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PubMed1975

Plaque development by vaccinia-viruses on the chicken chorio-allantois under the influence of cyclophosphamide.

The development of Vaccinia-virus plaques on the chorioallantois of embryonated eggs was studied under the influence of active cyclophosphamide metabolites. The viruses were inoculated on the 9th or the 13th incubation day. Cyclophosphamide was injected in doses of 62.5--500 mug in 0.2 ml NaCl into the yolk sac either 7 hrs after the virus inoculation or 3, 6, or 9 hrs in advance. The plaque development was not influenced when cyclophosphamide was given after the virus inoculation. But in treating the embryos before the infection a decrease dependent on the dose in the number of embryos with recognizable plaques occurred. This decrease was more marked with cyclophosphamide treatment 6 or 9 hrs, than with cyclophosphamide treatment 3 hrs before the virus inoculation. When the embryos were inoculated on the 13th day and treated with cyclophosphamide 9 hrs in advance, the mean effective dose was 316 mug/egg. The range of effective doses corresponds with that of the inhibitory effective doses of cyclophosphamide on transplantation tumors grown on the chorio-allantois of embryonated eggs.

Allantois↗

PubMed1977

Detection of induced tumour-resistance to cyclophosphamide by the in vitro short term test.

Treatment of the solid Walker carcinosarcoma of the rat for a period of one year with cyclophosphamide (40 mg/kg at each passage; tumours were transplanted weekly) resulted in the formation of a cyclophosphamide-resistant tumour cell line. Without further treatment, animals injected with non-treated or cyclophosphamide pre-treated cells survived for 10 days on an average. After therapy with cyclophosphamide (2 x 38 mg/kg), rats with non-treated tumour cells survived 22 days whereas those with pre-treated tumours survived only for 17 days. Tumour cells which were shown to be sensitive in vivo also exhibited a larger reduction in 3H-thymidine and 3H-uridine incorporation in the in vitro short term test after incubation with urine from cyclophosphamide-treated rats or with 4-hydroperoxy-cyclophosphamide. The resistance to cyclophosphamide which was detected in animal experiments with Walker carcinosarcoma can therefore also be observed using the in vitro short term test.

Animals↗

PubMed1990

The effect of cimetidine on cyclophosphamide metabolism in rabbits.

Six female rabbits were given 20 mg/kg cyclophosphamide (containing 100 microCi [3H-chloroethyl]-cyclophosphamide) alone or 1 h following 100 mg/kg cimetidine. Serial plasma and urine specimens were collected and levels of cyclophosphamide and its metabolites (4-hydroxycyclophosphamide, 4-ketocyclophosphamide, phosphoramide mustard, and carboxyphosphamide) were measured. 4-Ketocyclophosphamide was the major metabolite present in rabbit plasma and urine, with lesser amounts of 4-hydroxycyclophosphamide, carboxyphosphamide, and phosphoramide mustard also being identified. Cimetidine pretreatment resulted in prolongation of cyclophosphamide's half-life from 24.3 +/- 7.3 to 33.5 +/- 9.5 min (mean +/- SD; P = 0.036) but did not significantly alter the AUC0-8 h for the latter drug. Cimetidine pretreatment resulted in a significantly greater AUC0-8 h for 4-hydroxycyclophosphamide (189.4 +/- 77 vs 364.6 +/- 126.7 mumol min/l-1; P = 0.016) as compared with control values. A higher AUC0-8 h value for phosphoramide mustard (53.7 +/- 69.2 vs 95.7 +/- 34.7 mumol min/l-1) was also observed after cimetidine dosing but the difference was not significant (P = 0.21). Kinetics of 4-ketocyclophosphamide and carboxyphosphamide were not significantly affected by cimetidine treatment. Cimetidine was added to hepatic microsomes isolated from phenobarbital-treated rabbits; it did not inhibit cyclophosphamide's metabolism in vitro, suggesting that its in vivo effect may be mediated through mechanisms other than cytochrome P-450 inhibition. Cimetidine pretreatment increases exposure to cyclophosphamide and its major activated metabolite, 4-hydroxycyclophosphamide. Potentiation rather than inhibition of cyclophosphamide's pharmacodynamic effect is to be predicted when cimetidine is given concomitantly with the former. Alterations in hepatic blood flow or mechanisms other than microsomal inhibition by cimetidine may explain this potentiation.

