ABVD and BEACOPP regimens' effects on fertility in young males with Hodgkin lymphoma.

PURPOSE: Considering the increased cancer patient survivorship, the focus is now on addressing the impacts of treatment on quality of life. In young people, altered reproductive function is a major issue and its effects in young males are largely neglected by novel research. To improve clinician awareness, we systematically reviewed side effects of chemotherapy for Hodgkin lymphoma (HL) in young males. METHODS: The review was prospectively registered (PROSPERO N. CRD42019122868). Three databases (Medline via PUBMED, SCOPUS, and Cochrane Library) were searched for studies featuring males aged 13-51-years who underwent chemotherapy for HL using ABVD (Adriamycin® (doxorubicin), bleomycin, vinblastine, and dacarbazine) or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone) regimens. These chemotherapy regimens were compared against each other using sperm characteristics, FSH, and inhibin B levels to measure fertility levels. RESULTS: Data were extracted from five studies featuring 1344 patients. 6 months post-ABVD saw marked deterioration in sperm count, further reduced by more cycles (P = 0.05). Patients treated with BEACOPP rather than ABVD were more prone to oligospermia. Receiving fewer cycles of both regimens increased the likelihood of sperm production recovering. Patients treated with 6-8 cycles of BEACOPP did not recover spermiogenesis. CONCLUSIONS: ABVD and BEACOPP regimens significantly reduce fertility function to varying effects depending on treatment duration. ABVD temporarily causes significant reductions in male fertility, whereas BEACOPP's effects are more permanent. Therefore, clinicians should discuss fertility preservation with male patients receiving infertility-inducing gonadotoxic therapy. Further high-quality studies are required to more adequality describe the risk to fertility by chemotherapy.

Increased Brain Serotonin Rather Than Increased Blood Acetaldehyde as a Common Denominator Behind Alleged Disulfiram-Like Reactions.

Several pharmaceutical agents are known to produce ethanol intolerance, which is often depicted as disulfiram-like reaction. As in the case with disulfiram, the underlying mechanism is believed to be the accumulation of acetaldehyde in the blood, due to inhibition of the hepatic aldehyde dehydrogenases, albeit this has not been confirmed in all cases by blood acetaldehyde measurements. Herein, cefamandole, cotrimoxazole, griseofulvin, procarbazine, and propranolol, which are reported to produce a disulfiram-like reaction, as well as disulfiram, were administered to Wistar rats and the hepatic activities of ethanol metabolizing enzymes along with the levels of brain monoamines were determined. Blood acetaldehyde was also evaluated after ethanol administration in rats pretreated with the abovementioned pharmaceutical products. Disulfiram, cefamandole, and procarbazine significantly increased blood acetaldehyde levels after ethanol administration, while on the contrary, cotrimoxazole, griseofulvin, and propranolol had no effect on blood acetaldehyde. Interestingly, all substances used, except disulfiram, increased the levels of brain serotonin. According to our findings, cotrimoxazole, griseofulvin, and propranolol do not produce a typical disulfiram-like reaction, because they do not increase blood acetaldehyde when given together with ethanol. On the other hand, all tested agents share the common property to enhance brain serotonin, whereas a respective effect of ethanol is well established. Hence, the ethanol intolerance produced by these agents, whether blood acetaldehyde concentration is elevated or not, could be the result of a "toxic serotonin syndrome," as in the case of the concomitant use of serotonin-active medications that provoke clinical manifestations similar to those of a disulfiram reaction.

Introduction of Z-GP scaffold into procarbazine reduces spermatoxicity and myelosuppression.

Incorporation of carbobenzoxy-glycylprolyl (Z-GP) to either α or ß position of the hydrazine moiety in procarbazine (Pcb) has been carried on in 5-steps process. The overall yield was 32.7%. The new entity Z-GP-Pcb was confirmed targeting to fibroblast activation protein-α (FAPα). Z-GP-Pcb may be hydrolyzed by either isolated rhFAPα or tumor homogenate. It was shown far less cytotoxicity against NCI-H460 cell line than Pcb. Z-GP-Pcb was displayed the potency to reduce spermatoxcity in H22-bearing mice. The mechanism may be ascribed to the blockade of dehydrogenation by α-glycerolphosphate dehydrogenase. This candidate was further proved equal antitumor activity to Pcb. However, the introduction of Z-GP scaffold decreased myelosuppression. All the evidences support that Z-GP-Pcb is a better antitumor agent than Pcb.

