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PubMed1983

Clinical trial of the effect of S-2-(3-aminopropylamino)-ethylphosphorothioic acid (WR-2721) (NSC 296961) on the toxicity of cyclophosphamide.

S-2-(3-Aminopropylamino)-ethylphosphorothioic acid (WR-2721) is reported to protect normal tissues from the effects of ionizing radiation and possibly alkylating agents as well. The present trial assessed the ability of this compound to modify the clinical toxicity of cyclophosphamide. Patients with advanced cancer first received a dose of 1000 mg/m2 cyclophosphamide intravenously and were observed for toxicity, principally myelosuppression. After the nadir in white blood cell counts and/or platelets had been documented and adequate recovery had occurred, a second course of cyclophosphamide was given, this time preceded by WR-2721 30 min earlier. In this fashion, each patient served as his own control. Doses of WR-2721 ranging from 250 to 1000 mg/m2 were tested. A total of 13 evaluable courses of WR-2721 were given with cyclophosphamide. In no instance did the prior administration of WR-2721 diminish the bone marrow toxicity of cyclophosphamide alone. At the end of the trial two additional patients received the WR-2721 in a split dose, one-half prior to the cyclophosphamide and one-half 6 hr later; again there was no protection. The side effects of WR-2721 included nausea, vomiting, hypotension, sneezing, and swelling of the tongue. We conclude that WR-2721 is a potentially toxic compound that produces no amelioration of cyclophosphamide toxicity in the doses used. Because of the severity of the side effects of WR-2721, principally hypotension, the trial was terminated after 1000 mg/m2 WR-2721 failed to protect against the toxicity of 1000 mg/m2 cyclophosphamide.

Adult↗

PubMed1985

Phase I trial of misonidazole (NSC#261037) plus cyclophosphamide in solid tumors.

Misonidazole, a hypoxic cell sensitizer, enhances the antitumor effects of cyclophosphamide in preclinical studies. Several studies also showed increased cytotoxicity for normal tissues. We undertook a phase I study of this combination. The regimen consisted of oral administration of misonidazole at one of two dose levels, 1 g/m2 and 2 g/m2, followed by an intravenous (IV) injection of cyclophosphamide four hours later. The cycle was repeated every twenty-one days. The dose of misonidazole remained constant for each regimen, but the dose of cyclophosphamide ranged from 0.4 g/m2 to 1.3 g/m2. Thirty-eight trials in 35 patients with advanced solid tumors were considered evaluable. Dose-limiting toxicity was granulocytopenia at 1 g/m2 of cyclophosphamide without significant thrombocytopenia or anemia. Peripheral neuropathy was negligible. Two patients received cumulative doses of 8 and 16 g/m2 of misonidazole without neurotoxicity. One patient developed hemorrhagic cystitis. Nausea and vomiting was mild to moderate. Possible evidence of tumor stabilization was seen in three patients, and one patient had a mixed response. The mean serum half-life for misonidazole was 11.3 hours (range, 8.4 to 20.0) and for cyclophosphamide 8.3 hours (range, 3.2 to 15.5), both within the previously reported ranges. In conclusion, it appears that this combination is well tolerated and that misonidazole does not significantly potentiate myelotoxicity caused by cyclophosphamide or alter its pharmacokinetics. The recommended starting doses for misonidazole and cyclophosphamide in phase II trials using this schedule of administration should be 2 g/m2 and 1 g/m2, respectively, with escalation for cyclophosphamide to individual tolerance.

Adult↗

PubMed1992

Cyclophosphamide pharmacokinetics: correlation with cardiac toxicity and tumor response.

