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PubMed1983

The in vivo cytotoxic activity of procarbazine and procarbazine metabolites against L1210 ascites leukemia cells in CDF1 mice and the effects of pretreatment with procarbazine, phenobarbital, diphenylhydantoin, and methylprednisolone upon in vivo procarbazine activity.

An in vivo assay of the activity of procarbazine, N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide hydrochloride, and several metabolic intermediates against IP-implanted L1210 leukemia cells in CDF1 male mice is described. Treatment of tumor-bearing mice with procarbazine at doses of 300-500 mg/kg IP increased the mean lifespan of treated mice by 29%-32% relative to that of untreated animals. Procarbazine treatment with doses of 200-400 mg/kg/day given IP for 3 consecutive days increased mean lifespan by 39%-46%. The major circulating metabolite, azoprocarbazine (N-isopropyl-alpha-(2-methylazo)-p-toluamide), was as active as procarbazine when administered at equivalent doses for 3 consecutive days. A 2:1 mixture of azoxyprocarbazines (N-isopropyl-alpha-(2-methyl-ONN-azoxy)-: and N-isopropyl-alpha-(2-methyl-NNO-azoxy)-p-toluamide) was more active than procarbazine, increasing mean lifespan by 76% using the 3-consecutive-day dose schedule. The effects of pretreatment with procarbazine and drugs that are often co-administered with procarbazine, i.e., phenobarbital, diphenylhydantoin, and methylprednisolone, upon procarbazine anticancer activity against L1210 ascites leukemia cells was also determined. Pretreatment of CDF1 male mice with phenobarbital and diphenylhydantoin for 7 days was found to increase the antineoplastic activity of procarbazine by 13%-24%. Pretreatment with methylprednisolone did not significantly alter procarbazine activity. The effects of pretreatment with procarbazine, which is often administered daily for a period of 2-4 weeks, on procarbazine antineoplastic activity were varied. The results of these preliminary pretreatment studies combined with the finding that procarbazine metabolites have antitumor activity that is equal to or greater than that of the parent drug suggest that current clinical protocols that use procarbazine along with agents capable of altering procarbazine metabolism may involve drug interactions that alter the efficacy of procarbazine as an anticancer agent.

Animals↗
PubMed1982

Quantitative analysis of procarbazine, procarbazine metabolites and chemical degradation products with application to pharmacokinetic studies.

Quantitative analytical methods are described for the analysis of the anticancer drug procarbazine and eight known metabolites including those known to have cytotoxic activity. A direct sample insertion mass spectrometric assay for procarbazine and the urinary excretion product, N-isopropyl-terephthalamic acid, has been developed. This method employs stable isotope labeled variants in a procedure that minimizes analytical errors that may be encountered in the quantitation of the chemically unstable parent drug. a liquid chromatographic method is described for the analysis of seven known procarbazine metabolites. Use of these methods is demonstrated by the analysis of procarbazine metabolism during incubation in a 9000-g rat liver homogenate preparation. Procarbazine disappearance and metabolite appearance are also monitored in rat plasma following intraperitoneal administration of a 150 mg/kg bolus dose. Applications to patient pharmacokinetics is demonstrated using the liquid chromatographic assay to follow the appearance of active procarbazine metabolites on the first and fourteenth day of an oral 250 mg/kg/day course of therapy of a patient being treated for cancer.

Animals↗
PubMed1992

Hypersensitivity reactions to procarbazine with mechlorethamine, vincristine, and procarbazine chemotherapy in the treatment of glioma.

The authors report the clinical features of hypersensitivity reactions believed to result from procarbazine in eight patients treated with mechlorethamine, vincristine, and procarbazine (MOP) for high-grade glioma. There was one instance of hypersensitivity in 7 patients treated for recurrent disease and seven instances in 16 patients treated with an adjuvant protocol using MOP directly after surgery. Maculopapular rash was seen in seven of eight, fever was seen in four of eight, and reversible abnormal liver function test results were seen in three of four patients. Pulmonary toxic effects were seen in five of eight patients and consisted of isolated interstitial pneumonitis in one, fever and infiltrate after rechallenge with procarbazine after previous rash in two, and cough accompanying rash in two. The toxic effects were mild to moderate in six patients but severe to life threatening in the two who were rechallenged after development of rash. The observed incidence of rash during adjuvant therapy was higher than that previously found by the authors for recurrent disease, and it appears to be higher than has been reported in Hodgkin's disease, lymphoma, and other solid tumors. The findings by the authors suggest that a high index of suspicion be kept for hypersensitivity reactions to procarbazine when treating primary brain tumors and that, contrary to the experience in other settings, procarbazine be stopped if rash develops.