Risk of subsequent gastrointestinal cancer among childhood cancer survivors: A systematic review.

BACKGROUND: Childhood cancer survivors (CCS) are at increased risk of developing subsequent malignant neoplasms, including gastrointestinal (GI) cancer. We performed a systematic review to summarize all available literature on the risk of, risk factors for, and outcome after subsequent GI cancer among CCS. METHODS: A systematic search of the literature databases Medline/PubMed (1945-2014) and Embase (1947-2014) was performed to identify studies that consisted of ⩾1000 CCS and assessed incidence of or mortality from subsequent GI cancer as an outcome. RESULTS: A total of 45 studies were included. Studies that reported risk measures for subsequent GI cancer compared to the general population showed a 3.2 to 9.7-fold elevated risk in cohort studies including all childhood cancer types. Abdominal radiotherapy was associated with an increased risk of subsequent GI cancer in all four studies that assessed this risk. Survivors who had received procarbazine and platinum agents were also suggested to be at increased risk. CONCLUSION: Abdominal radiotherapy is a risk factor for developing a subsequent GI cancer. Few studies examined detailed treatment-related risk factors and most studies had small number of GI cancer cases. Therefore, no conclusions could be drawn on the effect of time since childhood cancer on GI cancer risk and on outcome after a subsequent GI cancer. Additional research is necessary to further explore risk factors for and outcome after a subsequent GI cancer, and to systematically evaluate the harms and benefits of GI screening among high-risk survivors in order to give sound screening recommendations.

Prolonged survival associated with the use of intraoperative carmustine (Gliadel) in a paediatric patient with recurrent grade III astrocytoma.

A 15-year-old female presented with a middle cranial fossa anaplastic astrocytoma that was completely excised. She received local radiotherapy (54 Gy) and oral temozolomide. Five months after therapy, MRI showed local relapse. She underwent resection of the tumour with implantation of seven carmustine-impregnated wafers (Gliadel). She then received six cycles of procarbazine and lomustine therapy. Three years later, she is well and disease free. This case supports the further investigation of Gliadel in children and young people with relapsed high-grade glioma, particularly in the setting of a second complete resection.

Chemotherapy in low-grade gliomas.

PURPOSE OF REVIEW: This review summarizes the recent studies in adults' diffuse low-grade gliomas (LGGs) chemotherapy, including response assessment and potential predictive biomarkers of chemosensitivity. RECENT FINDINGS: Recent studies have confirmed that chemotherapy is an interesting treatment option in LGGs. About 25-50% of LGGs achieve radiological responses with temozolomide or a procarbazine-CCNU-vincristine (PCV) regimen. Clinical and quality-of-life improvements are commonly observed with more than half of the patients with epilepsy, demonstrating a significant reduction of seizure frequency. Dynamic volumetric studies have provided a better description of LGGs evolution after chemotherapy. They have shown that an ongoing volume decrease can be observed many months after chemotherapy discontinuation, particularly after PCV, raising the question of how and for how long should LGGs be treated. New response criteria have been defined by the Response Assessment in Neuro-Oncology group. In addition to 1p/19q codeletion and MGMT promoter methylation, IDH1 mutation might also be a potential predictive biomarker of chemosensitivity. SUMMARY: It has now been widely accepted that chemotherapy is an interesting treatment option in LGGs. However, several questions remain unanswered regarding its optimal use. Ongoing phase III studies will allow a better delineation of the role of chemotherapy in LGGs and will also help to better determine the potential predictive value of a 1p/19q codeletion, a MGMT promoter methylation and an IDH1 mutation.

Bone mineral density, growth, and thyroid function in long-term survivors of pediatric Hodgkin's lymphoma treated with chemotherapy only.