Animals↗

PubMed1995

Modulation of cyclophosphamide-induced early lung injury by curcumin, an anti-inflammatory antioxidant.

Cyclophosphamide causes lung injury in rats through its ability to generate free radicals with subsequent endothelial and epithelial cell damage. In order to observe the protective effects of a potent anti-inflammatory antioxidant, curcumin (diferuloyl methane) on cyclophosphamide-induced early lung injury, healthy, pathogen free male Wistar rats were exposed to 20 mg/100 g body weight of cyclophosphamide, intraperitoneally as a single injection. Prior to cyclophosphamide intoxication oral administration of curcumin was performed daily for 7 days. At various time intervals (2, 3, 5 and 7 days post insult) serum and lung samples were analyzed for angiotensin converting enzyme, lipid peroxidation, reduced glutathione and ascorbic acid. Bronchoalveolar lavage fluid was analyzed for biochemical constituents. The lavage cells were examined for lipid peroxidation and glutathione content. Excised lungs were analyzed for antioxidant enzyme levels. Biochemical analyses revealed time course increases in lavage fluid total protein, albumin, angiotensin converting enzyme (ACE), lactate dehydrogenase, N-acetyl-beta-D-glucosaminidase, alkaline phosphatase, acid phosphatase, lipid peroxide levels and decreased levels of glutathione (GSH) and ascorbic acid 2, 3, 5 and 7 days after cyclophosphamide intoxication. Increased levels of lipid peroxidation and decreased levels of glutathione and ascorbic acid were seen in serum, lung tissue and lavage cells of cyclophosphamide groups. Serum angiotensin converting enzyme activity increased which coincided with the decrease in lung tissue levels. Activities of antioxidant enzymes were reduced with time in the lungs of cyclophosphamide groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Pharmacology, relative bioavailability, and toxicity of three different oral cyclophosphamide preparations in a randomized, cross-over study.

Thirty-six patients were entered on this study to determine the pharmacology, bioavailability, and toxicity of three different oral formulations of cyclophosphamide (Cytoxan, Endoxan, and an investigational direct compression tablet). Patients were randomized with respect to the order in which they received the different oral cyclophosphamide preparations, and received each one for two weeks followed by a two week washout period. Concurrent chemotherapy was allowed provided it remained constant across all 3 courses of cyclophosphamide. Plasma concentrations of cyclophosphamide and phosphoramide mustard were measured by gas chromatography with electron capture detection. Peak plasma cyclophosphamide concentrations and times to peak plasma cyclophosphamide and phosphoramide mustard preparations were significantly greater for Endoxan than for Cytoxan and the investigational direct compression tablet. Drug area under the concentration-time curve (AUC), bioavailability, and plasma elimination half-life could not be reliably calculated for Endoxan but were similar for Cytoxan and the investigational formulation. Based on AUC comparisons, bioavailability of parent compound (relative to an oral cyclophosphamide solution) was 85% for Cytoxan and 69% for the investigational formulation. This difference was not significant. There were no significant differences between the 3 formulations with respect to any individual type of toxicity, although the investigational formulation tended to be associated with somewhat less overall toxicity (p = 0.08).

Administration, Oral↗

PubMed1996

Antitumor efficacy and pharmacokinetic analysis of 4-hydroperoxycyclophosphamide in comparison with cyclophosphamide +/- hepatic enzyme effectors.