Aged↗
PubMed1986

Cytotoxic chemotherapy of disseminated cutaneous malignant melanoma--a prospective and randomized clinical trial of procarbazine, vindesine and lomustine versus procarbazine, DTIC and lomustine.

Forty-three patients with measurable disseminated cutaneous malignant melanoma, stages III-IV, and without previous cytotoxic chemotherapy or immunotherapy, were randomly allocated from 30 June 1980 to 30 November 1984, to receive either a schedule of procarbazine (100 mg/m2 p.o., max 150 mg) days 1-10, vindesine (3 mg/m2 i.v., max 5 mg) days 1 and 8, and CCNU (150 mg/m2 p.o., max 200 mg) day 1, (regimen A), with 4-6 weeks interval between the courses, or a combination of procarbazine (100 mg/m2 p.o., max 150 mg) days 1-10, DTIC (250 mg/m2 i.v. max 400 mg) days 1-5, and CCNU (150 mg/m2 p.o. max 200 mg) day 1 (regimen B), also repeated every 4-6 weeks. Twenty-one patients were treated according to regimen A and 22, by regimen B. Objective responses (three PR, two CR) were seen in 5 out of 21 patients (23.8%) in group A and 8 out of 22 (four PR, four CR), (36%) in the group B, this difference not being statistically significant. The median duration of response was 8 and 10 months, respectively, and the estimated median survival 10 months for regimen A and 14 months for regimen B. Regimens A and B must be regarded as of no value in view of poor response rate and the unacceptable toxicity, respectively. Therefore, we are now conducting a further phase II study, to determine, prospectively, whether the previously noted high response rate obtained with our previous POC protocol can be reaffirmed.

Adult↗
PubMed1990

Protection of spermatogenesis in rats from the cytotoxic procarbazine by the depot formulation of Zoladex, a gonadotropin-releasing hormone agonist.

The hypothesis that adjuvant treatment designed to produce testicular atrophy would preserve fertility in males receiving cancer chemotherapy was examined in the rat. Testicular atrophy was induced by a depot formulation of Zoladex [D-Ser(Bu(t))6-Aza-Gly10-GnRH], a gonadotropin-releasing hormone (GnRH) analogue. The experiments were conducted in albino Wistar as well as in the piebald variegated rat. Rats received the depot Zoladex formulation 2 weeks before and immediately prior to being treated with four weekly doses of procarbazine (200 mg/kg). Testicular function was evaluated 50 and 90 days after the last procarbazine dose. Procarbazine induced testicular atrophy concomitant with marked germinal cell aplasia in both strains of rat. In the Wistar rat adjuvant treatment with Zoladex caused slight but not significant alleviation of the testicular toxicity of procarbazine. The testicular toxicity of procarbazine was more extensive in the piebald variegated rat, and 50 days after the last procarbazine treatment the testes were small, sperm were absent, and the stem cell index was close to zero. Serum luteinizing hormone (LH) concentrations were raised and testicular LH receptor binding was low in the presence of normal serum and testicular testosterone concentrations, indicating compensated Leydig cell failure. Testicular weight and sperm content, as well as LH receptor binding, were still decreased in rats which received both Zoladex and procarbazine, suggesting that the analogue offered no protection. However, the stem cell index of the seminiferous tubules in the procarbazine-Zoladex-treated rats was not significantly different from vehicle-treated rats, which suggested that recovery from the effects of procarbazine was in progress. Ninety days after the end of procarbazine treatment alone the testes of rats were still atrophied and there was little evidence of active spermatogenesis. Leydig cell failure appeared to have progressed as, in addition to the low testicular LH receptor content and raised serum LH concentration, the prostate and seminal vehicle weights were decreased. The combination of Zoladex treatment with procarbazine was successful in preserving testicular function in the piebald variegated rats as virtually all the functional and morphological parameters of both the seminiferous tubule and the Leydig cell were not significantly different from those of vehicle-treated rats. This study demonstrates for the first time that effective gonadal protection from the toxic effects of procarbazine chemotherapy can be achieved by administration of the depot formulation of the gonadotropin-releasing hormone analogue Zoladex. The results show clearly that complete suppression of spermatogenesis is not a prerequisite for the successful outcome of treatments designed to protect the gonad from cytotoxic chemotherapy.

