-steroidal antiinflammatory agents. A more complete understanding of the chemopreventive utility of oltipraz awaits completion of an assessment of the efficacy of oltipraz in modulating levels of aflatoxin biomarkers.

Dissolution properties of praziquantel-beta-cyclodextrin systems.

The purpose of this study was to characterize the dissolution behavior of a poorly water-soluble antischistosomal agent, praziquantel (PZQ), from PZQ-beta-cyclodextrin systems containing 20-100% w/w of drug. Dissolution parameters obtained from the release data of simple physical mixtures and inclusion compounds prepared by the solvent method were employed to characterize the effect of drug loading on the release kinetics of PZQ. All the systems investigated showed improved dissolution in comparison with the free drug due to the ability to form a complex in solution. The systems prepared by the solvent method showed different characteristics and mechanism of dissolution than the physical mixtures: At low beta-cyclodextrin (beta-CD) weight fractions (high drug loading) their dissolution profiles were higher than those of the physical mixtures. At high polymer weight fractions (low drug loading and equimolar ratio) the physical mixtures exhibited a 7-fold higher dissolution rate than the pure drug. The inclusion systems, on the other hand, showed an improvement in the dissolution rate, but to a lesser degree than the physical mixtures. The observed changes in the mechanism of release kinetics of the different PZQ-beta-CD systems were interpreted using the principles of percolation theory and the results of thermal analysis of the physical mixtures and the inclusion compounds.

Failure of dietary oltipraz to inhibit benzo[a]pyrene-induced lung tumorigenesis in strain a mice.

Oltipraz (OLT), an antischistosomal agent, is known to inhibit tumorigenesis induced by a variety of carcinogens. In this study, we examined the ability of dietary oltipraz to inhibit benzo[a]pyrene (BP)-induced pulmonary adenoma formation in A/J mice. In a 6-week study, the maximum tolerated dietary concentration of OLT was found to be 450 ppm. Accordingly, OLT was tested at 0.8 MTD and 0.4 MTD. OLT diets were initiated 48 h prior to administration of a single i.p. dose of BP (100 mg/kg). Control or experimental diets were continued for the duration of the study. At 6 months, mice treated with BP only had a multiplicity of 9.0 tumors/animal and at 8.5 months, mice treated with BP only had a multiplicity of 21.4 tumors/animal. No inhibition of lung tumor formation by dietary OLT was observed at 6 or at 8.5 months after BP administration. In parallel experiments performed to assess the effects of OLT on pulmonary glutathione S-transferase activity, no induction of GST activity was found at the various time points examined. Doses of OLT that induced GST activity and inhibited tumorigenesis in mice in experiments conducted by other investigators would have exceeded the predetermined MTD for dietary OLT established in A/J mice in this study.

RECOVERY OF THE HEPATIC CARCINOGEN-METABOLIZING CAPACITY IN SCHISTOSOME-INFECTED MICE AFTER TREATMENT WITH THE ANTISCHISTOSOMAL PRAZIQUANTEL

The influence of Schistosoma mansoni infection on the capacity of the carcinogen-metabolizing enzymes was investigated prior to and after treatment of the infected male mice with praziquantel, an anti-schistosomal agent. The drug was administered in a daily dose of 60 mg/kg body weight for three days before decapitation at various infection intervals. After 20 and 30 days post-infection the hepatic content of cytochrome P-450 and cytochrome b-5 and the activity of aryl hydrocarbon hydroxylase were markedly increased. However, the constitutive levels of the above mentioned enzymes were significantly decreased at 45, 60 and 75 days post-infection. Treatment of the infected mice with praziquantel for three days, however, recovered the changes in these activities at each individual time point. Praziquantel showed no effect on either of the studied enzymes when administered alone except for that of NADPH-cytochrome C reductase activity which exhibited significant increase. The activity of NADPH-cytochrome C reductase gave inconsistent results after treatment of the infected animals with praziquantel. It is concluded that praziquantel can be considered as a safe and useful drug for the chemotherapy of schistosomiasis and it possessed a recovery for the activities of the drug-metabolizing enzyme.