BACKGROUND: The aim of this study was to investigate the long-term side effects of treatment for childhood Hodgkin's lymphoma with chemotherapy only on growth, bone mineral density (BMD), body composition, and thyroid function. PROCEDURE: A total of 88 patients (56 male, 32 female; 17.6-42.6 yr), treated for childhood Hodgkin's lymphoma from 1974-1998 with combination chemotherapy adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine or epirubicin, bleomycin, vinblastine, dacarbazine with or without mechlorethamine, oncovin (vincristine), procarbazine, and prednisone (MOPP) with the intention to avoid radiotherapy, participated in this study. Median follow-up was 15.5 yr (range 5.6-30.2). BMD of lumbar spine and total body (BMD-TB), and body composition were measured using dual-energy x-ray absorptiometry. Bone mineral apparent density of the lumbar spine was calculated to correct for bone size. Free T4 and TSH were measured. RESULTS: Men treated with MOPP had a significantly reduced height with normal body proportions. Women treated with MOPP had decreased BMD-TB and bone mineral apparent density of the lumbar spine as compared with healthy controls. Percent body fat was significantly increased in female patients treated without MOPP. Body mass index was significantly increased in male patients treated without MOPP, whereas lean body mass was normal in all patients. All patients, except one, treated with chemotherapy only had normal thyroid function. However, five patients who received additional radiation to the thyroid either had abnormal levels of TSH or free T4, or used thyroid hormones. CONCLUSIONS: Lean body mass was normal in all patients; thyroid function was normal in all but one patient. The use of MOPP leads to decreased height and increased body mass index in men and decreased BMD-TB in women.

Single-molecule PCR analysis of germ line mutation induction by anticancer drugs in mice.

Understanding and estimating the genetic hazards of exposure to chemical mutagens and anticancer drugs in humans requires the development of efficient systems for monitoring germ line mutation. The suitability of a single-molecule PCR-based approach for monitoring mutation induction at the mouse expanded simple tandem repeat (ESTR) locus Ms6-hm by chemical mutagens and anticancer drugs has been validated. The frequency of ESTR mutation was evaluated in the germ line of male mice exposed to the well-characterized alkylating agent and mutagen, ethylnitrosourea, and four widely used anticancer drugs, bleomycin, cyclophosphamide, mitomycin C, and procarbazine. The dose-response of ethylnitrosourea-induced mutation was found to be very close to that previously established using a pedigree-based approach for ESTR mutation detection. Paternal exposure to the clinically relevant doses of bleomycin (15-30 mg/kg), cyclophosphamide (40-80 mg/kg), and mitomycin C (2.5-5 mg/kg) led to statistically significant, dose-dependent increases in ESTR mutation frequencies in the germ line of treated male mice. Exposure to procarbazine led to a maximal increase in mutation frequency at 50 mg/kg, with a plateau at the higher concentrations. The results of this study show that the single-molecule PCR technique provides a new and efficient experimental system for monitoring the genetic effects of anticancer drugs, capable of detecting increases in mutation rates at clinically relevant doses of exposure. In addition, this approach dramatically reduces the number of mice needed for the measurement of germ line mutation induction.

Determination of terephthalic acid isopropylamide in urine with a liquid chromatography/mass spectrometry (LC/MS) method.

A sensitive and simple liquid chromatography/mass spectrometry (LC/MS) method was developed for the determination of terephthalic acid isopropylamide, the final metabolite of procarbazine in human urine. A solid-phase extraction with C(18) cartridges was used followed by LC/MS with a single mass spectrometer (SSQ 7000 from Finnigan). Terephthalic acid isobutylamide was the internal standard. The quantification limit was 30 ng/mL in urine (6 x noise). This assay was applied for drug monitoring of terephthalic acid isopropylamide in urine after oral administration of procarbazine in children and adolescents with Hodgkin lymphomas.

Procarbacine radiolysis and experiments in vitro.

Steady-state radiolysis of aqueous procarbazine (PC) was studied in air-free, aerated and solutions saturated with N2O. The corresponding Gi(-PC)-values obtained at pH=7.4 were: 2.85, 5.60 and 3.45, respectively. The investigations in vitro, using E. coli (AB 1157) as a model for living systems, demonstrated that PC acts as a cytostatic in air-free as well as in aerated media. However, it shows radiation protecting ability in the presence of N2O, where OH-radicals are the predominant reactants. Similar results were observed at pH=6.2. The experimental data contribute to a better understanding of the many-sided and frequently contradictory behavior of PC.