4-Hydroperoxycyclophosphamide is an oxazaphosphorine which is readily converted without enzymatic involvement to 4-hydroxycyclophosphamide-a key intermediate in the antitumor activity of this class of drugs. The efficacy of 4-hydroperoxycyclophosphamide as a systemically administered antitumor drug was examined in mice bearing EMT-6 mammary carcinoma and in rats bearing 13762 mammary carcinoma in comparison with other oxazaphosphorines. 4-Hydroperoxycyclophosphamide was a more potent tumor cell killing agent than cyclophosphamide or ifosfamide in animals bearing the EMT-6 tumor. There were no significant differences in the toxicity to bone marrow amongst the three oxazaphosphorines. 4-Hydroperoxycyclophosphamide (90 mg/kg) on days 7, 9 and 11 produced 11.5 days of tumor growth delay compared with 10.4 days and 7.1 days for cyclophosphamide (150 mg/kg) and ifosfamide (150 mg/kg) administered on the same schedule, respectively. 4-Hydroperoxycyclophosphamide was tolerated at 90 mg/kg daily for 5 days and at 75 mg/kg twice daily for 4 days producing tumor growth delays of 14.4 days and 16.6 days, respectively. In rats bearing 13762 tumors, 4-hydroperoxycyclophosphamide (90 mg/kg) on days 8, 10 and 12 produced a tumor growth delay of 14.5 days compared with 8.9 days for cyclophosphamide (100 mg/kg) administered on the same schedule. Treatment of 13762 tumor-bearing rats with phenobarbital, pentobarbital or etanidazole increased the tumor growth delay produced by cyclophosphamide while treatment with cimetidine decreased the tumor growth delay produced by cyclophosphamide but not significantly. Administration of 4-hydroperoxycyclophosphamide (90 mg/kg) produced blood concentrations of 4-hydroxycyclophosphamide three-fold higher than those produced by administration of cyclophosphamide (100 mg/kg) at 15 min after drug injection. Treatment with phenobarbital or pentobarbital increased 4-hydroxycyclophosphamide blood concentration while pretreatment with cimetidine decreased 4-hydroxycyclophosphamide blood concentration from cyclophosphamide. 4-Hydroperoxycyclophosphamide is an effective antitumor agent worthy of further investigation.

Adenocarcinoma↗

PubMedDate not supplied

[Cyclophosphamide therapy in systemic lupus erythematosus].

Cyclophosphamide is a potent immunosuppressive drug which is widely used to treat renal and central nervous system manifestation of Systemic Lupus Erythematosus (SLE). It is employed especially to prevent renal failure in lupus nephritis. Within the last decade intravenous cyclophosphamide bolus therapy has become the standard therapy in severe SLE due to its tendency towards a higher efficacy and fewer side effects as compared to oral application. Studies on the slightly more cost-effective oral cyclophosphamide bolus therapy have recently been published, however, there are no data on long-term results yet. Here, we review the effects and side effects of cyclophosphamide as well as recent clinical studies on cyclophosphamide bolus therapy in SLE. Because of the possible side effects, especially the high risk of malignancies, which sharply increases at a cumulative dose of approximately 60 g, cyclophosphamide should be used cautiously. Cyclophosphamide bolus therapy should only be performed in hospitals with special experience.

Cyclophosphamide↗

PubMed1990

The effect of cyclophosphamide on the eruption of impeded and resected incisors in rats.

It is known that a single dose of cyclophosphamide (40 mg.kg-1 intraperitoneal) slows the eruption of unimpeded incisors but has no effect on impeded incisors. In this study incisors that were impeded when cyclophosphamide was given were subsequently made unimpeded. When they were unimpeded they erupted more slowly than the controls. Therefore the changes cyclophosphamide produces which slow eruption are formed in impeded incisors but have an effect only in unimpeded incisors. It has been reported that cyclophosphamide slows the eruption of resected incisors when it is given before the resection. In a second experiment cyclophosphamide was given after the resection and had no effect on eruption rates. It is suggested from these and earlier findings that cyclophosphamide slows eruption by imposing a maximum on the rate at which it can occur and that it does so through the changes it produces in the periodontal ligament. The periodontal changes make it harder for the tooth to move rather than altering the forces moving the tooth. This explanation of how cyclophosphamide slow eruption produces an alternative interpretation of some, but not all, of the findings that have been cited as evidence that there are two mechanisms of tooth eruption.