BACKGROUND: Cyclophosphamide, which forms the nucleus for virtually all preparative regimens for autologous bone marrow transplantation (ABMT), is an alkylating agent of which cytotoxicity is not directly caused by the parent compound but by its biologically active metabolites. Its nonmyelosuppressive toxicity in the ABMT setting is cardiomyopathy. We attempted to determine any correlation between plasma levels of total cyclophosphamide and the subsequent development of cardiac dysfunction. PATIENTS AND METHODS: Analyses of plasma levels and the derivation of plasma concentration-time curves (area under the curve [AUC]) were performed in 19 women with metastatic breast carcinoma, who received a continuous 96-hour infusion of cyclophosphamide, thiotepa, and carboplatin (CTCb) with ABMT. The assay for total cyclophosphamide measures the inactive parent compound; reliable assays of the active metabolites of cyclophosphamide are not yet available. RESULTS: Six of 19 women developed moderate, but transient, congestive heart failure (CHF) as assessed by clinical and radiologic criteria. These patients had a significantly lower AUC of total cyclophosphamide (median, 2,888 mumol/L/h) than patients who did not develop CHF (median, 6,121 mumol/L/h) (P less than .002). Median duration of tumor response in these patients was also more durable; at least 22 months in patients with lower AUCs versus a median of 5.25 months in those with higher AUCs (P = .008). CONCLUSION: These pharmacokinetic data support the premise that enhancement of cyclophosphamide activation may lead to both greater tumor cytotoxicity and increased but reversible end-organ toxicity. Early analysis of pharmacokinetic data may allow modulation of cyclophosphamide administration in an attempt to enhance therapeutic efficacy.

Adult↗

PubMed1999

Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-25.

PURPOSE: In 1989, the National Surgical Adjuvant Breast and Bowel Project initiated the B-22 trial to determine whether intensifying or intensifying and increasing the total dose of cyclophosphamide in a doxorubicin-cyclophosphamide combination would benefit women with primary breast cancer and positive axillary nodes. B-25 was initiated to determine whether further intensifying and increasing the cyclophosphamide dose would yield more favorable results. PATIENTS AND METHODS: Patients (n = 2,548) were randomly assigned to three groups. The dose and intensity of doxorubicin were similar in all groups. Group 1 received four courses, ie, double the dose and intensity of cyclophosphamide given in the B-22 standard therapy group; group 2 received the same dose of cyclophosphamide as in group 1, administered in two courses (intensified); group 3 received double the dose of cyclophosphamide (intensified and increased) given in group 1. All patients received recombinant human granulocyte colony-stimulating factor. Life-table estimates were used to determine disease-free survival (DFS) and overall survival. RESULTS: No significant difference was observed in DFS (P =.20), distant DFS (P =.31), or survival (P =.76) among the three groups. At 5 years, the DFS in groups 1 and 2 (61% v 64%, respectively; P =. 29) was similar to but slightly lower than that in group 3 (61% v 66%, respectively; P = 08). Survival in group 1 was concordant with that in groups 2 (78% v 77%, respectively; P =.71) and 3 (78% v 79%, respectively; P =.86). Grade 4 toxicity was 20%, 34%, and 49% in groups 1, 2, and 3, respectively. Severe infection and septic episodes increased in group 3. The decrease in the amount and intensity of cyclophosphamide and delays in therapy were greatest in courses 3 and 4 in group 3. The incidence of acute myeloid leukemia increased in all groups. CONCLUSION: Because intensifying and increasing cyclophosphamide two or four times that given in standard clinical practice did not substantively improve outcome, such therapy should be reserved for the clinical trial setting.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2003

Treatment of pediatric idiopathic pulmonary hemosiderosis with low-dose cyclophosphamide.

