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PubMed1990

Effect of cyclophosphamide pretreatment on daunorubicin in rat acute leukaemia model.

The total number of leukaemic cells at the time of therapy may affect the tissue and target cell distribution and antitumour efficacy of cytotoxic drugs. The effects of low dose cyclophosphamide pretreatment on daunorubicin concentrations in leukaemic bone marrow were investigated in rats. At day 12 after transplantation of the leukaemia, rats were injected intraperitoneally with cyclophosphamide (30 mg/kg). 2 days later the leukaemic rats received daunorubicin intravenously (7.5 mg/kg). Cyclophosphamide pretreatment led to a significant increase in daunorubicin concentration in the femoral bone marrow, by a factor of about 7. The log leukaemic stem cell kill (LCK) values, as estimated by a survival assay, were 1.8, 0.7, and 5.4 for the leukaemic rats injected with cyclophosphamide (day 12), with daunorubicin (day 14), or with cyclophosphamide (day 12) plus daunorubicin (day 14), respectively). The simultaneous administration of cyclophosphamide and daunorubicin at day 14, induced a LCK of 2.7, a value that was the sum of the LCKs of cyclophosphamide and daunorubicin alone. Low-dose cyclophosphamide pretreatment led to an increased daunorubicin accumulation in femoral bone marrow of leukaemic rats, and was synergistic with daunorubicin.

Animals↗

PubMed2005

Metabolism-based cyclophosphamide dosing for hematopoietic cell transplant.

When cyclophosphamide (120 mg/kg) is used for hematopoietic cell transplant, the increased area under the curve of carboxyethylphosphoramide mustard (AUC(CEPM)) is related to liver toxicity and death. We determined the feasibility of dose-adjusting cyclophosphamide to a preset metabolic endpoint (AUC(CEPM), 325 +/- 25 micromol/L.h). In 20 patients blood sampling was done over a 16-hour period after administration of 45 mg/kg cyclophosphamide; AUC(CEPM) from 0 to 16 hours was calculated by noncompartmental analysis. The expected AUC(CEPM) for 0 to 48 hours was estimated, and the second cyclophosphamide dose was determined. The mean second cyclophosphamide dose was 42 mg/kg, and the mean total cyclophosphamide dose was 86 mg/kg (range, 54-120 mg/kg). The mean AUC(CEPM) for the time from 0 to 48 hours was 296 micromol/L.h (95% confidence interval, 275-317 micromol/L.h). A retrospective analysis indicated that AUC(CEPM) could be more accurately predicted by use of a population pharmacokinetic model. We conclude that metabolism-based dosing of cyclophosphamide is feasible and that a lower cyclophosphamide dose does not affect engraftment.

Adolescent↗

PubMed1981

Long-term impairment of suppressor-cell function by cyclophosphamide in minimal-change nephropathy and its association with therapeutic response.

Lymphocyte suppressor-cell function was studied by induction with concanavalin A in 31 patients with minimal-change nephropathy (MCN) in remission. 21 patients had been treated with cyclophosphamide 0.5--12.0 years previously (mean 6.5 years) and had been in remission for 0.5--9.0 years (mean 5.1 years). The remaining 10 patients had never received cyclophosphamide and had been in remission for 1--10 years (mean 5.3 years). The cyclophosphamide-treated group had significantly less suppressor-cell function than either the controls or the non-cyclophosphamide-treated group, the latter being not significantly different from normal. When patients who had received cyclophosphamide were divided into those who had relapsed after taking this drug (10 patients) and those who had not (11 patients), suppressor-cell function was significantly impaired in the non-relapsing group. This association of impaired suppressor-cell function with failure to relapse may indicate that suppressor cells have a pathogenetic role in MCN and that the therapeutic effect of cyclophosphamide in this disease is to diminish their function. Alternatively, the impaired suppressor-cell function in the non-relapsing group may be simply a marker of effective treatment with cyclophosphamide. The finding of long-term suppression of lymphocyte function after cyclophosphamide coupled with this drug's risks of causing malignancy and gonadal dysfunction reinforces the need for caution in its use in MCN.