Animals↗

PubMed1983

Relative mutagenicity and teratogenicity of cyclophosphamide and two of its structural analogs.

In this report, cyclophosphamide was compared to two of its structural analogs, 5,5-dimethylcyclophosphamide and diethylcyclophosphamide, with respect to mutagenic and teratogenic activities. Mutagenicity was assessed using Salmonella typhimurium TA 1535; teratogenicity was assessed in Sprague-Dawley rats on day 20 of gestation after intra-amniotic drug administration on day 13. After metabolic activation, cyclophosphamide caused base substitution mutations in S. typhimurium TA 1535 and major structural defects in both intra-amniotically injected and contralateral uninjected fetuses. 5,5-Dimethylcyclophosphamide was neither mutagenic nor teratogenic. Diethylcyclophosphamide was not mutagenic but was teratogenic. However, diethylcyclophosphamide was less potent as a teratogen than cyclophosphamide and, unlike cyclophosphamide, caused malformations only in the intra-amniotically injected fetuses. Diethylcyclophosphamide does liberate acrolein after metabolic activation. If acrolein is responsible for the teratogenic effects of diethylcyclophosphamide, the other major cytotoxic metabolite of cyclophosphamide, phosphoramide mustard, may account for the difference in teratogenic potency between cyclophosphamide and diethylcyclophosphamide. These results would suggest that acrolein, although apparently not mutagenic, mediates the teratogenicity of diethylcyclophosphamide and a significant proportion of the teratogenicity of cyclophosphamide.

Abnormalities, Drug-Induced↗

PubMed1990

Reversibility of the effects of chronic paternal exposure to cyclophosphamide on pregnancy outcome in rats.

Low-dose chronic treatment of the male rat with the antitumor drug cyclophosphamide causes a time- and dose-dependent increase in pre- and post-implantation loss in the untreated females to which he is mated. The objective of the present study was to determine whether such effects are reversed, and if so at what time after cessation of drug treatment. Adult male Sprague-Dawley rats were gavage fed daily, 6 times per week for 9 weeks, with saline (control) or with 1 of 3 doses of cyclophosphamide, 1.4, 3.4 or 5.1 mg/kg/day. After the 9 weeks of treatment and at 2-week intervals thereafter, each male was mated with 2 females in proestrus. The females were caesarian sectioned 20 days later and pregnancy outcome assessed. After 9 weeks of drug treatment, pre-implantation loss increased more than 3-fold from 6% in the control group to 21% in the 5.1 mg/kg/day cyclophosphamide treatment group. Post-implantation loss increased in a dose dependent fashion from 5% in the control group to 74% in the 5.1 mg/kg/day cyclosphosphamide treatment group. Pre-implantation loss rapidly decreased upon cessation of treatment with cyclophosphamide: within 2 weeks it had returned to within the control range. Within just 2 weeks after termination of drug treatment in the 5.1 mg/kg/day cyclophosphamide treatment group, post-implantation loss decreased by half to 44%; it had decreased to 11% by 4 weeks and then was maintained at 4-6% thereafter. In the 3.4 mg/kg/day cyclophosphamide treatment group, post-implantation loss returned to the control range by 4 weeks. Thus, the effects of paternally administered cyclophosphamide on progeny outcome are reversible. The timing of reversal suggests that the effects on pre-implantation loss are due to a drug effect on spermatozoa either in the epididymis or near the time of spermiation while those on post-implantation loss are due to an additional effect on spermatids in the seminiferous tubules.

Abnormalities, Drug-Induced↗

PubMed1978

Does cyclophosphamide induce bladder cancer?