Oltipraz: Clinical opportunities for cancer chemoprevention

Oltipraz [4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione], originally developed as an antischistosomal agent, protects against chemical carcinogenesis in lung, trachea, forestomach, small intestine, colon, breast, skin, liver and urinary bladder in rodents. Oltipraz induces electrophile detoxication enzymes, resulting in diminished carcinogen-DNA adduct formation and reduced cytotoxicity, an important component of anticarcinogenic actions. Phase I trials of this drug have been recently conducted in the United States and indicate that the maximum tolerated dose is about 125 mg/day over a six-month period. Grade I/II dose-limiting toxicities included photosensitivity/heat intolerance, gastrointestinal, and neurologic toxicities. Ongoing studies are monitoring relationships between dose scheduling, drug plasma concentrations and pharmacodynamic action. Subsequent trials with this agent might most appropriately target individuals at high risk for occupational or environmental exposures to genotoxic carcinogens. Towards this end, a randomized, placebo-controlled Phase II study is planned for people at high risk for exposure to aflatoxins and development of hepatocellular carcinoma. Modulation of biomarkers reflecting the biologically effective dose of aflatoxin will serve as study endpoints.

32] Anethole dithiolethione: Biochemical considerations

This chapter focuses on the biochemical considerations of Anethole Dithiolethione (ADT). Certain sulfur-containing compounds likely play vital roles in the physiology of the organism, and others are among the effective drugs currently employed in human therapy. The cyclic sulfur-containing compounds, termed 1,2-dithiol-3-thiones, are representatives of a specific class of sulfur-containing compounds, primarily of synthetic origin but also found in trace amounts in certain cruciferous vegetables. These agents possess antioxidant, chemoprotective, and chemotherapeutic activities. One substituted member of this class is prescribed as choleretic and sialagogue, another was used as antischistosomal agent. One molecule of special interest is 5-(p-methoxyphenyl)-3H-1,2-dithiol-3-thione, also termed anethole dithiolethione. Early experiments with dogs bearing fixed biliary fistulae revealed that ADT induces an intense, enduring choleresis after ingestion, which can be demonstrated by monitoring the secretion of biliary cholesterol. Among the cyclic sulfur-containing compounds, termed 1,2-dithiol-3-thiones, a molecule of particular interest is ADT, which is marketed as a choleretic and sialagogue, and which also exerts chemoprotective effects. The chemoprotective effects of this 1,2-dithiol-3-thione may be related mainly to the increase in the activity of detoxification enzymes such as glutathione S-transferases and NAD(P)H:quinone reductase, which promote the elimination of xenobiotics and their activated metabolites via conjugation reactions, particularly with glutathione.

Antitumour activity of N-[[1-[[2-(diethylamino)ethyl]amino]-9-oxo-9H-thioxanthen-4-yl]methyl]methanesulfonamide (WIN33377) and analogues

WIN33377 (Sterling/Kodak) entered Phase I clinical trials in 1994. The dose limiting toxicity has not been reached with completion of the 225 mg/m2 level, Q28 day schedule. To date, the agent has been very well tolerated with no evidence of liver toxicity. Eventually, a weekly schedule will be undertaken, which is consistent with the rapid host recovery time for this agent (six days). WIN33377 is an analogue of Hycanthone, an antischistosomal agent, that also has antitumour activity in preclinical models. However, Hycanthone is very poorly tolerated at the efficacious dose levels. Clinical trials of Hycanthone were carried out between 1978 and 1983, producing severe liver toxicity with drug induced deaths. No antitumour activity was recorded. WIN33377 and a variety of analogues were discovered to have markedly improved antitumour activity, and were well tolerated in mice. Most analogues had no evidence of liver toxicity with WIN33377 being totally devoid of liver toxicity. The key to better efficacy and t...

O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE ACTIVITY IN TISSUES OF MICE TREATED WITH ANTISCHISTOSOMAL AGENTS

The activity of O-6-alkylguanine-DNA alkyl transferase (ATase), the enzyme responsible for repairing promutagenic methylation damage in DNA, was measured at various time intervals in tissue extracts of mice administered (in vivo) a single therapeutic dose of the antischistosomal agents hycanthone, oxaminiquine and metrifonate. In control animals, liver contained the highest levels of ATase activity (15.8+/-1.8 fmole ATase/mu g DNA) followed by spleen (11.0+/-1.7 fmole/mu g DNA), intestine (2.3+/-0.3 fmole/mu g DNA) and bladder (0.22+/-0.04 fmole/mu g DNA). With hycanthone, ATase activity was reduced by 6 and 24 h post treatment to 74% and 27% below the control value, respectively. Bladder exhibited a 25% inactivation in the ATase level at 6 h time point. Spleen and bladder did not show any alteration in the ATase activity. In animals administered oxaminiquine, liver and bladder had a near identical pattern to that observed for hycanthone. Spleen and intestine, however, revealed activation in ATase by 50% and 42%, respectively after 6 h of treatment. This activation was also observed in the bladder of metrifonate-treated mice. In a previous study (Badawi et al, Cancer Lett 75: 167, 1993), DNA-alkylation damage (O-6-methyldeoxyguanosine; O-6-MedG) was evaluated in these tissues and there was an inverse correlation between the levels of methylation damage and ATase activity in liver (r=-0.85, p<0.01), intestine (r=-0.62, p<0.01) and bladder (r=-0.59, p<0.05).