Adolescent↗

PubMed1999

Different effect of granulocyte colony-stimulating factor or bacterial infection on bone-marrow cells of cyclophosphamide-treated or irradiated mice.

In the present study, the effect of treatment with granulocyte colony-stimulating factor (G-CSF) on cellular composition of the bone marrow and the number of circulating leucocytes of granulocytopenic mice, whether or not infected with Staphylococcus aureus, was assessed. With two monoclonal antibodies, six morphologically distinct cell populations in the bone marrow could be characterised and quantitated by two-dimensional flow cytometry. Granulocytopenia was induced by cyclophosphamide or sublethal irradiation. Cyclophosphamide predominantly affected the later stages of dividing cells in the bone marrow resulting in a decrease in number of granulocytic cells, monocytic cells, lymphoid cells and myeloid blasts. G-CSF administration to cyclophosphamide-treated mice increased the number of early blasts, myeloid blasts and granulocytic cells in the bone marrow, which indicates that this growth factor stimulates the proliferation of these cells in the bone marrow. During infection in cyclophosphamide-treated mice the number of myeloid blasts increased. However, when an infection was induced in cyclophosphamide and G-CSF-treated mice, the proliferation of bone-marrow cells was not changed compared to that in noninfected similarly treated mice. Sublethal irradiation affected all bone-marrow cell populations, including the early blasts. G-CSF-treatment of irradiated mice increased only the number of myeloid blasts slightly, whereas an infection in irradiated mice, whether or not treated with G-CSF, did not affect the number of bone-marrow cells. Together, these studies demonstrated that irradiation affects the early blasts and myeloid blasts in the bone marrow more severely than treatment with cyclophosphamide. Irradiation probably depletes the bone marrow from G-CSF-responsive cells, while cyclophosphamide spared G-CSF responsive cells, thus enabling the enhanced G-CSF-mediated recovery after cyclophosphamide treatment. Only in these mice, bone marrow recovery is followed by a strong mobilisation of mature granulocytes and their band forms from the bone marrow into the circulation during a bacterial infection.

Agranulocytosis↗

PubMed2002

Testicular gametogenic and steroidogenic activities in cyclophosphamide treated rat: a correlative study with testicular oxidative stress.

The present work examined the changes in testicular activities in relation to testicular oxidative stress in cyclophosphamide as well as human chorionic gonadotrophin (hCG) co-treated cyclophosphamide treated Wistar strain rats. Testicular activities were evaluated by the quantification of spermatogenesis and by the measurement of steroidogenic key enzyme activities along with plasma levels of testosterone. Testicular oxidative stress in relation to cyclophosphamide treatment was monitored by the study of products of free radicals like conjugated dienes and malondialdehyde (MDA) as well as the activity of testicular antioxidant enzymes like peroxidase and catalase. Cyclophosphamide treatment at the dose of 5 mg/kg body weight/day for 28 days resulted a significant diminution in the activities of testicular delta 5, 3 beta-hydroxysteroid dehydrogenase (delta 5, 3 beta-HSD), 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activities, plasma level of testosterone along with significant reduction in the number of germ cells at stage-VII of spermatogenesis. Levels of testicular MDA and conjugated dienes both were elevated whereas testicular peroxidase and catalase activities both were inhibited significantly in cyclophosphamide treated rats in comparison to control. After hCG co-administration at the dose of 5 I.U./kg body weight/day for 28 days in cyclophosphamide treated rats resulted a significant protection in the activities of testicular peroxidase and catalase along with significant decrease in the levels of MDA and conjugated dienes to the control level. Moreover, the testicular steroidogenic key enzyme activities and spermatogenesis along with plasma levels of testosterone were restored to the control level. Therefore, it may be concluded that there is a correlation between testicular steroidogenic activities as well as spermatogenesis and testicular oxidative stress in cyclophosphamide treated rats. Moreover, as restoration of plasma testosterone to the control level is noted in hCG co-treated cyclophosphamide treated rat, therefore, the results suggest that testosterone may be the key regulator for this correlation.

Animals↗

PubMed1992

Individual variation in the activation and inactivation of metabolic pathways of cyclophosphamide.