OBJECTIVE: To report the safety and efficacy of long-term, low-dose cyclophosphamide therapy in a child with idiopathic pulmonary hemosiderosis (IPH). CASE SUMMARY: A 7-year-old boy diagnosed with IPH 4 years previously was initially prescribed prednisolone. Because he only had a transient response to prednisolone, oral cyclophosphamide 2 mg/kg/d was later added. A dramatic improvement was noted during the subsequent follow-up. One year after cyclophosphamide therapy, the patient suddenly developed thrombocytopenia (platelet count 75 x 10(3)/mm(3)), with the platelet count decreasing to 10 x 10(3)/mm(3) over the following 10 months. Cyclophosphamide was tapered to an alternating daily dosage of 1 mg/kg. The tapering resulted in a subsequent increase in the platelet count, which was maintained between 20 and 50 x 10(3)/mm(3) without occurrence of petechiae or spontaneous bleeding. Under this reduced dosing regimen, the disease has remained in remission for >1 year. DISCUSSION: Due to the low prevalence of IPH, only limited data document the safety and efficacy of immunosuppressive therapy in treating this disease. Although our patient showed a good response to low-dose cyclophosphamide, he developed thrombocytopenia with its use. The mechanism is unclear, but it may be similar to that of high-dose cyclophosphamide-induced myelosuppression. Due to the development of thrombocytopenia, the use of cyclophosphamide was maintained under a reduced dosing regimen. The benefit of long-term immunosuppressive therapy is controversial, and more clinical evidence is required to support its continued usage. CONCLUSIONS: Long-term, low-dose cyclophosphamide is effective in treating childhood IPH, but caution should be exercised due to the possible development of thrombocytopenia. Periodic monitoring of the platelet count in long-term treatment is recommended.

Child↗

PubMed1991

Clinical pharmacokinetics of cyclophosphamide.

Cyclophosphamide has been in clinical use for the treatment of malignant disease for over 30 years. It remains one of the most useful anticancer agents, and is also widely used for its immunosuppressive properties. Cyclophosphamide is inactive until it undergoes hepatic transformation to form 4-hydroxycyclophosphamide, which then breaks down to form the ultimate alkylating agent, phosphoramide mustard. Sensitive and specific methods are now available for the measurement of cyclophosphamide, its metabolites and its stereoisomers in plasma and urine. The pharmacokinetics of cyclophosphamide have been understood for many years; those of the cytotoxic metabolites have been described more recently. The pharmacokinetics are not significantly altered in the presence of hepatic or renal insufficiency. As activity resides exclusively in the metabolites, whose pharmacokinetics are not predicted by those of the parent compound, correlations between cyclophosphamide pharmacokinetics and pharmacodynamics have not been demonstrated. Cyclophosphamide is used in doses that range from 1.5 to 60 mg/kg/day. A steep dose-response curve exists, and reductions in dose can lead to unfavourable outcomes. Myelosuppression is the dose-limiting toxicity, although in the setting of bone marrow transplantation, escalation beyond that dosage range is limited by cardiac toxicity. Longer term complications of cyclophosphamide therapy include infertility and an increased incidence of second malignancies. Cellular sensitivity to cyclophosphamide is a function of cellular thiol concentration, metabolism by aldehyde dehydrogenases to form inactive metabolites, and the ability of DNA to repair alkylated nucleotides. Whether alteration of these cellular functions will lead to further improvements in clinical outcomes is an area of active investigation.

Aldehyde Dehydrogenase↗

PubMed2001

Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis.

BACKGROUND: Controlled trials in lupus nephritis have demonstrated that cyclophosphamide therapy is superior to corticosteroid therapy alone. The long-term effectiveness and side-effect profiles of pulse immunosuppressive regimens warrant further study. OBJECTIVE: To define the long-term risk and benefit of monthly treatment with boluses of methylprednisolone, cyclophosphamide, or both. DESIGN: Extended follow-up (median, 11 years) of a randomized, controlled trial. SETTING: U.S. government research hospital. PATIENTS: 82 patients with proliferative lupus nephritis. MEASUREMENTS: Rates of treatment failure (defined as need for supplemental immunosuppressive therapy or doubling of serum creatinine concentration, or death) and adverse events. RESULTS: In an intention-to-treat survival analysis, the likelihood of treatment failure was significantly lower in the cyclophosphamide (P = 0.04) and combination therapy (P = 0.002) groups than in the methylprednisolone group. Combination therapy and cyclophosphamide therapy alone did not differ statistically in terms of effectiveness or adverse events. Of patients who completed the protocol (n = 65), the proportion of patients who had doubling of serum creatinine concentration was significantly lower in the combination group than in the cyclophosphamide group (relative risk, 0.095 [95% CI, 0.01 to 0.842]). CONCLUSION: With extended follow-up, pulse cyclophosphamide continued to show superior efficacy over pulse methylprednisolone alone for treatment of lupus nephritis. The combination of pulse cyclophosphamide and methylprednisolone appears to provide additional benefit over pulse cyclophosphamide alone and does not confer additional risk for adverse events.