Animals↗
PubMed1987

Separate mechanisms for procarbazine spermatotoxicity and anticancer activity.

Procarbazine causes dose-dependent decreases in sperm count after a single i.p. injection in (C57BL/6 X DBA/2)F1 male mice. Two antioxidants, N-acetylcysteine and sodium ascorbate, administered with equimolar doses of procarbazine decreased the spermatotoxicity of procarbazine. At the highest doses of procarbazine (400 mg/kg) that caused a 56% decrease in sperm count, equimolar doses of N-acetylcysteine coadministered with procarbazine caused only a 17% decrease in sperm count, and equimolar doses of ascorbate coadministered with procarbazine caused only a 13% decrease in sperm count. Thus, protection against the spermatotoxic effects of procarbazine was demonstrated with either antioxidant. The effect of the antioxidants on the chemotherapeutic efficacy of procarbazine against murine L1210 leukemia was also assessed. Procarbazine at the highest dose (600 mg/kg) increased mean survival time of mice inoculated i.p. with 1 X 10(5) L1210 leukemia cells by 31%. Simultaneous administration of equimolar doses of either N-acetylcysteine or ascorbate given with procarbazine caused no change in the increased mean survival time of tumor-bearing mice. These results indicate a decrease in the toxicity of procarbazine when coadministered with antioxidants, via decreased spermatotoxicity without changing anticancer efficacy. The results also indicate that different mechanisms are involved in the spermatotoxicity and anticancer activity of procarbazine.

Acetylcysteine↗
PubMed1979

Procarbazine-induced specific-locus mutations in male mice.

Procarbazine is used in drug-combination treatment of Hodgkin's disease. The specific locus method was used to test and confirm the ability of procarbazine to induce gene mutations in pre- and post-meiotic germ cells of male mice. The lowest dose of procarbazine that significantly increased the mutation frequency in As spermatogonia over the control frequency was 400 mg/kg (P = 0.003). The corresponding dose for the post-spermatogonial germ-cell stages was 600 mg/kg (P = 0.009). The dose--response was linear for the point estimates of the mutation frequencies after treatment of As spermatogonia with 0, 200, 400 and 600 mg/kg. The point estimate of the mutation frequency at the 800 mg/kg level was one-third of that expected from a linear extrapolation. Variation in mutation rates among the 7 loci between the lowest (a locus) and the highest (p locus) was 12-fold. Only 24% of procarbazine-induced specific locus mutations in As spermatogonia were lethal in the homozygous condition. From the mutation spectra and the viability tests, it is concluded that procarbazine-induced mutations may be mainly due to base-pair changes. Procarbazine-induced specific-locus mutations fulfilled the criteria for the estimation of the doubling dose, the dose necessary to induce as many mutations as occur spontaneously. The doubling dose of procarbazine in As spermatogonia of mice was 114 mg/kg. The therapeutic dose for procarbazine is about 215 mg/kg. If man and mouse were equally sensitive, this dose would induce 1.9 times as many mutations as arise spontaneously. From the incidence of patients with Hodgkin's disease (1 : 42 000) the calculated population dose of procarbazine is 5.12 micrograms/kg. Assuming equal sensitivity between the sexes we can calculate, for an estimated number of 30 000 genes, the induction of about 22 mutations per million children due to procarbazine treatment. The same number of induced mutations can be calculated if the risk of patients is used for the estimation of the genetic hazard.

Animals↗
PubMed1985

Procarbazine spermatogenesis toxicity: deuterium isotope effects point to regioselective metabolism in mice.