BACKGROUND: Carboxyphosphamide is an inactive metabolite of cyclophosphamide, which is a widely used antineoplastic drug. Deficiencies in the production of this metabolite have been reported. Such deficiencies would have important consequences for therapeutic and toxic effects of oxazaphosphorines like cyclophosphamide. PURPOSE: This study further investigates the variability in cyclophosphamide metabolism and carboxyphosphamide recovery in urine. METHODS: The 24-hour urinary metabolic profile of cyclophosphamide was investigated in 17 Turkish patients receiving doses of 100-1080 mg orally or by short intravenous infusion. Urine samples were assayed quantitatively for cyclophosphamide and its principal metabolites (phosphoramide mustard, 4-ketocyclophosphamide, carboxyphosphamide, and dechloroethylcyclophosphamide) with combined thin-layer chromatography-photography-densitometry. The amount of each metabolite excreted in 24 hours was expressed as a percentage of the dose. RESULTS: Recovery of drug and metabolites varied greatly among individuals (range, 0.01%-13.56% of dose). In particular, the amount of carboxyphosphamide varied over a thousandfold range and was undetectable in urine from four patients. The patients were classified by phenotype as demonstrating low or high carboxylation. Those with low carboxylation excreted less than 0.2% of the cyclophosphamide dose as carboxyphosphamide, while those with high carboxylation excreted 0.8%-13.6% (median, 1.81%). No association was observed between carboxylation phenotype and patient age, sex, disease, or concomitant therapy, although the three lifetime nonsmokers all showed poor carboxylation. No correlation was observed between the percent of dose excreted as any of the other metabolites and that excreted as carboxyphosphamide. There was a statistically significant inverse correlation between the combined recovery of carboxyphosphamide and phosphoramide mustard and the dose of prednisolone administered. CONCLUSIONS: These data confirm an earlier observation of a phenotypic deficiency of carboxyphosphamide excretion in British patients treated with cyclophosphamide. This deficiency may arise from a polymorphism in the enzyme aldehyde dehydrogenase. Carboxylation phenotype may have important implications for both the therapeutic effect and toxicity of cyclophosphamide.

Adolescent↗

PubMed1993

Phase I trial of granulocyte-macrophage colony-stimulating factor plus high-dose cyclophosphamide given every 2 weeks: a Cancer and Leukemia Group B study.

BACKGROUND: Chemotherapy-induced myelosuppression often limits escalation of cancer chemotherapy doses. Cyclophosphamide, an alkylating agent, is an ideal candidate for dose escalation: A log-linear relationship between cell kill and dose has been demonstrated, and the drug spares hematopoietic stem cells. In addition, studies suggest that granulocyte-macrophage colony-stimulating factor (GM-CSF) can enhance the ability to achieve optimal dose intensity as well as ameliorating chemotherapy-induced myelosuppression. PURPOSE: The purpose of this study was to determine the maximum tolerated dose and the toxic effects of cyclophosphamide administered every 2 weeks with GM-CSF support. METHODS: For this trial by the Cancer and Leukemia Group B (CALGB), cohorts of patients were treated with cyclophosphamide as a 1-hour intravenous infusion every 14 days; GM-CSF was given subcutaneously on days 3-10. Four dose levels of cyclophosphamide (1.5, 3.0, 4.5, and 6.0 g/m2) and three dose levels of GM-CSF (2.5, 5.0, and 10.0 micrograms/kg per day) were evaluated. There was no dose escalation in individual patients. Fifty-one patients with solid tumors who had CALGB performance status 0 or 1 and minimal prior radiotherapy were eligible for analysis. Drug clearance and area under the curve for plasma drug concentration x time (AUC) were estimated at completion of the infusion and at 4 and 24 hours after the start of the infusion. RESULTS: Ninety-five courses of therapy were analyzed. Treatment with cyclophosphamide at 3.0 g/m2 or more resulted in neutropenia (absolute neutrophil counts < 100/microL) in all cycles of therapy. At those doses, blood cell count recovery adequate for re-treatment occurred in 67%-85% of cycles (median, 16 days). Doses of 6.0 g/m2 were associated with the greatest degree of myelosuppression and frequent hospitalization (88% of cycles); requirements for blood transfusion prohibited further dose escalation. Nonhematologic toxic effects were tolerable, with two episodes of reversible cardiotoxicity and four episodes of hemorrhagic cystitis that precluded further therapy. Degree of myelosuppression was not correlated with cyclophosphamide AUC or clearance. CONCLUSIONS: The recommended phase II dose of cyclophosphamide is 4.5 g/m2 administered every 2 weeks with GM-CSF given at 5.0 micrograms/kg per day of GM-CSF. Our results suggest that, with GM-CSF support, high cumulative doses of cyclophosphamide can be given to achieve optimal dose intensity, with reproducible blood cell count recovery and without the need for autologous bone marrow transplantation. IMPLICATIONS: Phase II studies of this intensive regimen in malignant diseases sensitive to alkylating agents are currently being done in CALGB.