Adult↗

PubMed1999

Effects of the antiestrogen EM-800 (SCH 57050) and cyclophosphamide alone and in combination on growth of human ZR-75-1 breast cancer xenografts in nude mice.

Human breast cancer proliferates as heterogeneous cell populations that exhibit different sensitivities to therapeutic agents. A logical approach to control these different cancer cell populations is the use of combined treatment with agents that block cell proliferation or induce apoptosis via different mechanisms. We therefore investigated the effect of treatment with the novel pure antiestrogen EM-800, alone or in combination with chemotherapy, on the growth of ZR-75-1 human breast tumors in nude mice, a well-recognized model of human breast cancer. Mice bearing estrone-releasing silastic implants as estrogenic stimulus received EM-800 or cyclophosphamide alone or in combination for 227 days. Cyclophosphamide (256 mg/kg/2 weeks) was administered by i.p. injection in 64 mg/kg fractions over 4 consecutive days with repetition of the cycle every 14 days. EM-800 was administered p.o. once daily at the maximally effective dose of 300 microg/mouse. After 227 days of treatment, average tumor size in mice receiving estrone alone was 192% higher than pretreatment. The average tumor size of mice treated with chemotherapy was reduced by 47%, whereas on the other hand, EM-800 caused a 81% decrease of the value of the same parameter. The combined treatment (EM-800 + cyclophosphamide), on the other hand, resulted in a 95% decrease in tumor size compared with control estrogen alone. In fact, EM-800 alone decreased tumor size to 55% of the value at the start of treatment, whereas the addition of cyclophosphamide to the antiestrogen further decreased tumor size to as low as 15% of the pretreatment value. The combination of EM-800 and cyclophosphamide resulted in 95% of complete or partial responses compared with 61 and 27% with EM-800 and cyclophosphamide alone, respectively. In fact, in the combination therapy group, only one tumor remained stable, while 17 regressed >50% and four disappeared. It is noteworthy that no tumor progressed with EM-800 alone or in combination with cyclophosphamide. The present data show, for the first time, that the addition of cyclophosphamide to a pure antiestrogen used at a maximal dose causes a more potent inhibition of human breast tumor growth, thus suggesting that combined treatment using a maximal dose of a pure antiestrogen and a chemotherapeutic agent(s), two classes of compounds having different mechanisms of action, could further improve breast cancer therapy above the results achieved with a potent and pure antiestrogen alone in estrogen-sensitive breast cancer.

Animals↗

PubMed1976

The effect of allopurinol on cyclophosphamide antitumor activity.

