O6-methylguanine and O6-methylguanine-DNA [corrected] methyltransferase activity in tissues of BDF-1 mice treated with antiparasitic drugs.

Levels of the DNA promutagenic methylation damage, O6-methylguanine (O6-MeG) and the activity of the O6-methylguanine-DNA methyltransferase (MGMT), the enzyme responsible for repairing O6-MeG, were measured at various time intervals in tissues of BDF-I mice administered a single therapeutic dose of the antischistosomal agents hycanthone, oxaminiquine and metrifonate. Hycanthone increased O6-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 O6-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 O6-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 (approximately 38%) than the control values after 6 h, then restored by 48 h. A significant negative correlation was obtained between O6-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.

Evaluation of external-beam radiation therapy plus 5-fluorouracil (5-FU) versus external-beam radiation therapy plus hycanthone (HYC) in confined, unresectable pancreatic cancer.

From March 1981 to November 1987, 87 patients with histologically confirmed pancreatic adenocarcinoma, unresectable but confined to the pancreatic region, were randomized to two treatments. The standard treatment was 40-50 Gy external-beam radiation therapy (RT) to gross tumor plus potential microscopic tumor with a 5 Gy boost to gross tumor plus a 1.5-2.0 cm margin, using multiple fields and 5-fluorouracil (5-FU) 500 mg/m2/d intravenously by rapid infusion. The 5-FU was given each of the initial 3 days of each of three 20 Gy radiation courses. The experimental treatment used identical radiation fields, but the two Gy daily radiation fractions were administered in a continuous course to a total dose of 50 Gy. Hycanthone was administered 60 mg/m2 intravenously within 2 to 4 hr during each day of the 5-day course of infusions during the first and fifth weeks of radiation therapy. There was no statistically significant difference between treatment arms in survival (p = 0.82) or disease-free survival (p = 0.27). Seven percent of hycanthone-treated patients demonstrated hepatic toxicity which was usually mild in nature. There was, however, one death due to hepatic toxicity.

Schistosoma mansoni: an in vivo study of drug-induced autophagy in the gastrodermis.

The effects of Astiban, Lucanthone, Hycanthone and Niridazole on autophagic activities in the gastrodermis of Schistosoma mansoni were determined in vivo, using different dosage levels and dosage times. With Astiban, high levels of autophagy were observed in the gastrodermis 2 hours after an injection of the drug into the mouse, and this response had declined by 20 hours, marking a recovery by the parasite from the drug. Hycanthone and Lucanthone produced an autophagic response several days after the onset of treatment, and no recovery was observed in the morphology of the gastrodermis after the drug was discontinued. The effects of Niridazole on the gastrodermis were to produce the most dramatic ultrastructural changes after high doses and over several days of treatment. With all the drugs examined, gastrodermal autophagy was characterized by the formation of vacuoles containing cell components, lipid droplets and sometimes hydrolytic enzyme reaction product. The autophagic vacuoles appeared to be formed by the sequestration of cytoplasmic material by the basal membrane infoldings, and the transfer of enzymes into the vacuole from within the limiting membrane. The residues from intracellular digestion appeared to be emptied into the caecal lumen.

Hepatotoxicity of hycanthone in patients with metastatic breast cancer.

Hycanthone is an antischistosomal drug with promising antitumor activity against experimental animal tumors. In phase I clinical trials, hepatitis weas the dose-limiting toxic effect and a dose of 60-70 mg/m2/day for 5 days was reported as the maximum-tolerated dose. In a phase II study of hycanthone in patients with breast cancer we have recently observed severe hepatotoxicity, even at lower doses, which resulted in two drug-related deaths. From this study and the previously available data, we conclude that this drug is too toxic for human trials at the currently recommended doses. Its radiosensitizing effect may be worth exploring at a lower dose level.

Phase I study of hycanthone.

Hycanthone was given to 15 patients with metastatic cancer in order to determine the maximum tolerable dose. The drug was administered in 5-day courses at 3-week intervals. The starting dose was 30 mg/m2/day and the highest dose level reached was 90 mg/m2/day. The most common (13 patients) side effect was nausea and/or vomiting. The dose-limiting toxicity was toxic hepatitis manifested as elevation in serum transaminases in eight of 15 patients and an increase in serum bilirubin in three patients. Hepatotoxicity was dose-related and was observed in two of 25 courses given at the dose level of less than or equal to 70 mg/m2 compared to seven of nine courses given at the dose level of greater than or equal to 80 mg/m2. Because of an unacceptable incidence of hepatotoxicity at higher doses, 70 mg/m2/day x 5 appears to be a safe dose for phase II studies.

Hycanthone dose-response in Schistosoma mansoni infection in Kenya.

The recommended doses of the drugs now used to cure schistosomiasis mansoni may be associated with toxic side-effects. Since Schistosoma mansoni does not multiply in the human host and the disease seems to be closely associated with the intensity of infection, it may not be necessary to use 100% lethal antischistosomal doses, particularly in endemic areas. A dose-response to the antischistosomal drug, hycanthone was established for three different doses in 169 patients with heavy S. mansoni infections in the Machakos district of Kenya. The highest dose used (1.5 mg/kg or half the recommended package-insert dose) resulted in a 96% decrease in egg output (equivalent ot death of the worms); 0.75 mg/kg in an 85% decrease; and 0.375 mg/kg in an 11% decrease one month after treatment. In contrast to the vomiting common with the package-insert dose (3.0 mg/kg), there were no side-effects with any of the lower doses.

The activity of a benzothiopyranoindazole (IA-4 N-oxide) against Schistosoma mansoni infection in rhesus monkeys.