Adult↗

PubMed1987

A time-course study of chronic paternal cyclophosphamide treatment in rats: effects on pregnancy outcome and the male reproductive and hematologic systems.

We have found previously that daily treatment of male rats for 11 wk with low doses of the anticancer drug cyclophosphamide had no apparent effect on male reproductive organ weights, epididymal sperm counts, or serum hormones at the end of the treatment period; yet, upon breeding to untreated females, these males produced a high rate of post-implantation loss and fetal anomalies. The present study was designed to investigate the time course and dose response of the effects of chronic cyclophosphamide treatment on the male reproductive and hematologic systems. Male Sprague-Dawley rats were gavage-fed for 1, 3, 6 and 9 wk with saline (control), or 5.1 (low dose) or 6.8 (high dose) mg/kg/day of cyclophosphamide. After each of the treatment periods, males were mated to determine the effect on pregnancy outcome, then killed, and the effects on the male reproductive and hematologic systems were assessed. After 6 wk of treatment, a sharp increase in mortality was found between the 5.1 and 6.8 mg/kg/day doses of cyclophosphamide. The high dose of cyclophosphamide induced higher levels of pre- and post-implantation loss but fewer fetal anomalies than did the low dose. The low dose of cyclophosphamide did not affect reproductive organ weights; in contrast, the high dose caused decreases in epididymal, ventral prostate, and seminal vesicle weights after 3, 6, and 9 wk. Testicular and epididymal sperm counts were decreased in a dose-dependent manner after 3 wk; in addition, the high dose led to a decrease in epididymal sperm counts after 6 wk of treatment. Another rapidly proliferative tissue, the bone marrow, was dramatically affected by both doses of cyclophosphamide at all time points, with leukocyte counts decreasing to 40% of control by 1 wk. After 9 wk of treatment, effects on the male reproductive system were less marked, compared to earlier time points, whereas those on the hematologic system and pregnancy outcome persisted. Thus chronic low-dose treatment of male rats with cyclophosphamide not only had early and striking effects on the bone marrow and the pregnancy outcome but also affected the male reproductive system in a clear time- and dose-dependent manner.

Abnormalities, Drug-Induced↗

PubMed2002

Chronic cyclophosphamide treatment alters the expression of stress response genes in rat male germ cells.

Increases in the survival rate of men treated with chemotherapeutic drugs and their desire to have children precipitate concerns about the effects of these drugs on germ cells. Azoospermia, oligospermia, and infertility are common outcomes resulting from treatment with cyclophosphamide, an alkylating agent. Exposure of male rats to cyclophosphamide results in dose-dependent and time-specific adverse effects on progeny outcome. Elucidation of the effects of chronic low-dose cyclophosphamide treatment on the expression of stress response genes in male germ cells may provide insight into the mechanisms underlying such adverse effects. Male rats were gavaged with saline or cyclophosphamide (6 mg/kg) for 4-5 wk; pachytene spermatocytes, round spermatids, and elongating spermatids were isolated; RNA was extracted and probed on cDNA arrays containing 216 cDNAs. After saline treatment, 125 stress response genes were expressed in pachytene spermatocytes (57% of genes studied), 122 in round spermatids (56%), and 83 in elongating spermatids (38%). Cyclophosphamide treatment reduced the number of genes detected in all germ cell types. The predominant effect of chronic cyclophosphamide exposure was to decrease the expression level of genes in pachytene spermatocytes (34% of genes studied), round spermatids (29%), and elongating spermatids (4%). In elongating spermatids only, drug treatment increased the expression of 8% of the genes studied. The expression profiles of genes involved in DNA repair, posttranslational modification, and antioxidant defense in male germ cells were altered by chronic cyclophosphamide treatment. We hypothesize that the effects of cyclophosphamide exposure on germ cell gene expression during spermatogenesis may have adverse consequences on male fertility and progeny outcome.