Procarbazine was shown to decrease spermatogenesis in male mice in a dose-dependent manner. Significant decreases (44% of controls) in spermatogenesis were observed when a dose of 400 mg/kg was administered 18 days prior to determination of sperm count. Procarbazine caused no significant acute spermatocidal activity in vivo. Procarbazine-associated decreases in spermatogenesis were thus used as an index of toxicity to developing spermatid cells. Procarbazine analogs were synthesized that had deuterium substituted for hydrogen at the benzylic position, N-isopropyl-alpha-(2-methylhydrazino)-p-[alpha, alpha-2H2]toluamide (d2-procarbazine), or at the methyl position, N-isopropyl-alpha-(2-[alpha, alpha, alpha-2H3]methylhydrazino)-p-toluamide (d3-procarbazine). Spermatogenesis decreases caused by d3-procarbazine were essentially the same as with procarbazine in mice (66% of controls at a dose of 200 mg/kg), but d2-procarbazine was nontoxic to developing sperm cells (99% of control at a dose of 200 mg/kg). The decrease in toxicity caused by deuterium substitution at the benzylic position, coupled with the absence of an effect with the methyl-labeled analog, indicate the requirement for regioselective oxidative metabolism of procarbazine at the benzylic position prior to the toxic event.

Animals↗
PubMed1997

Anticonvulsant usage is associated with an increased risk of procarbazine hypersensitivity reactions in patients with brain tumors.

BACKGROUND: Procarbazine usage in brain tumors has a high incidence of hypersensitivity reactions compared with its use in other malignancies. Procarbazine oxidation to a reactive intermediate is enhanced by phenobarbital. Patients with primary brain tumors would have a preferential exposure to anticonvulsants compared to patients with other malignancies. OBJECTIVE: To determine whether anticonvulsant exposure is associated with procarbazine hypersensitivity reactions in patients with primary brain tumors. METHODS: This retrospective cohort study included 83 patients with primary brain tumors who were treated with procarbazine between 1981 and 1996 at a university hospital-based regional oncology center. Data were extracted by chart review. The data collected included age, sex, race, tumor type, smoking, alcohol usage, and all concomitant medications, as well as creatinine, aspartate aminotransferase, total bilirubin, and anticonvulsant serum levels. Anticonvulsant exposure was determined by the presence of detectable serum levels. Cases of procarbazine hypersensitivity reactions were identified through a review of progress notes. RESULTS: There were 20 patients with procarbazine hypersensitivity reactions. A significant association between the exposure to anticonvulsants and the development of procarbazine hypersensitivity reactions was found (p = 0.05). In addition, there was a significant dose-response association between the development of procarbazine hypersensitivity and the presence of therapeutic anticonvulsant serum levels (p = 0.03). CONCLUSIONS: Concomitant exposure to anticonvulsants is associated with procarbazine hypersensitivity reactions, possibly though a reactive intermediate generated by CYP3A isoform induction. All patients in this cohort received enzyme-inducing anticonvulsants. New anticonvulsants devoid of this property are available. These data support trials that use these newer agents for the prophylaxis of seizures in patients with brain tumors who are to receive procarbazine.

Adult↗
PubMedDate not supplied

Metabolism of azoxy derivatives of procarbazine by aldehyde dehydrogenase and xanthine oxidase.

Procarbazine, a 1,2-disubstituted hydrazine, is employed therapeutically in the treatment of Hodgkin's disease and a limited number of other neoplasias. The isomeric azoxy metabolites of procarbazine have recently been identified as the precursors of species responsible for both the anti-cancer efficacy and toxic effects mediated by this drug. This study demonstrates that cytosolic enzymes are involved in the metabolism of the azoxy metabolites of procarbazine. Two azoxy procarbazine oxidase activities were resolved by diethylaminoethyl (DEAE)-cellulose chromatography. The activity which did not bind to this column was purified to homogeneity and was identified as a phenobarbital-inducible form of cytosolic aldehyde dehydrogenase. This protein fraction was shown to metabolize only the azoxy 2 procarbazine isomer to yield N-isopropy-p-formylbenzamide (ALD) in a reaction which did not require NAD+ as cofactor. The ALD product formed was also a substrate for a subsequent NAD(+)-dependent reduction reaction catalyzed by that purified protein. The azoxy 2 procarbazine isomer and ALD were shown to be potent inhibitors of both the dehydrogenase and esterase activities of aldehyde dehydrogenase. The second azoxy procarbazine oxidase activity which was retained by the DEAE-cellulose column co-eluted with xanthine oxidase activity. Both the xanthine dehydrogenase/oxidase and azoxy procarbazine oxidase activities of this protein fraction were inhibited by allopurinol, a specific inhibitor of xanthine dehydrogenase. Xanthine dehydrogenase/oxidase was partially purified by an alternative procedure and was shown to metabolize both the azoxy 2 procarbazine isomer and ALD, ultimately producing N-isopropylterephthalamic acid. The ability of xanthine oxidase to metabolize azoxy 2 procarbazine and ALD was confirmed using commercial, purified milk xanthine oxidase.