The prophylactic and therapeutic efficacies of IA-4 N-oxide against Schistosoma mansoni in rhesus monkeys (Macaca mulatta) have been evaluated. Ten monkeys were divided into 5 groups of 2 monkeys each. All monkeys were exposed to S. mansoni cercariae on day 0 and treatment groups were established as follows: untreated controls, oral prophylactic administration, intramuscular prophylactic administration, oral therapeutic administration, and intramuscular therapeutic administration. Analysis of parasitologic and pathologic criteria indicate that the compound is most effective when administered as a therapeutic regimen. Complete cures were effected in these monkeys. Prophylactic treatments resulted in a delay in onset of patency and reductions in fecal egg excretion, worm burdens, and tissue damage.

Hycanthone dose-response in treatment of schistosomiasis mansoni in St. Lucia.

Clinical trials of hycanthone (single intramuscular dose) were undertaken in schistosomiasis mansoni patients in St. Lucia at five dose levels: 3.0, 2.5, 2.0, 1.5, and 1.0 mg/kg body weight. The most common side effect, vomiting, decreased in frequency from 51% at the highest dose to 3% at the lowest; minor side effects showed a similar trend. Three fecal specimens were examined before and at 6 months after treatment by qualitative, quantitative, and hatching techniques. All dose levels caused reductions in egg excretion of 89 to 98%. Rates of cure (absence of eggs by all three methods) according to dose (descending), pretreatment egg output (0-19, 20-49, 50-399, 400+ eggs/ml feces), and age (0-7, 8-14, 15-29, 30+ years) were analyzed to estimate the effect of each variable if the others had been constant. For dose, the standardized percentage success rates were 53.9%, 62.0%, 51.2% 54.0%, and 27.4%; for egg output, 67.0%, 51.8%, 43.2%, and 21.7%; and for age, 25.2%, 34.5%, 59.3% and 57.4%. Logit regression analysis shows a significant difference in cure rate (a) between the lowest dose and all others, among which latter there was no difference, (b) between patients excreting 0 to 49 eggs/ml before treatment and those excreting 50+ eggs/ml, and (c) between the age groups 0 to 14 and 15+ years. All dose levels caused some regression in enlargement of liver or spleen. A dose of 1.5 to 2.0 mg/kg body weight is considered to be as effective as one of 3.0 mg/kg and more acceptable for a control program because of the marked reduction in side effects.

Hycanthone dose-response in treatment of Schistosomiasis mansoni in St. Lucia

Clinical trials of hycanthone (single intramuscular dose) were undertaken in Schistosomiasis mansoni patients in St. Lucia at five dose levels: 3.0, 2.5, 2.0, 1.5, and 1.0mg/kg body weight. The most common side effect, vomiting, decreased in frequency from 51 percent at the highest dose to 3 percent at the lowest; minor side effects showed a similar trend. Three fecal specimens were examined before and at 6 months after treatment by qualitative, quantitative, and hatching techniques. All dose levels caused reductions in egg excretion of 89 to 98 percent. Rates of cure (absence of eggs by all three methods) according to dose(descending), pretreatment egg output (0-19, 20-49, 50-399, 400+ eggs/ml feces), and age (0-7, 8-14, 15-29, 30+ years) were analyzed to estimate the effect of each variable if the others had been constant. For dose, the standardized percentage success rates were 53.9 percent, 62.0 percent, 51.2 percent, 54.0 percent, and 27.4 percent; for egg output, 67.0 percent, 51.8 percent, 43.2 percent, and 21.7 percent; and for age, 25.2 percent, 34.5 percent, 59.3 percent, and 57.4 percent. Logit regression analysis shows a significant difference in cure rate (a) between the lowest dose and all others, among which latter there was no difference, (b) between patients excreting 0 to 49 eggs/ml before treatment and those excreting 50+ eggs/ml, and (c) between the age groups 0 to 14 and 15+ years. All dose levels caused some regression in enlargement of liver and spleen. A dose of 1.5 to 2.0mg/kg body weight is considered to be as effective as one of 3.0mg/kg and more acceptable for a control program because of the marked reduction in side effects. (AU)

Hycanthone in the treatment of Egyptian bilharzial patients.

Hycanthone has a schistosomicidal effect against S. haematobium and S. mansoni present singly or combined in the patient. It is effective in all age groups but better in old and adults than in children and better in females than in males. It gave a cure rate of 60.6% after single intramuscular dose of 3 mg/kg body weight. Second dose after three months gave 94.4% cure rate and a third injection after further two months gave 100% cure rate. So, the drug cannot be used in the treatment of bilharziasis as a single dose course.

An evaluation of the micronuclei test using triethylenemelamine, trimethylphosphate, hycanthone and niridazole.

To determine the feasibility of the micronuclei procedure for cytogenetic studies, a comparatively weak chromosome breaking agent, trimethylphosphate (TMP) and the potent alkylating agent, triethylenemelamine (TEM) were evaluated. The procedure followed was that of Matter and Schmid with the following modifications: (a) direct flushing of bone marrow with 0.2 ml calf fetal serum. (b) air drying slides for a period of only I h, and (c) the use of pH 6.0 phosphate buffer to dilute both Wright and Giemsa stains. With this technique a dose response curve was generated for both TMP and TEM, using mice as the experimental animal. With TMP, a doubling over background was found when a concentration of 0.5 g/kg per day for five days was administered. To establish a statistically significant doubling dose over the control, a minimum of five animals must be used with 2000 polychromatic cells being analyzed per animal. Of the two antischistosomal agents tested, hycanthone yielded an increase of 20-fold in the number of micronuclei over control at 40 mg/kg administered i.p. for five days, while with niridazole no increase in micronuclei at several concentrations tested both by single and multiple injection was found. The results obtained with these compounds compare favorably with what has been reported for the standard in vivo metaphase analysis.