Animals↗

PubMed1997

Identification of the polymorphically expressed CYP2C19 and the wild-type CYP2C9-ILE359 allele as low-Km catalysts of cyclophosphamide and ifosfamide activation.

Cyclophosphamide and ifosfamide are alkylating agent prodrugs that require activation by cytochrome P450 (CYP) to manifest their cancer chemotherapeutic activity. The present study investigates the activity of four individual human CYP2C enzymes and their allelic variants in cyclophosphamide and ifosfamide activation as an initial attempt to gain insight into the underlying basis for the large interpatient differences in the clinical pharmacokinetics and metabolism of these anticancer drugs. Recombinant CYP2C8, CYP2C19, two allelic variants of CYP2C18, and six variants of CYP2C9 expressed in a yeast cDNA expression system were each enzymatically active, as judged by the ability of the isolated microsomes to catalyse 7-ethoxycoumarin O-deethylation after reconstitution with purified NADPH-cytochrome P450 reductase and cytochrome b5. With cyclophosphamide as substrate, CYP2C19 had the lowest apparent Km, followed by CYP2C9, CYP2C18 and CYP2C8, whereas in the case of ifosfamide, the rank order was: Km CYP2C19 < CYP2C18 < CYP2C9 < CYP2C8. CYP2C18 had the highest in vitro intrinsic clearance/catalytic efficiency (apparent Vmax/Km) in cyclophosphamide and ifosfamide activation, followed by 2C19 > 2C9 approximately 2C8. Examination of a panel of CYP2C allelic variants revealed that CYP2C18-Thr385 had both a higher Vmax and a higher apparent Km toward cyclophosphamide than CYP2C18-Met385 with no difference in catalytic efficiency, whereas with ifosfamide the Thr385 allele exhibited a strikingly lower apparent Km resulting in a six-fold higher catalytic efficiency. In the case of CYP2C9, a Ile359 to Leu mutation associated with poor metabolism of the hypoglycemic drug tolbutamide decreased catalytic efficiency toward cyclophosphamide by increasing the apparent Km, whereas the same mutation reduced the efficiency of this P450 toward ifosfamide by decreasing the Vmax. Substitution of CYP2C9-Gly417 by Asp resulted in a two-fold lower catalytic efficiency for cyclophosphamide metabolism but a three-fold higher efficiency for ifosfamide metabolism. A His276 to Gly substitution resulted in an increase in both Vmax and apparent Km with no net change in catalytic efficiency for either oxazaphosphorine. Mutations at CYP2C9 residues 144 and 358 had little or no effect. Thus (a) wild type CYP2C19 and CYP2C9 are relatively low Km catalysts of cyclophosphamide and ifosfamide activation, and (b) all four human CYP2C enzymes activate these two anticancer prodrugs with varying efficiencies and with striking differences among naturally occurring allelic variants in the case of CYP2C9 and CYP2C18.

7-Alkoxycoumarin O-Dealkylase↗

PubMed1977

Cyclophosphamide effect on collagen metabolism in granulation tissue, skin, and aorta of rats.