We have used the spleen colony assay system and survival duration studies in male DBA/2 mice with P388 leukemia to study the effects of allopurinol pretreatment on the antileukemic activity of cyclophosphamide and its bone marrow toxicity. Allopurinol drinking water (0.5 mg/ml) was given for 7 days prior to cyclophosphamide (10 to 200 mg/kg i.p.). Average daily allopurinol intake per mouse was 1.25 mg (equivalent to 4 mg/kg/day human dosage). Dose-response curves with and without allopurinol pretreatment showed an almost constant 0.9-log increase in the toxicity of cyclophosphamide to leukemic colony-forming units, whereas allopurinol had no effect on the toxicity of cyclophosphamide to normal bone marrow colony-forming units. Parallel survival studies revealed no difference in the antileukemic activity of cyclophosphamide as a result of allopurinol pretreatment. The allopurinol-induced change in the antitumor activity of cyclophosphamide as seen in the spleen colony assay was not explainable on the pharmacokinetic basis. Flow microfluorometric analysis of P388 leukemia tumor cell cycle parameters revealed no change in the blockading effects of cyclophosphamide as a result of allopurinol preexposure. Although we have failed to explain the underlying mechanism of this drug interaction, our data suggest that allopurinol may increase the antitumor activity of cyclophosphamide without increasing its bone marrow toxicity.

Alkylation↗

PubMed1990

Residual damage in mouse lungs at long intervals after cyclophosphamide treatment.

The purpose of these studies was to quantify the effects of radiation given to mouse lungs at intervals up to 6 months after injection of the maximally tolerated dose of cyclophosphamide. In one set of experiments a single i.p. injection of 300 mg/kg of cyclophosphamide was followed at either 1, 3, or 6 months by a range of single doses of gamma-rays delivered to the whole thorax only. In a second set of experiments mice were given five daily i.p. injections of cyclophosphamide, 100 mg/kg, followed at 1, 3, and 6 months by a range of fractionated doses of X-rays. Breathing rate, histology, and mortality were used to assess lung damage. These data were compared with age-matched animals given either the drug alone or single doses of radiation alone. Dose-response curves of lethality were constructed and fitted by a logit program, and 50% lethal doses with 95% confidence limits were determined at monthly intervals after irradiation. Dose enhancement factors were then calculated at this isoeffect for the mice given the drug and radiation. Deaths from radiation pneumonitis occurred as early as 6 weeks in mice given cyclophosphamide before irradiation; few deaths occurred after 26 weeks. However, in the mice given radiation alone, deaths from pneumonitis did not occur before 12 weeks. Cyclophosphamide given as either single doses or fractionated doses at all three times before irradiation enhanced radiation pneumonitis in mouse lung. Dose enhancement factors of 1.2, 1.4, and 1.3 were obtained when single doses of radiation followed single doses of cyclophosphamide at 1, 3, and 6 months, respectively. The dose enhancement factor for radiation pneumonitis after the fractionated exposures was less, 1.1, and was independent of time between the two treatments. An enhancement factor of 1.2 was observed for the later wave of lung damage in those few studies available for analysis at this time. These data clearly show that prior treatment of the animal with cyclophosphamide significantly reduces the radiation dose that can be given to the lung for as long as 6 months after drug treatment. In addition, lung damage occurred sooner when the drug was given prior to irradiation. These data indicate that the lung will be sensitive to retreatment with radiation when a full tolerance dose of cyclophosphamide precedes radiation.

Animals↗

PubMed1989

Oxidative metabolism of cyclophosphamide: identification of the hepatic monooxygenase catalysts of drug activation.