Heme oxygenase-1 prevents superoxide anion-associated endothelial cell sloughing in diabetic rats.

Heme oxygenase-1 (HO-1) represents a key defense mechanism against oxidative injury. Hyperglycemia has been linked to increased oxidative stress, leading to endothelial dysfunction, delayed cell replication, and enhanced apoptosis. The effect of streptozotocin (STZ)-induced diabetes on HO activity, HO-1 promoter activity, superoxide anion (O*-2, and the number of circulating endothelial cells was measured. The expression of HO-1/HO-2 protein was unchanged, but HO activity was decreased in aortas of diabetic rats compared with control (p < 0.05). High glucose decreased HO-1 promoter activity (p < 0.05). Hyperglycemia increased O*-2 and this increase was augmented with HO-1 inhibition and diminished with HO-1 upregulation (p < 0.05). Circulating endothelial cells were significantly higher in diabetic rats and were decreased or increased with administration of the HO-1 inducer (CoPP) or inhibitor (SnMP), respectively (p<0.05). In conclusion, HO-1 upregulation in diabetic rats brings about an increase in serum bilirubin, a reduction in O*-2 production, and a decrease in endothelial cell sloughing.

Effects of prenatal procarbazine administration on intrauterine development in rats.

The effects of prenatal procarbazine (PCZ) administration on the intrauterine development of rat fetuses were investigated. Gravid rats were treated on day 14 of gestation (GD14) with 25 mg or 50 mg/kg body weight PCZ via stomach tube. Controls received normal saline in the same dosis and manner. On GD20, all fetuses were collected by caesarian section. Live and dead fetuses as well as resorptions were counted. In the live fetuses, the following investigations were conducted: measurement of body weight, occipito-coccygeal-lenght (OCL), tail length (TL), placental weight and diameter, external macroscopic and binocular microscopic examination, and sectional analysis of the animals using the razorblade sectioning technique. Both PCZ doses caused a significant reduction in the number of live fetuses and a significant increase in resorptions. Mean body weight in PCZ groups was antidromic affected. OCL and TL were significantly depressed. Placental weight and diameter as well as number of dead fetuses were comparable to those of controls. External and sectional investigations revealed no PCZ-related deviations. In the light of our findings we conclude that PCZ in the doses used in this experimental study significantly affects the intrauterine development in rats in terms of fetal toxicity but displays no teratological properties.

Identification of novel enzyme-prodrug combinations for use in cytochrome P450-based gene therapy for cancer.

Gene-directed enzyme prodrug therapy can be used to increase the therapeutic activity of anti-cancer prodrugs that undergo liver cytochrome P450 (CYP)-catalyzed prodrug to active drug conversion. The present report describes a cell-culture-based assay to identify CYP gene-CYP prodrug combinations that generate bystander cytotoxic metabolites and that may potentially be useful for CYP-based gene therapy for cancer. A panel of rat liver microsomes, comprising distinct subsets of drug-inducible hepatic CYPs, was evaluated for prodrug activation in a four-day 9L gliosarcoma cell growth inhibition assay. A strong NADPH- and liver microsome-dependent increase in 9L cytotoxicity was observed for the CYP prodrugs cyclophosphamide, ifosfamide, and methoxymorpholinyl doxorubicin (MMDX) but not with three other CYP prodrugs, procarbazine, dacarbazine, and tamoxifen. MMDX activation was potentiated approximately 250-fold by liver microsomes from dexamethasone-induced rats (IC(50) (MMDX) approximately 0.1nM), suggesting that dexamethasone-inducible CYP3A enzymes contribute to activation of this novel anthracycline anti-tumor agent. This CYP3A dependence was verified in studies using liver microsomes from uninduced male and female rats and by using the CYP3A-selective inhibitors troleandomycin and ketoconazole. These findings highlight the advantages of using cell culture assays to identify novel CYP prodrug-CYP gene combinations that are characterized by production of cell-permeable, cytotoxic metabolites and that may potentially be incorporated into CYP-based gene therapies for cancer treatment.

Procarbazine effects on spermatogenesis in golden hamster: a flow cytometric evaluation.