An increasing incidence of bladder neoplasms temporally associated with chemotherapy, usually cyclophosphamide, is being reported. These secondary primary bladder malignancies are characteristically found in two groups of patients: those with lymphoproliferative or myeloproliferative tumors, and those with immunosuppression after organ transplantation. A case of adenocarcinoma of the bladder associated with malignant lymphoma is reported, and the known cases of second primary bladder malignancies after cyclophosphamide therapy as reported in the literature are reviewed. Studies relating to the enhanced occurrence of second primary cancers in lymphoproliferative disorders are presented. The recognized urologic toxicities of cyclophosphamide, including cytopathologic changes in animals and humans, are discussed. The observed association between immunosuppression and second primary malignancies is explored, as supported by studies on congenital immunodeficiency in humans, viral oncogenesis in experimental animals, and neoplasia after organ transplantation. Possible mechanisms of carcinogenesis associated with cyclophosphamide are reviewed, including suppression of humoral and cell-mediated immune defense mechanisms, direct carcinogenesis, or cocarcinogenesis. A plea is made for the orderly reporting and careful documentation of bladder tumors in patients receiving cyclophosphamide. It is suggested that prospective studies in these patients and in patients receiving cyclophosphamide for nonmalignant disorders would be of value in assessing the culpability of cyclophosphamide as a carcinogen.

Abdominal Neoplasms↗

PubMed1990

Metabolism and pulmonary toxicity of cyclophosphamide.

Pulmonary toxicity caused by an antineoplastic drug, cyclophosphamide is becoming a more frequently recognized entity. Metabolism of cyclophosphamide in lung to alkylating metabolites and acrolein, a reactive aldehyde are in part responsible for pulmonary toxicity. Alterations in pulmonary mixed-function oxidase activity, glutathione content, and microsomal lipid peroxidation may be caused by the reactive metabolite acrolein. Potentiation of cyclophosphamide-induced pulmonary injury under hyperoxic conditions is caused by depression of pulmonary antioxidant defense mechanisms by cyclophosphamide and its other metabolites but not acrolein. Cyclophosphamide- and acrolein-induced alterations in the physical state of membrane lipid bilayer may be the major cause of inactivation of membrane-bound enzymes. These data suggest that cyclophosphamide and its reactive metabolites initiate peroxidative injury resulting in alterations in the physical state of membrane lipids which may be functionally linked to manifestations of cyclophosphamide-induced pulmonary toxicity.

Animals↗

PubMed1993

Folinic acid, 5-fluorouracil bolus and infusion and mitoxantrone with or without cyclophosphamide in metastatic breast cancer.

60 patients with metastatic breast cancer were entered in a phase II study using folinic acid, 5-fluorouracil bolus and infusion and mitoxantrone with or without cyclophosphamide. 47 had measurable visceral metastases and 13 had exclusively bone metastases. 36 had received previous adjuvant or metastatic treatment (33/36 with anthracycline-based regimens). Overall response rate in visceral metastatic patients was 57.1% [95% confidence interval (CI) 35.4-78.8%]; 45.5% and 70% in previously and non-previously treated patients, respectively; duration of response was 9 and 13 months, respectively. 10 out 13 patients with exclusive bone metastases improved for a median time of 18 months. Median survival was 22 months for the 60 patients; 18 and 31 months for previously and non-previously treated patients, respectively. Cyclophosphamide was scheduled only in the absence of nadir grade 4 neutropenia. However, this toxicity occurred in the first 7 patients. For this reason, we chose to avoid cyclophosphamide in patients over 60 years, or with a performance status of 1-2, or who had received previous chemotherapy. Overall, cyclophosphamide was stopped due to nadir grade 4 neutropenia in 17/24 patients for whom this drug was planned. When mitoxantrone, 5-fluorouracil and folinic acid were used at the doses scheduled, the addition of cyclophosphamide appeared feasible in only about 25% of the patients. Furthermore, survival was identical for patients receiving or not receiving cyclophosphamide. Therefore, cyclophosphamide does not contribute substantially to this regimen. This study confirms the value of folinic acid, 5-fluorouracil and mitoxantrone in metastatic breast cancer.

Adult↗

PubMed1992

A pilot study of intensive cyclophosphamide, epirubicin and fluorouracil in patients with axillary node positive or locally advanced breast cancer.