Aldehyde Dehydrogenase↗
PubMed1992

Non-enzymatic activation of procarbazine to active cytotoxic species.

The cellular cytotoxicity of procarbazine is thought to result from bioactivation of the parent compound through reactive intermediates to an ultimate alkylating species. Procarbazine is converted initially to azoprocarbazine, which is then N-oxidized through a cytochrome P-450-mediated process to a mixture of the positional isomers, benzylazoxyprocarbazine and methylazoxyprocarbazine. In order to define the bioactivation events that lead to the cytotoxic species, the in vitro cytotoxicities of the purified azoxy isomers as well as of the parent compound, procarbazine, were evaluated with the human leukemia cell line, CCRF-CEM. The methylazoxy isomer was found to be the most active species. Procarbazine inhibited the growth of CCRF-CEM cells but at a concentration much higher than that required for the methylazoxy isomer. Since procarbazine must be metabolized to form the cytotoxic species, we sought to determine if the active metabolite, methylazoxyprocarbazine, was being formed in the incubations. Solutions of procarbazine incubated with and without cells at 37 degrees C were analyzed by combined liquid chromatography-mass spectrometry with a thermospray interface. The azoxy metabolites of procarbazine appeared rapidly in cellular incubations and in the aqueous solutions without cells. More of the methylazoxy isomer was formed initially, but by 72 hr the benzylazoxy isomer was the predominant species. Thus, in these studies it appears that procarbazine was benzylazoxy isomer was the predominant species. Thus, in these studies it appears that procarbazine was non-enzymatically oxidized to the two azoxyprocarbazine isomers and that the methylazoxy compound was the most cytotoxic to CCRF-CEM cells.

Biotransformation↗
PubMed1989

Cytotoxicity and DNA damage caused by the azoxy metabolites of procarbazine in L1210 tumor cells.

Procarbazine, a chemotherapeutic hydrazine, is thought to be metabolized to an alkylating species similar to methyl carbonium ion by multistep reactions involving cytochrome P-450, monoamine oxidase, and cytosolic enzymes. The DNA-damaging and cytotoxic potential of procarbazine and its metabolites in murine L1210 leukemia tumor cells in vitro was determined using alkaline elution techniques and extrapolation of growth curves. Neither procarbazine nor any of the chemical degradation products (except for the aldehyde derivative at high concentrations) caused significant amounts of DNA strand breakage. The primary enzymatic oxidation product, azo-procarbazine, did not produce strand breakage. However, exposure of the cells to either of the two isomers of azoxy-procarbazine led to significant DNA damage and cytotoxicity. DNA damage included both single-strand breaks and alkali-labile sites. At equimolar concentrations, the azoxy 2 isomer of procarbazine caused 14 to 20 times more DNA damage than did the azoxy 1 metabolite. When cell growth is expressed as percentage survival of L1210 cells, the azoxy 2 isomer was approximately 7-fold more toxic than the azoxy 1 metabolite. The other metabolites tested showed little or no cytotoxicity. L1210 cells were shown to contain little or no cytochrome P-450 or monoamine oxidase activity, which may account for the lack of toxicity of the parent drug or the primary oxidative metabolite, azo-PCZ, to these cells. The conversion of procarbazine to the azoxy-procarbazine isomers in vivo must occur in cells which contain these enzymes, such as liver. However, the azoxy isomers of procarbazine were metabolized in L1210 cells, presumably leading to the DNA or cytotoxic damage observed.