The response of hamster testis to the administration of 450mg/kg procarbazine (PCB) over a period of 4 weeks was evaluated. Flow cytometry was used to investigate changes in cell populations in testicular single cell suspensions and to correlate these changes with those observed in histological sections. PCB caused significant decrease in testicular and epididymal weight and a drastic reduction in haploid cells and spermatogenic arrest, demonstrating variation among the test animals. The results obtained confirm previous observations concerning detrimental effects of PCB upon spermatogenesis in species such as the rat and mouse, though its effect on hamster testis is milder and does not include the germinal stem cells. The histological evaluation of the testis showed a good correlation with flow cytometric evaluation, emphasizing the usefulness of this method in providing quantitative and rapid results.

Mechanism of protection of rat spermatogenesis by hormonal pretreatment: stimulation of spermatogonial differentiation after irradiation.

Pretreatment of rats with hormones that suppress testosterone levels and sperm production enhances the recovery of spermatogenesis from stem cells after a cytotoxic insult. It is not known whether the enhanced recovery results from an increase in the numbers of surviving stem cells or whether their ability to differentiate is enhanced. In this study, untreated rats and rats pretreated with testosterone plus estradiol-17beta (T + E) were irradiated with 3.5 or 6 Gy, and the recovery of spermatogenesis from surviving stem cells was assessed at 6, 10, and 20 weeks after irradiation. T + E pretreatment did not significantly affect the numbers of A spermatogonia remaining in the tubules at 6 weeks after irradiation. In rats that were given irradiation alone, spermatogenesis steadily declined after 6 weeks because the stem cells lost their ability to differentiate. However, when rats were treated with T + E before irradiation, this decline was prevented, and in fact, at least at the lower dose of radiation, there was a progressive recovery of spermatogenesis. Given the similar spermatogonial counts at 6 weeks after irradiation in the irradiated-only and T + E-treated, irradiated rats, the hormone treatment appears not to protect stem cells from being killed by the cytotoxic agent. Rather, the later enhancement of spermatogenic recovery results from prevention of an injury-induced change in spermatogonia or in their environment, which would have otherwise resulted in failure of spermatogonial differentiation.

The effects of anticancer drugs in combination with nimodipine and verapamil on cultured cells of glioblastoma multiforme.

The presence of the cellular multidrug resistance (MDR1) gene and its product, P-glycoprotein (Pgp), is thought to be a mechanism for the failure of chemotherapy in cancer patients. Calcium channel blockers have been shown to sensitise cancer cells to anticancer drugs by reversing Pgp expression in cell lines. The interactions between anticancer drugs such as carmustine (BCNU), vincristine (VCR) and procarbazine (PCB) and calcium channel blockers such as nimodipine and verapamil on cultured cells of glioblastoma from eight patients were therefore tested. Pgp expression was examined immunohistochemically using C219 monoclonal antibody in cytospin preparation. The cytotoxicity of the drugs was screened using microculture tetrazolium assay. The cells from five patients showed positive immunoreaction for Pgp. Nimodipine showed growth-inhibitory activity against glioblastoma cells at a rate of 16.55-26.88% (P < 0.05), but a similar effect was not observed with verapamil. While antiproliferative effects of BCNU were around 20.91-45.09% (P < 0.05) on the cells from seven patients, VCR was the most effective agent in inhibition of cell growth at a rate of 26.43-48.47% (P < 0.05). The response of the cells from five patients to PCB was from 11.98 to 16.32% (P < 0.05). When used together, nimodipine further enriched cytotoxicity of the anticancer drugs up to 11.14-40.85% (P < 0.05) without relation to Pgp expression. In conclusion, the enhancement of cytotoxicity of anticancer drugs by nimodipine suggests that there might be a synergy between anticancer drugs and nimodipine in the inhibition of glioma cell growth.

The effects of etoposide on testicular function in boys treated for Hodgkin's disease.