Cloning and characterization of a cDNA encoding phosphofructokinase from Schistosoma mansoni

Schistosoma mansoni, a human parasitic worm, depends on anaerobic glycolysis as the main source of energy. Phosphofructokinase (ATP: D-fructose-6-phosphate 1-phosphotransferase, EC 2.7.1.11; PFK) limits the rate of glycolysis in these organisms and it has been found to be a target for some antischistosomal agents. A cDNA clone from this parasite has been isolated and characterized. The cDNA is 3046 base pairs long, contains an open reading frame of 2346 bp and codes for a deduced protein of 781 amino acids. The putative protein encoded by the clone has an exact match with the human muscle PFK of 58% and a 73% match when conserved amino acid substitutions are considered. ATP and Fructose-6-P sites have been identified by crystallographic data in the Escherichia coli and Bacillus stearothermophilus PFKs. There is excellent homology between those PFKs and the schistosome PFK at those sites. The PFK-coding cDNA was expressed in insect cells and was shown to be enzymatically active. Western blot analysis of the recombinant protein in cell extracts gave a positive band with the expected molecular weight of 86 kDa.

Formation of promutagenic methylation damage in tissue-DNA of mice treated with antischistosomal agents

The existence of the promutagenic methylation damage O 6-MedG has been measured at various time intervals in different tissue DNAs of mice received a single therapeutic dose of various antischistosomal agents (hycanthone, oxaminiquine and metrifonate). Liver-DNA exhibited the highest levels of O 6-MedG in all treated animals while, spleen DNA contained the lowest. The three antischistosoml agents tested seemed to exert the peak concentrations of their alkylating metabolites over a period of several hours following the administration. In mice which had received hycanthone, liver-DNA contained readily detectable amounts of O 6-MedG by 6 h post-treatment (0,089 mol O 6-MedG/mol dG) and by the end of 48 h, this was decreased by about 3-fold to reach a level of 0.026 μmol/mol dG. In intestinal-DNA, however, O 6-MedG was formed more slowly and contained about half the level of that found in the liver-DNA. In the tissue-DNA of animals which had received oxaminiquine, the highest level of O 6-MedG was observed at 6 h after administration and at a 24-h time point, the adduct dramatically decreased in the liver and intestine-DNA to undetectable values. In neither tissues was there any evidence for O 6-MedG accumulation in the DNA at the end of a 48-h post-treatment. A pattern of O 6-MedG, almost similar to that of oxaminiquine, was also observed in tissue-DNA of mice pretreated with metrifonate. These results demonstrate that treatment with antischistosomal agents leads to the formation of highly promutagenic alkylated lesions in the tissue-DNA. The implication of such existence for antischistosomal-induced toxicity and carcinogenicity are discussed.

Response of drug resistant isolates of Schistosoma mansoni to antischistosomal agents.

The susceptibility of four isolates of Schistosoma mansoni (BH, MAP, MPR-1 and K) to four multiple doses of anti-schistosomal agents (hycanthone, niridazole, oxamniquine, and praziquantel) were evaluated in infected female Swiss albino mice. These schistosomal isolates had been maintained in the laboratory without further drug pressure for 20 to 30 generations. Multiple dosage regimens were used for each drug against each isolate of S. mansoni to generate ED50 (effective dose 50%) values. Results demonstrated that the K isolate is resistant to niridazole, the MPR-1 isolate to oxamniquine, and the MAP isolate to both hycanthone and oxamniquine. The BH isolate was susceptible to all drugs and was used as the reference isolate. All isolates were susceptible to parziquantel. The significance of the difference in response of the MPR-1 and MAP isolates is discussed. These results confirm the resistance of these isolates of S. mansoni to three schistosomicides and demonstrate that the resistance of these isolates are stable over long periods of time without exposure to drugs.