A multicentre pilot study has been conducted to determine an intensive regimen of cyclophosphamide, epirubicin, and fluorouracil which was tolerable and acceptable to patients with node positive breast cancer. Consecutive patients with operable axillary node positive breast cancer (T1-3, N1-2, M0), 266 patients, or locally advanced breast cancer (T4), 22 patients, were treated with cyclophosphamide post-operatively for 14 days and epirubicin and fluorouracil, both intravenously on days 1 and 8. Each cycle was repeated monthly for 6 months. Dosages were increased according to predetermined guidelines. Outcome measures were admission to hospital for febrile neutropenia and change in cardiac function as assessed by radionuclide angiography. The first 46 patients were treated at the doses of cyclophosphamide = 75 mg/m2, epirubicin = 50 mg/m2, fluorouracil = 375 mg/m2 (level 1), then 42 patients at cyclophosphamide = 75 mg/m2, epirubicin = 50 mg/m2 and fluorouracil = 500 mg/m2 (level 2), 69 patients at cyclophosphamide = 75 mg/m2, epirubicin = 60 mg/m2, and fluorouracil = 500 mg/m2 (level 3), and 42 patients at cyclophosphamide = 75 mg/m2, epirubicin = 70 mg/m2, and fluorouracil = 500 mg/m2 with concurrent antibiotics (level 4). The rates of febrile neutropenia were 8.7% (level 1), 7.1% (level 2), 18.8% (level 3), and 31% (level 4), respectively, P = 0.002. Accrual to level 4 was discontinued according to study guidelines and a further 89 patients were recruited at level 3 dosages with antibiotic prophylaxis (level 3a), resulting in a 5.6% rate of febrile neutropenia. The difference in febrile neutropenia rates between levels 3 and 3a was statistically significant. There were no toxic deaths and 2 cases of heart failure. In conclusion, through a careful dose-finding study in patients with operable or locally advanced breast cancer, an intensive epirubicin-containing adjuvant regimen has been established which is presently being compared with standard CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy in a randomised trial. In addition, this study suggests that antibiotic prophylaxis reduces the risk of febrile neutropenia in breast cancer patients receiving intensive chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Prevention of gonadal toxicity and preservation of gonadal function and fertility in young women with systemic lupus erythematosus treated by cyclophosphamide: the PREGO-Study.

BACKGROUND: With dramatically improved survival rates of SLE patients, comorbidity and long-term damage such as premature ovarian failure (POF) gain increasing importance. In the Erlangen cohort, 14% of cyclophosphamide treated patients younger than 41 years have POF, which is a common consequence of cyclophosphamide treatment. PATIENTS AND METHODS: We tested the concentrations of FSH and LH, before, during and after cyclophosphamide treatment in 63 premenopausal women with SLE without ovarian protection and initiated the PREGO-Study (Prospective randomized study on protection against gonadal toxicity) in patients with SLE. RESULTS: In lupus patients treated with cyclophosphamide, 60% suffered from POF and hypergonadotropic amenorrhea. Whereas the POF rate was <50% in women below 30 years, it was 60% between 30 and 40 years. The cumulative dosage of cyclophosphamide also strongly influenced POF rate. CONCLUSIONS: Our present results, with a high POF rate in Cyclophosphamide treated SLE patients demonstrate the urgent need for ovarian protection in this patient group. Besides POF these women are at high risk for premature atherosclerosis which is the major cause of death in lupus. Following preliminary encouraging experience in women with lymphoma, in whom the temporary induction of a prepubertal hormonal milieu during chemotherapy, has significantly decreased the risk of POF, we have initiated the PREGO-Study, comparing randomised monthly injection versus no injection of gonadotropin-releasing hormone analogue (GnRH-a) to young SLE patients during cyclophosphamide therapy.

Adult↗

PubMed2005

Quality control and stability study using HPTLC: applications to cyclophosphamide in various pharmaceutical products.