Granulation tissue was produced in rats by subcutaneous implantation of viscose cellulose sponges. Cyclophosphamide 10 mg/kg was given daily intraperitoneally to 15 rats from the day of sponge implantation. Fifteen rats served as pair-fed controls, and 15 rats served as non-starved controls. After 14 days of treatment the animals were decapitated. Groups of 3 rats were given 50 muci 14C-proline intraperitoneally 1, 3, 6, 12, or 24 hours before death. The aorta, skin, and granulation tissue were examined. Cyclophosphamide caused no effect on collagen of the aorta, while in skin, the only detectable effect was a decrease in 14C-OH-proline biosynthesis. In granulation tissue, cyclophosphamide caused a fall in the dry weight, a decrease in 14C-proline uptake and 14C-OH-proline synthesis, as well as an increase in the alpha-amino nitrogen to OH-proline ratio in purified collagen. These results indicate that cyclophosphamide inhibits the synthesis of proteins, including collagen, and inhibits the hydroxylation of proline in collagen. No effect of cyclophosphamide could be detected on the amount of salt soluble OH-proline or on collagen cross-linking. The registered effects of cyclophosphamide on granulation tissue is probably of importance with regard to the anti-inflammatory action of cyclophosphamide. This action as well as the tissue differences in the sensitivity of cyclophosphamide may be of relevance to the clinical application of cytostatics in rheumatological diseases.

Animals↗

PubMed1978

Effects of different cyclophosphamide treatment schedules on collagen and collagenolytic activity in granulation tissue.

Cyclophosphamide was injected intraperitoneally into rats in doses of 6 or 10 mg/kg/day. The controls had daily intraperitoneal injections of physiological saline. After 14 days of treatment, granulation tissue was produced by subcutaneous implantation of viscose cellulose sponges. The treatment with cyclophosphamide and physiological saline was continued in different sequences for a further one or two 14-day periods. The rats were killed 14 or 28 days after the sponge implantation. Cyclophosphamide caused a decrease in body weight, in the number of leucocytes, in granuloma dry weight and in the granuloma content of free OH-proline while the water percentage increased. Ten mg/kg/day of cyclophosphamide had a more pronounced effect than 6 mg/kg/day. The results are consistent with an inhibitory effect of cyclophosphamide on granuloma formation and on the degradation of collagen. Accordingly, measurements of collagenolytic activity in granulation tissue after culture in vitro suggested an inhibition of collagenolysis after cyclophosphamide treatment. No effect of pretreatment was observed, and the effect of cyclophosphamide was independent of whether cyclophosphamide was given during the early or late phase of granulation tissue production.

Animals↗

PubMed1991

Perturbation of metabolism and disposition of cyclophosphamide by interferon and poly I:C, an interferon inducer, in mice.

The effects of interferon and poly I:C on the metabolism and disposition of cyclophosphamide were investigated in mice. Elimination of cyclophosphamide from the blood was decreased in mice treated 24 hr previously with interferon (2.5 x 10(6) U/kg, intraperitoneally) or poly I:C (10 mg/kg, intraperitoneally). The blood half-life of cyclophosphamide in interferon or poly I:C-pretreated mice was prolonged to a first order of disappearance of 29.3 and 41.6 min., respectively, compared to 19.0 min. in control mice. Also, the rate of formation of activated cyclophosphamide was delayed and the peak blood level of activated cyclophosphamide was not as high in poly I:C-pretreated and interferon-pretreated mice as in control mice. The decreased elimination and elevated blood levels of activated cyclophosphamide were reflected by changes in its antitumour activity and toxicity in the mice. In 9,000 x g supernatants prepared from the liver homogenate of mice treated with interferon or poly I:C, the oxidation of cyclophosphamide in vitro has decreased by 29 and 37%, respectively. However, the addition of these agents to normal 9,000 x g supernatant suspensions had no effect on cyclophosphamide oxidation. Modulation of the metabolism and disposition resulted from depressed levels of cytochrome P-450 in the hepatic microsomes of the mice administered interferon or poly I:C.

Animals↗

PubMed2005

Cyclophosphamide inhibition of anti-CD40 monoclonal antibody-based therapy of B cell lymphoma is dependent on CD11b+ cells.