Reduction in chromosomal damage in schistosomiasis patients after treatment with praziquantel

Schistosoma haematobium infection is the most common health problem in Egypt. It is strongly associated with the development of urinary bladder carcinoma. The aim of this study was to determine whether infection with this parasite resulted in an increase of chromosomal breakage in the exfoliated urothelial cells. Urine samples were collected from 211 Egyptian male farmers and schoolchildren with Schistosoma haematobium ova in their urine. 66 samples were suitable for scoring. Accordingly, 66 non-infected males attending the same village clinic were included in the study as a control group. The urine was centrifuged and the urothelial cells present in the sediment were assayed for the presence of micronuclei, a quantitative indicator of chromosomal breakage. Micronucleus frequencies were significantly higher in the infected group (mean frequency, 0.84 ± 0.69%) than among controls (mean frequency, 0.12 ± 0.21%, p < 0.001). There was a trend towards an increase in micronucleus frequencies in infected individuals who smoked (17 of the 66 subjects) compared with those who were non-smokers, although this effect was not significant ( p > 0.05). Bladder infection was associated with a 6.1-fold increase in micronucleus frequencies among non-smokers. In this study, patients were treated with praziquantel, an anti-schistosomal agent. Out of the 66 studied patients, only 37 gave scoreable samples after treatment. The mean micronucleus frequencies were reduced significantly (before treatment, 0.80 ± 0.70%, after treatment, 0.19 ± 0.23%, p < 0.001), thus supporting a direct involvement of the infection in increased chromosomal breakage in the urothelium.

Oltipraz: a laboratory and clinical review.

Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione; RP 35972] is a synthetic, substituted 1,2-dithiole-3-thione previously used in humans as an antischistosomal agent. Cruciferous vegetables (e.g., Brussels sprouts, cabbage) contain several agents, including dithiolethiones, which appear to inhibit carcinogenesis; however, it is unclear which dietary compounds produce the protective effects. Animal studies have demonstrated that oltipraz is a potent inducer of Phase II detoxification enzymes, most notably glutathione-S-transferase (GST). Laboratory evaluations have shown that dietary concentrations of oltipraz produce marked inhibition of aflatoxin B1-induced hepatic tumorigenesis in rats. Levels of hepatic aflatoxin-DNA adducts, urinary aflatoxin-N7-guanine, and serum aflatoxin-albumin adducts decreased when biliary elimination of aflatoxin-glutathione conjugants increased, thus providing predictive biomarkers that measured a chemopreventive effect. In other animal experiments, oltipraz was found to inhibit chemically induced carcinogenesis in bladder, colon, breast, stomach, and skin cancer models. In addition, oltipraz has been shown to be non-mutagenic, a radioprotector, and a chemoprotective agent against carbon tetrachloride and acetaminophen toxicity. More recent studies in rats suggest that unsubstituted 1,2-dithiole-3-thiones may more effectively inhibit aflatoxin-induced hepatic tumorigenesis and induce electrophile detoxification enzymes. Multiple human clinical trials have been conducted using 1.0-4.5 gram doses of oltipraz over 1-3 days for the treatment of schistosomiasis. Phototoxicity has precluded its use in tropical areas. More recently, a 6 month Phase I trial was completed in which patients with resected colon polyps, or females with first degree relatives with breast cancer, were given oral daily doses of oltipraz at 125 mg or 250 mg. The maximum tolerated dose of oltipraz was < or = 125 mg daily. Grade I/II toxicities included photosensitivity/heat intolerance, GI and neurologic toxicity. Peak plasma concentrations were analyzed by HPLC with wide variability. In another Phase I study, a single oral dose of oltipraz was given to normal volunteers at dose levels of 125, 250, 375, and 500 mg. There was no significant difference in half-life (t1/2) between the four dose levels nor in clearance at the 125 and 250 mg levels. Peak oltipraz levels > or = 1.0 microgram/mL were achievable with marked interpatient variability. A series of small trials evaluating single oral doses of oltipraz for up to 28 days (dosing range 1 mg/kg-3 mg/kg/day) also showed a short t1/2 (4.1-5.3 hours), a sustained steady state without variation after a loading dose, and increased serum and urine concentrations with consumption of a high-fat diet.(ABSTRACT TRUNCATED AT 400 WORDS)