Cyclophosphamide is an alkylating agent widely used from cancer chemotherapy to immunotherapy purposes. In paediatrics oncology, oral cyclophosphamide prescribed at low dosages for a long time treatment is currently investigated. This treatment is a putative well tolerated regimen for children treated for a wide variety of recurrent solid tumours. For these purposes, new oral formulations more convenient for children than cyclophosphamide 50mg tablets are needed. Thus, we present a rapid method for the assay of cyclophosphamide in various pharmaceutical preparations using high-performance thin-layer chromatography (HPTLC) and derivatization with phosphomolybdic acid. This method is accurate and precise and allows quantitation of cyclophosphamide in aqueous solutions from 400 to 1200 microg/mL. It is suitable for quantitation and stability studies of cyclophosphamide in pharmaceutical products, i.e. capsules and infusion bags prepared in a hospital pharmacy. According to pharmaceutical guidelines, we demonstrated that low dose cyclophosphamide capsules, extemporaneously prepared for children, are stable at least for 70 days.

Calibration↗

PubMed2004

Noradrenergic responses of peripheral organs to cyclophosphamide in mice.

To determine if the chemotherapeutic drug cyclophosphamide influences the activity of the sympathetic nervous system, the effects of cyclophosphamide on norepinephrine concentration in the heart, adrenal gland, spleen, and thymus gland were evaluated. Male BALB/cByJ mice were administered a single injection of cyclophosphamide (15, 50, or 100 mg/kg, i.p) or saline-vehicle. Organs were collected 72 or 120 h after injection and norepinephrine concentrations were determined by high pressure liquid chromatography with electrochemical detection. Cyclophosphamide reduced spleen, thymus gland, and heart mass while also elevating spleen and thymus gland norepinephrine concentrations (both pmoles/mg tissue and pmoles/mg protein) in a dose- and time-dependent manner. Norepinephrine concentrations in heart and adrenal gland were not altered by cyclophosphamide at any drug dose or time point. Dose- and time-dependent cyclophosphamide-mediated changes in peripheral norepinephrine levels in the spleen and thymus gland are interesting because subjects administered cyclophosphamide may be more susceptible to opportunistic infections, not only because the drug is antineoplastic, but also because the drug alters nervous system-immune system communication and the neurochemical milieu in which surviving cells interact.

Adrenal Glands↗

PubMed1997

Peroxisome proliferator nafenopin potentiated cytotoxicity and genotoxicity of cyclophosphamide in the liver and bone marrow cells.

Peroxisome proliferators are ubiquitous rodent hepatocarcinogens, known to modulate the activities of xenobiotic-metabolising enzymes such as glutathione S-transferases (GST) and mixed-function oxidase (cytochrome P-450). In addition these compounds induce pleiotropic changes in the liver of rodents even after a short-term treatment. It has been hypothesised that the enzymatic and cellular changes induced by peroxisome proliferators may alter the toxicity of other compounds activated by cytochrome P-450 and detoxified by GST isoenzymes. The effect of nafenopin-induced changes in the liver of rats on the toxicity of an anti-cancer drug cyclophosphamide was studied using cyto- and geno-toxicity parameters in the liver and bone marrow cells. The administration of cyclophosphamide (10 or 20 mg/kg bw) to the rats pre-treated with 80 mg/kg bw of nafenopin for 2 days resulted in significantly increased cytotoxic response in bone marrow cells. However, genotoxicity of cyclophosphamide was increased only in the liver of nafenopin pre-treated rats. Low level of genotoxicity in bone marrow could be accounted for potentiated cytotoxicity of cyclophosphamide. These events coincided with a significant, up to 5-fold, increase in indirect activation-detoxication index for cyclophosphamide, determined as a ratio of ECOD and GST activities, in nafenopin treated rats. This resulted from the induction of ECOD responsible for the formation of reactive metabolites of cyclophosphamide and reduced activity of GST responsible for their detoxication. In addition, mitotic activity of hepatocytes was increased in nafenopin treated rats that might also have an impact on the genotoxicity of cyclophosphamide in this organ.

7-Alkoxycoumarin O-Dealkylase↗