Monoclonal antibody (mAb)-based immunotherapy is now established as an important option for treating some cancers. The antitumor effects may be further enhanced by combining mAb with conventional chemotherapy. Certain novel immunomodulatory mAbs such as anti-CD40 have shown significant activity in preclinical models. We therefore assessed the efficacy of combining anti-CD40 mAb, known to elicit CTL responses against murine lymphoma models with the commonly used cytotoxic drug, cyclophosphamide. Using the syngeneic tumor model, BCL1, we have shown that timing of cyclophosphamide relative to mAb is critical to therapeutic outcome. Pretreatment with cyclophosphamide 7 to 10 days prior to mAb results in markedly reduced survival levels, similar to that achieved with cyclophosphamide alone. Conversely, when anti-CD40 is given before cyclophosphamide, the level of tumor protection was moderately increased. In vivo tracking experiments reveal that pretreatment with cyclophosphamide leads to diminished CTL expansion, as well as an increased number of CD11b+ cells that display an activated phenotype. These latter cells are able to inhibit T-cell proliferation, at least in part via production of nitric oxide, but do not induce T-cell apoptosis. Furthermore, adoptive transfer of the induced CD11b+ cells is sufficient to inhibit anti-CD40 therapy in tumor-bearing recipients. We have shown that the timing of cyclophosphamide relative to mAb administration is critical to the therapeutic outcome, and although the combination can improve survival, cyclophosphamide given prior to immunotherapy may generate a population of myeloid cells that can interfere with CTL responses and compromise the therapeutic outcome.

Animals↗

PubMed2006

Enhanced antitumor activity of P450 prodrug-based gene therapy using the low Km cyclophosphamide 4-hydroxylase P450 2B11.

Gene therapy using the prodrug-activating enzyme P450 2B6 has shown substantial promise in preclinical and initial clinical studies with the P450 prodrugs cyclophosphamide and ifosfamide. We sought to optimize this therapy using the canine P450 enzyme 2B11, which activates cyclophosphamide and ifosfamide with Km of 80 to 160 micromol/L, approximately 10- to 20-fold lower than the Km of P450 2B6. Retrovirus encoding a P450 2B11-internal ribosome entry signal-P450 reductase expression cassette induced marked cyclophosphamide and ifosfamide cytotoxicity toward 9L gliosarcoma cells and exhibited an impressive bystander killing effect at micromolar prodrug concentrations, where P450 2B6 displayed low activity. Adeno-2B11, a replication-defective, E1/E3 region-deleted adenovirus engineered to coexpress P450 2B11 and P450 reductase, dramatically increased tumor cell-catalyzed cyclophosphamide 4-hydroxylation and cytotoxicity compared with Adeno-2B6 and effected strong bystander killing at low (20 micromol/L) cyclophosphamide concentrations. Further increases in cyclophosphamide cytotoxicity were obtained in several human cancer cell lines, including a 4-hydroperoxycyclophosphamide-resistant MCF-7 breast cancer cell line, when Adeno-2B11 was combined with Onyx-017, an E1b-55-kDa gene-deleted, tumor cell-replicating adenovirus that coamplifies and facilitates tumor cell spread of Adeno-2B11. To evaluate the therapeutic effect of P450 2B11 expression in vivo, 9L gliosarcoma cells transduced with P450-expressing retrovirus were grown as solid s.c. tumors in immunodeficient mice. Cyclophosphamide treatment on a metronomic, 6-day repeating schedule led to full regression of 9L/2B11 tumors but not P450-deficient control tumors, resulting in a tumor-free period lasting up to approximately 100 days. 9L/2B6 tumors regressed more slowly and exhibited a tumor-free period of only 21 to 39 days. Thus, P450 gene-directed enzyme prodrug therapy can be greatly improved by using the low Km P450 enzyme 2B11, which catalyzes intratumoral activation of cyclophosphamide and ifosfamide at pharmacologically relevant drug concentrations.

Adenoviridae↗

PubMed1986

Cyclophosphamide modulation of bronchoalveolar cellular populations and macrophage oxidative metabolism. Possible mechanisms of pulmonary pharmacotoxicity.