Cytochrome P-450-catalyzed activation of cyclophosphamide to alkylating metabolites was studied in isolated rat liver microsomes and purified, reconstituted P-450 enzyme systems in order to identify the major enzymatic catalysts of drug activation in both uninduced and drug-induced liver tissue. P-450 form PB-4 (P-450 gene IIB1) activated cyclophosphamide with high efficiency [Vmax (app) = 18.2 nmol metabolite/min/nmol P-450; Km (app) = 0.16 mM] via the formation of 4-hydroxycyclophosphamide, which was quantitatively trapped as a bisulfite adduct then characterized following its conversion to cyano derivatives. Antibodies to P-450 PB-4 inhibited cyclophosphamide activation catalyzed by phenobarbital-induced adult male rat liver microsomes (specific activity, 5.4 nmol metabolite/min/mg liver microsomes) in a selective and near quantitative (greater than 80%) fashion; little or no inhibition was obtained using antibodies inhibitory towards six other rat hepatic P-450 forms. Cyclophosphamide activation catalyzed by uninduced adult male rat liver microsomes (specific activity, 0.68 nmol/min/mg), although not inhibited by anti-P-450 PB-4 antibodies, was partially inhibited (approximately 60%) by antibodies to P-450 PB-1 (gene IIC6) and more completely inhibited (greater than 95%) by antibodies reactive with both P-450 PB-1 and P-450 2c (gene IIC11). Consistent with these observations, P-450 PB-1 and P-450 2c both activated cyclophosphamide at moderate rates in reconstituted systems (turnover, 1.6-2.7 nmol metabolite/min/nmol P-450), while seven other purified hepatic P-450 forms exhibited significantly lower activities (turnover less than or equal to 0.5 nmol metabolite/min/nmol P-450). Further studies revealed that the changes in liver microsomal cyclophosphamide activation rates with age and sex and in response to in vivo administration of cisplatin primarily reflect changes in the levels of P-450 forms PB-1 and 2c. These studies establish that P-450 forms PB-1, 2c, and PB-4 are the major catalysts of cyclophosphamide activation in rat hepatic tissue and that the modulation of microsomal cyclophosphamide activation with development and in response to drug exposure largely reflects alterations in the levels of these three hepatic P-450 enzymes.

Animals↗

PubMed1979

Contact sensitivity and the DNA response in mice to high and low doses of oxazolone: low dose unresponsiveness following painting and feeding and its prevention by pretreatment with cyclophosphamide.

Cyclophosphamide was used to assess the role of suppressor cells in the contact sensitivity reaction. A single painting with 300 microgram and 30 microgram oxazolone produced poor contact sensitivity reactions (ear swelling). Cyclophosphamide (200 mg/kg) 2 days before painting increased the response to the lower doses but had less effect on the response to 3 mg oxazolone. A single feed with 10 mg oxazolone caused strong contact sensitivity while lower doses (10-1000 microgram) caused poor responses. Cyclophosphamide increased the response to the lower doses but not to the highest dose of oxazolone. These results suggested that the poor response to painting and feeding lower doses of oxazolone was due to a suppressor system which was sensitive to cyclophosphamide. A different result was obtained when contact sensitivity was measured by arrival of radioactively labelled cells. Cyclophosphamide had the greatest effect on cell arrival when high doses were fed. This indicates that ear swelling and cell arrival measure separate aspects of the contact sensitivity response. The lower doses of oxazolone, which caused little contact sensitivity, reduced the response to a standard immunizing dose. This low dose unresponsiveness occurred after either painting or feeding (Chase-Sulzberger phenomenon). It did not occur in mice treated with cyclophosphamide before the first exposure to oxazolone. This suggested that the low dose unresponsiveness was due to suppressor cells. The response to oxazolone was also assessed by DNA synthesis in the regional lymph nodes. A small dose of oxazolone (30 microgram) caused a peak of DNA synthesis on day four while a high dose (3 mg) caused a peak on day three. Pretreatment with cyclophosphamide depressed the response to 30 microgram although it increased contact sensitivity. The secondary response was smaller than the primary on days 3, 4 and 5 after immunization but larger on day two. The depression but not the increase was prevented by cyclophosphamide and was probably due to a suppressor system.

Animals↗

PubMed1988

Disposition of cyclophosphamide on two consecutive cycles of treatment in patients with ovarian carcinoma.