Animals↗
PubMed1989

Comparative genotoxicities of procarbazine and two deuterated analogs in mammalian cells in vitro and in vivo.

N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide hydrochloride (procarbazine; 50-1000 micrograms/ml) induced DNA damage in hepatocytes measured by an automated alkaline elution method, whereas no significant increase in unscheduled DNA synthesis was seen. In hepatocytes isolated from PCB-treated rats, DNA damage was detected in both test systems at concentrations as low as 1-10 micrograms/ml. DNA damage, as measured by alkaline elution and sister-chromatid exchange(s), was observed also in V79 cells incubated with PCB-hepatocytes. In contrast, no mutagenic activity was observed in the Salmonella typhimurium strain TA1530 co-incubated with the hepatocytes. Exposure of rats to low doses of procarbazine (25-50 mg/kg) caused DNA damage measured by alkaline elution in liver and testis, with the liver being somewhat more sensitive. The genotoxicity caused by procarbazine was increased by a factor of 2-3 in both organs by PCB-treatment of the rats. N-isopropyl-alpha-(2-methyl-hydrazino)-p-[alpha,alpha-2H2]toluamide (d2-procarbazine), was found to cause significantly less genotoxicity in control rats than either procarbazine itself, or N-isopropyl-alpha-(2-[alpha,alpha,alpha-2H3]methylhydrazino)-p-tol uamide (d3-procarbazine). This indicates that benzylic C-H oxidation of procarbazine is an important step in the activation of procarbazine to genotoxic metabolites in uninduced rats.

Animals↗
PubMed1988

Effect of sexual maturity on testicular injury subsequent to procarbazine administration in rats.

The present study examined the effect of age on various aspects of Leydig cell and Sertoli cell function in Sprague-Dawley rats administered procarbazine. Procarbazine was administered intraperitoneally to Sprague-Dawley rats aged 14, 24, and 60 days in 3 weekly injections of 200 mg/kg. Animals were sacrificed 1 week after the last injection. Severe impairment of spermatogenesis was evident in all animals. Sertoli cell function, as assessed by total testicular ABP content, was not significantly different between procarbazine-treated animals and controls in any age group. On the other hand, procarbazine administration resulted in a 60% reduction in total intratesticular testosterone content in the 14-day-old rats but not in the 24- or 60-day-old animals. Serum testosterone was significantly reduced by 50% in the group of 14-day-old animals but not in the other age groups. Serum LH values were not significantly changed from control levels in any age group. Testicular content of Fe, Zn, Mn, and Cn were unaltered by procarbazine administration in any age group. Since serum LH and testicular cation content were not affected by procarbazine treatment, the significant decreases in serum and testicular testosterone in 14-day-old animals after procarbazine administration may indicate a direct age-dependent effect of procarbazine on Leydig cell function.

Animals↗
PubMed1983

Studies on the pathway of methane formation from procarbazine, a 2-methylbenzylhydrazine derivative, by rat liver microsomes.

The oxidative metabolism of procarbazine, its azo, hydrazone, and two azoxy derivatives, and methylhydrazine by hepatic microsomes from phenobarbital-pretreated rats was investigated to elucidate the pathway of metabolism that resulted in methane formation from procarbazine. When incubated with microsomal reaction mixtures fortified with NADPH, all of the compounds, except the azoxy isomers, were metabolized to yield methane. A lag phase in methane formation was noted for procarbazine, but not for the other compounds. Kinetic and inhibition studies utilizing methimazole and ethylhydrazine precluded methylhydrazine as an intermediate in methane formation from procarbazine. When the azo derivative was oxidatively metabolized in the presence of liver microsomes, no hydrazone tautomer was detected. Upon monitoring the production of the azo and hydrazone metabolites formed during microsomal metabolism of procarbazine, the azo derivative was formed in sufficient quantities to account for the majority of the methane produced. In addition, small amounts of hydrazone were also detected. It was concluded that both the azo and hydrazone metabolites of procarbazine contribute to methane formation from the terminal methyl group of the hydrazine with the azo derivative being the predominant source and the hydrazone derivative being a minor source of methane. Consideration of the chemical and enzymatic pathways of procarbazine oxidation and the implication of a methyl radical intermediate in methane formation are discussed.