Chromosomal damage in urothelial cells from egyptians with chronic Schistosoma haematobium infections

The most common cancer in Egypt is urinary-bladder carcinoma, which is strongly associated with infection with Schistosoma haematobium. The object of this study was to determine whether infection with this parasite resulted in an increase in chromosomal breakage in the urothelium. Urine samples were collected from 37 Egyptian farmers with S. haematobium ova in their urine and from 32 non-infected males attending the same village clinic. The urine was centrifuged and the urothelial cells present in the sediment were assayed for the presence of micronuclei, a quantitative indicator of chromosomal breakage. Micronucleus frequencies were significantly higher in the infected group (mean frequency, 0.97 +/- 0.12%) than among controls (mean frequency, 0.12 +/- 0.04%, p less than 0.001). There was a trend towards an increase in micronucleus frequencies in infected individuals who smoked (10 of the 37 subjects) compared with those who were non-smokers, although this effect was not significant (p = 0.12). Bladder infection was associated with a 6.8-fold increase in micronucleus frequencies among non-smokers. In a pilot study, 11 patients were treated with praziquantel, an anti-schistosomal agent. Mean micronucleus frequencies were reduced significantly (before treatment, 1.27 +/- 0.16%; after treatment, 0.30 +/- 0.16%, p less than 0.001), thus supporting a direct involvement of the infection in increased chromosomal breakage in the urothelium.

Mechanisms of chemoprotection by oltipraz.

1,2-Dithiole-3-thiones are five-membered cyclic sulfur-containing compounds with antioxidant, chemotherapeutic, radioprotective and cancer chemoprotective properties. One substituted dithiolethione, oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione], originally developed as an antischistosomal agent, has recently been observed to protect against chemically induced carcinogenesis in lung, trachea, forestomach, colon, breast, skin, liver and urinary bladder in rodents. The induction of electrophilic detoxication enzymes, which result in diminished carcinogen-DNA adduct formation and reduced cytotoxicity, appears to be an important component of the anticarcinogenic action of oltipraz and other dithiolethiones. Phase I trials of oltipraz are presently underway in the United States. Subsequent trials might be most appropriately targeted towards individuals at high risk for occupational or environmental exposures to genotoxic carcinogens.

Effect of praziquantel on Schistosoma mansoni eggs: leucine aminopeptidase (LAP) activity and anti-LAP antibodies.

High levels of leucine aminopeptidase (LAP) have been detected in Schistosoma mansoni eggs. In this report we demonstrate that this enzyme is immunogenic in mice infected with either S. mansoni or S. japonicum. The anti-schistosomal agent, praziquantel, causes rapid release of this enzyme from schistosome eggs in vitro. Praziquantel treatment of S. japonicum infected mice is associated with a significant decrease in anti-LAP antibodies. Anti-LAP IgM antibody levels decreased more than did anti-LAP IgG antibodies.

The effect of lucanthone on sublethal radiation damage, in vivo

The capacity of the Chinese hamster jejunal crypt cell to accumulate and repair sublethal radiation damage was determined by analyzing the return of the shoulder of the radiation dose-crypt microcolony survival curve (D r) after a priming dose of 1250 rad. The control split dose crypt cell survival curve exhibited a D 0, D r and “n” of 179 ± 3 rad, 261 ± 3 rad and 4.3 respectively; repair of sublethal radiation damage was completed by two hours post-irradiation. The effect of lucanthone (an antischistosomal DNA intercalating agent) on the crypt cell's capacity to accumulate and repair sublethal radiation damage was determined by injecting the drug (100 mg/kg, i.p.) at intervals before irradiation with a priming dose of 1250 rad, followed two hours later by graded doses. Injection coincident with the priming dose of radiation resulted in a 22 rad reduction of the D r (compared to control D r). Injection eight hours before the priming dose almost completely inhibited the accumulation and repair of sublethal radiation damage so that the resultant D r two hours later was only 29 rad (a 232 rad reduction). At no time was the D 0 of the crypt cell survival curve affected by lucanthone. These data confirm previous results from whole crypt analysis and LD 50 7 , analysis that non-toxic concentrations of lucanthone reversibly inhibit the accumulation and repair of sublethal radiation damage in a time-dependent manner with complete inhibition approximately eight hours post-injection. This drug is useful for the study of sublethal radiation damage in vivo and may be beneficial in radiation therapy of cancer when it is desirable to inhibit the repair of sublethal radiation damage.