The disposition of cyclophosphamide was determined in 12 women with ovarian carcinoma receiving cyclophosphamide 500 mg/m2, doxorubicin (adriamycin) 50 mg/m2 and cisplatin 50 mg/m2 during their first and second courses of therapy. Plasma samples were obtained over 24 h following the completion of the cyclophosphamide infusion and assayed for cyclophosphamide by high performance liquid chromatography. The mean disposition of cyclophosphamide conformed to a 2-compartment model with a mean terminal half-life of 7.14 h on the first course and 8.77 h on the second course. Mean area under the plasma concentration versus time curve appeared to increase from 248.8 mg.h/l for the initial course to 282.2 mg.h/l on the second. Mean total body clearance was 2.01 l/h/m2 on the first course and 1.77 l/h/m2 on the second. Volume of distribution on the first and second courses were 15.3 l/m2 and 18.1 l/m2, respectively. These results suggested that cyclophosphamide clearance decreased when given in a bolus fashion every 3 weeks. However, inter-patient and intra-patient variability was large and the differences in the calculated parameters were not statistically significant when the individual patient data was considered. It is concluded that: 1. cyclophosphamide disposition can best be fit by a bi-exponential equation; 2. considerable intra- and interpatient variability in the concentration-time profile will be encountered; 3. cyclophosphamide disposition does not change from the first to the second course. Reasons for the wide variation are proposed.

Adult↗

PubMed1984

Response to cyclophosphamide in steroid-resistant focal segmental glomerulosclerosis: a reappraisal.

The response to and clinical outcome of cyclophosphamide therapy were retrospectively assessed in 29 steroid-resistant patients with idiopathic nephrotic syndrome and focal segmental glomerulosclerosis (FSGS) to determine whether a partial response to this drug was associated with long-term clinical benefits. Twenty of the patients were nephrotic when cyclophosphamide was started and 9 were not. Three of the nephrotic patients had a complete response (i.e., sustained remission of disease) to cyclophosphamide. Nine nephrotic patients had partial responses. Of these, 8 have residual proteinuria and one has progressed to end-stage renal disease (ESRD). In contrast, of the 8 nephrotic patients who were resistant to cyclophosphamide, only one has residual proteinuria, while 7 have chronic renal failure (CRF) or ESRD. The incidence of CRF or ESRD in patients with a partial response to cyclophosphamide (1 of 9) was significantly lower (p = 0.004) than that in patients who were resistant to cyclophosphamide (7 of 8). The benefit of cyclophosphamide in patients who were not overtly nephrotic was less certain. This study indicates that a partial response to cyclophosphamide leads to improvement in the clinical outcome of many steroid-resistant nephrotic patients with FSGS.

Adolescent↗

PubMed1982

Protective role of thiols in cyclophosphamide-induced urotoxicity and depression of hepatic drug metabolism.

One of the serious toxicities of cyclophosphamide chemotherapy is urotoxicity. In addition to causing leukopenia, high-dose cyclophosphamide caused both depression of hepatic microsomal enzyme activities and extensive urinary bladder damage, suggesting that a common biochemical mechanism may be responsible for both of these effects. Administration of 180 or 200 mg cyclophosphamide per kg to Wistar rats caused 41 to 67% decrease in aryl hydrocarbon hydroxylase activity, a 21 to 54% decrease in aminopyrine demethylase activity, and a 34 to 40% decrease in cytochrome P-450 content. This dose of cyclophosphamide also caused hematuria as well as necrosis and edema in the urinary bladder. Administration of N-acetylcysteine or sodium-2-mercaptoethane sulfonate (mesnum) with cyclophosphamide, while not protecting against leukopenia, protected against the enzymatic inactivation and urotoxicity. The biochemical basis of these observations is discussed. The results suggest that a common metabolite of cyclophosphamide, most probably acrolein, is responsible for both of these undesirable effects of cyclophosphamide therapy. Use of combinations including cyclophosphamide and an appropriate thiol may increase the therapeutic index of this drug.

Acetylcysteine↗

PubMed1980

Residual marrow damage following therapy with cyclophosphamide.