Animals↗
PubMed1997

Sociosexual behaviour and paternity in procarbazine-exposed rats with or without regional testicular circulatory isolation.

Male Sprague-Dawley rats were used in two experiments in which a procarbazine bolus (400 mg kg-1 body mass) was administered with or without testicular circulatory isolation in the form of brief clamping of the spermatic cord and gubernaculum during drug administration. Separate tests of aggressiveness, sexual motivation, copulatory performance and paternity over the subsequent 6 weeks were used to assess functional changes resulting from testicular circulatory isolation. Experiment 1 compared intermale aggression and sexual motivation of animals in groups receiving procarbazine plus testicular circulatory isolation lasting 0, 15 or 45 min with that of animals in control groups with no clamp and no drug. Experiment 2 used a 2 x 2 factorial design to evaluate sexual performance and resulting paternity in animals 2 months after testicular circulatory isolation and drug exposure compared with that in control animals. Procarbazine treatment induced minimal disruption of normal interest in a receptive female, copulatory measures (intromissions or ejaculations) and structural integrity of seminal vesicles, bulbospongiosus muscles and ventral prostate glands. Animals exposed to the drug without testicular circulatory isolation were significantly less aggressive than animals in other groups. The most profound influence of procarbazine was on paternity. Males exposed to procarbazine with or without testicular circulatory isolation impregnated notably fewer females than did control males that were not exposed to the drug. There was no evidence of recovery of normal fertility up to 10 weeks after exposure to the drug. In conclusion, the deleterious influence of procarbazine on androgen-sensitive processes appears to be specific to intermale aggression and to fertility. The testicular circulatory isolation technique, for 45 min in particular, softened the impact of the drug on social behaviour, although procarbazine suppressed fecundity even with testicular circulatory isolation.

Animals↗
PubMed1990

Accumulation of O6-methylguanine in human blood leukocyte DNA during exposure to procarbazine and its relationships with dose and repair.

O6-Methylguanine was measured by a competitive repair assay in blood leukocyte DNA of seven patients with Hodgkin's or non-Hodgkin's lymphoma during therapeutic exposure to procarbazine involving three daily p.o. doses (50 mg each) for 10 days (corresponding to 2.1 mg/kg/day for a 70-kg human). Adduct accumulation was observed in all seven cases, reaching levels up to 0.28 fmol/microgram of DNA (0.45 mumol/mol of guanine). In one individual, maximal levels of adduct were reached after 7 days of exposure, followed by a steady decline, whereas in all other individuals continuous accumulation was observed throughout the exposure period. In four individuals for which data were available for Day 11 (12 to 16 h after the final intake of procarbazine), decreased amounts of O6-methylguanine were observed relative to the last previous measurements. The accumulation of O6-methylguanine was linearly correlated (P less than 0.01) with the cumulative dose of procarbazine, with a slope of 0.011 fmol of O6-methylguanine/microgram of DNA per mg/kg of body weight or 2.68 x 10(-4) fmol of O6 methylguanine DNA per mg/m2. (Two h after the administration of single p.o. doses of 1 to 10 mg/kg of procarbazine to rats, O6-methylguanine formation in leukocyte DNA was just under half that in liver DNA and showed a linear relationship with dose with a slope of 0.017 fmol/microgram of DNA per mg/kg of body weight or 5.67 x 10(-4) fmol of O6-methylguanine/microgram of DNA per mg/m2. A negative correlation (P less than 0.05) between the rate of accumulation of O6-methylguanine in different individuals and lymphocyte O6-alkylguanine-DNA alkyltransferase (AGT) was observed, demonstrating a probable protective effect of AGT against the accumulation of O6-methylguanine during exposure to methylating agents. This observation supports the suggestion of a possible role of procarbazine-induced O6-methylguanine in the pathogenesis of acute nonlymphocytic leukemia appearing after treatment with chemotherapeutic protocols which include procarbazine, based on the finding of low lymphocyte AGT levels in patients with such therapy-related neoplastic disease (Sagher et al., Cancer Res., 48: 3084-3089, 1988). Lymphocyte AGT levels were mainly in the range of 5 to 10 fmol/micrograms of DNA and showed no consistent variation during procarbazine exposure.

Adult↗