BACKGROUND: Testicular dysfunction with elevated follicle-stimulating hormone (FSH) levels (indicating oligospermia and/or azoospermia) is a major late sequelae after treatment for Hodgkin's disease (HD) with high cumulative doses of procarbazine, cyclophosphamide, or chlorambucil. Etoposide is a newer antineoplastic agent that is effective in the treatment of HD. However, little is known regarding its testicular toxicity, especially in the pediatric age group. METHODS: The authors evaluated testicular function in 46 young adults in first continuous complete remission after stage-dependent treatment for HD with the vincristine, etoposide, prednisone, and doxorubicin (OEPA) or OEPA/cyclophosphamide, vincristine, procarbazine, and prednisone [COPP] chemotherapy regimens and involved field irradiation, excluding patients with ilioinguinal radiotherapy. Pubertal development was documented and a standardized intravenous gonadotropin-releasing hormone test was performed measuring testosterone and basal and stimulated levels of FSH and luteinizing hormone (LH). RESULTS: Testicular volumes, Tanner stages of pubic hair, and genital development were found to be appropriate or slightly delayed for the patients' chronologic age. All 27 patients had normal basal levels of FSH and LH after treatment of Ann Arbor Stage I-IIA HD with 2 courses of OEPA. Stimulated FSH and LH levels were found to be elevated only in rare patients, thus indicating normal endocrine function and spermatogenesis. However, basal and stimulated FSH levels were outside the +2 standard deviation range in 37.5% and 83.3% of patients receiving 2 cycles of OEPA and 2 cycles of COPP chemotherapy, and in 36.4% and 66.7% of patients receiving 2 cycles of OEPA and 4 cycles of COPP chemotherapy, demonstrating a high risk of oligospermia or azoospermia with these regimens. Basal LH levels essentially were normal, whereas stimulated LH levels frequently were elevated. CONCLUSIONS: Testicular function was found to be normal in patients with Stage I-IIA HD when etoposide was used in combination with vincristine, prednisone, and doxorubicin (2 cycles of OEPA). Additional chemotherapy with cyclophosphamide and procarbazine (2 cycles of OEPA and 2 or 4 cycles of COPP) negatively affected spermatogenesis and possibly Leydig cell function in a considerable number of patients. This major gonadotoxic effect most likely is due to procarbazine, although an additional effect of etoposide and cyclophosphamide cannot be excluded.

Testing the gonadal regression-cytoprotection hypothesis.

Germinal damage is an almost universal accompaniment of cancer treatment as the result of bystander damage to the testis from cytotoxic drugs and/or irradiation. Cancer treatment for the most common cancers of the reproductive age group in men has improved such that most are now treated with curative intent, and many others are treated with likelihood of prolonged survival, so that the preservation of fertility is an important component of posttreatment quality of life. This has led to the consideration of developing adjuvant treatments that may reduce the gonadal toxicity of cancer therapy. One dominant hypothesis has been based on the supposition that the immature testis was resistant to cytotoxin damage. Hence, if hormonal treatment were able to cause spermatogenic regression to an immature state via an effective withdrawal of gonadotrophin secretion, the testis might be maintained temporarily in a protected state during cytotoxin exposure. However, clinical studies have been disappointing but have also been unable to test the hypothesis definitively thus far, due to the inability to completely suppress gonadotrophin secretion. Similarly, experimental models have also given conflicting results and, at best, a modest cytoprotection. To definitively test this hypothesis experimentally, we used the fact that the functionally hpg mouse has complete gonadotrophin deficiency but can undergo the induction of full spermatogenesis by testosterone. Thus, if complete gonadotrophin deficiency were an advantage during cytotoxin exposure, then the hpg mouse should exhibit some degree of germinal protection against cytotoxin-induced damage. We therefore administered three different cytotoxins (200 mg/kg procarbazine, 9 mg/kg doxorubicin, 8 Gy of X irradiation) to produce a range of severity in testicular damage and mechanism of action to either phenotypically normal or hpg mice. Testis weight and homogenization-resistant spermatid numbers were measured to evaluate the potential protective effects on spermatogenesis. Although the three cytotoxins produced a range of severity of spermatogenic damage, there was no evidence of cytoprotection in the hpg mice that were completely gonadotrophin deficient at the time of treatment. These findings cast doubt on the validity of the hypothesis that spermatogenic regression via gonadotrophin withdrawal can protect the mouse testis against cytotoxin-mediated spermatogenic damage.