Studies were performed to determine the type of residual marrow damage which occurs after injecting mice with 200 mg/kg of cyclophosphamide every 2 weeks for 5 courses. Mice treated with cyclophosphamide, and controls injected with normal saline, were studied 6 weeks after the last injection. Complete blood counts, and total nuclear cell counts from femoral marrow revealed no differences between the 2 groups. The number of CFUs in the marrow of cyclophosphamide treated mice was slightly, but significantly, lower than of controls. Cyclophosphamide treated and control mice were then exposed to 300 rad, and the rate of marrow CFUs recovery was determined. That of cyclophosphamide treated mice was significantly slower than that of controls. Stromal function of marrows from cyclophosphamide treated mice was significantly impaired. Also, however, the proliferative potential of marrow CFUs of cyclophosphamide treated mice was modestly reduced relative to that of controls. We conclude that cyclophosphamide treatment of mice results in significant residual marrow damage, due primarily to "stromal" damage, but also to decrease in the proliferative potential of CFUs.

Animals↗

PubMed1982

Influence of diuretics on urinary general base catalytic activity and cyclophosphamide-induced bladder toxicity.

The influence of diuretics on the induction of bladder toxicity by cyclophosphamide was investigated in rats. Following ip administration, about 3.5% of the cyclophosphamide was excreted as 4-hydroxycyclophosphamide. This amount was found to be compatible with the view that the urotoxic effects of cyclophosphamide are caused by the acrolein generated in the urine from 4-hydroxycyclophosphamide, the primary metabolite of cyclophosphamide. In situ, acrolein was more potent than 4-hydroperoxycyclophosphamide with regard to producing an increase in bladder weight; phosphoramide mustard was essentially without urotoxic activity. The urotoxic potency of 4-hydroperoxycyclophosphamide, but not that of acrolein, increased as the pH and/or the phosphate concentration of the infusion medium increased. This was as expected in view of the knowledge that release of acrolein from 4-hydroxycyclophosphamide or 4-hydroperoxycyclophosphamide is facilitated by the presence of general base catalysts, eg, phosphate and bicarbonate, and that the rate at which this reaction proceeds in the presence of these catalysts increases as their concentration and the pH increases. In vivo, diuretics that acidified the urine, eg, ammonium chloride and furosemide, prevented the increase in bladder weight ordinarily elicited by the dose of cyclophosphamide used in these experiments. In contrast, a diuretic, acetazolamide, that markedly increased urinary bicarbonate concentration and alkalinized the urine, did not. None of the diuretics altered the systemic metabolism and urinary excretion of cyclophosphamide nor did they alter the systemic action, as judged by spleen weight, of cyclophosphamide. These observations demonstrate that the pH of the urine and the urinary concentration of general base catalysts greatly influence the urotoxic potential of oxazaphosphorines such as cyclophosphamide. They indicate that while the use of acidifying diuretics is likely to be beneficial in minimizing oxazaphosphorine-induced bladder toxicity, the use of alkalinizing diuretics may not be helpful.

Acrolein↗

PubMed1980

[Effect of damaged liver parenchyma, renal insufficiency and hemodialysis on the pharmacokinetics of cyclophosphamide and its activated metabolites].

Patients with impaired liver function have a reduced biotransformation rate of the cytostatic agent cyclophosphamide. With pathologically reduced serum cholinesterase activity the half-life of the drug increases from normally 4.3 h to 6.7 h. These patients show significantly lower peak levels of activated cyclophosphamide (4-hydroxy-cyclophosphamide + aldophosphamide). Because of the low renal clearance of cyclophosphamide (16 ml/min) and equally low renal excretion of activated cyclophosphamide amounting to only 1% of the applied dose more than 80% of the drug is still metabolized and the area under the curve of activated cyclophosphamide (cXt) remains relatively constant. No change in the pharmacokinetics of cyclophosphamide and its activated metabolite is observed in an anuric patient. However, an accumulation of toxic, directly alkylating metabolites with a fourfold alkylation rate of plasma proteins is found in this case. Hemodialysis sufficiently eliminated the toxic alkylating metabolites without a measurable influence on the pharmacokinetics of activated cyclophosphamide.

Aged↗