Cyclophosphamide, an immunosuppressive alkylating agent, has been reported to cause acute and chronic pulmonary injury in both humans and animals. Cyclophosphamide is also a common component of multi-drug regimens that show high pulmonary toxic potential. Although mechanisms of pulmonary damage caused by cyclophosphamide or other cytotoxic agents are unknown, possibilities include direct toxicity to pulmonary tissue or indirect toxicity through activation of pulmonary inflammatory cells. We report here a model system for the study of acute effects of cyclophosphamide on pulmonary immune cells in rats. Our findings show that 16 h after 1 intraperitoneal dose of cyclophosphamide there is: a dose dependent release of locally produced low molecular weight chemotactic factors for blood monocytes into bronchoalveolar lavage (BAL) fluid, a pulmonary influx of immature myeloperoxidase positive macrophages in low dose cyclophosphamide treated animals, an enhancement of oxidant generation by pulmonary macrophages from low dose treated animals that correlates with the presence of myeloperoxidase positive macrophages, the presence of factors in BAL fluid of treated rats that modulate oxidant release by normal rat pulmonary macrophages, a dose dependent reduction in the percentage of BAL lymphocytes, and evidence for pulmonary injury as manifested by elevated BAL fluid albumin concentrations in low dose cyclophosphamide treated animals. These findings suggest that cyclophosphamide may induce pulmonary injury through activation of pulmonary immunocompetent cells and subsequent attraction of systemic inflammatory cells.

Albumins↗

PubMed1994

Cyclophosphamide-induced facial discomfort.

OBJECTIVE: To report the occurrence of cyclophosphamide-induced facial discomfort in patients at our institution, to review previous literature reports, and to discuss possible methods of prevention. SETTING: An oncology clinic in a university teaching hospital. PATIENTS: From January 1990 to March 1993, 14 patients experienced uncomfortable sensations of the skin or mucous membranes associated with cyclophosphamide administration. Details pertaining to each patient are described. INTERVENTIONS: Initial interventions included changing the duration of infusion or concentration of cyclophosphamide. We postulated that an anticholinergic medication such as ipratropium bromide may prevent cyclophosphamide-induced facial discomfort. MAIN OUTCOME MEASURES: Changing the infusion duration or cyclophosphamide concentration or administering ipratropium bromide intranasally resulted in variable degrees of improvement. CONCLUSIONS: The number of cyclophosphamide reactions seen at our institution indicates that facial or scalp burning, oropharyngeal tingling, nasal congestion, rhinorrhea, sneezing, and/or lacrimation may occur more frequently than previously noted. Thus, careful questioning is necessary to determine whether these clinical symptoms are present and bothersome in patients treated with cyclophosphamide. Intranasal ipratropium bromide, as well as other measures to prevent or decrease the intensity of cyclophosphamide-induced facial discomfort should be investigated.

Aged↗

PubMed2002

Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation.

Liver toxicity caused by high-dose myeloablative therapy leads to significant morbidity after hematopoietic cell transplantation. We examined the hypothesis that liver toxicity after cyclophosphamide and total body irradiation is related to cyclophosphamide through its metabolism to toxins. Cyclophosphamide was infused at 60 mg/kg over 1 to 2 hours on each of 2 consecutive days, followed by total body irradiation. Plasma was analyzed for cyclophosphamide and its major metabolites. Liver toxicity was scored by the development of sinusoidal obstruction syndrome (veno-occlusive disease) and by total serum bilirubin levels. The hazards of liver toxicity, nonrelapse mortality, tumor relapse, and survival were calculated using regression analysis that included exposure to cyclophosphamide metabolites (as the area under the curve). Of 147 patients, 23 (16%) developed moderate or severe sinusoidal obstruction syndrome. The median peak serum bilirubin level through day 20 was 2.6 mg/dL (range, 0.5-41.1 mg/dL). Metabolism of cyclophosphamide was highly variable, particularly for the metabolite o-carboxyethyl-phosphoramide mustard, whose area under the curve varied 16-fold. Exposure to this metabolite was statistically significantly related to sinusoidal obstruction syndrome, bilirubin elevation, nonrelapse mortality, and survival, after adjusting for age and irradiation dose. Patients in the highest quartile of o-carboxyethyl-phosphoramide mustard exposure had a 5.9-fold higher risk for nonrelapse mortality than did patients in the lowest quartile. Engraftment and tumor relapse were not statistically significantly related to cyclophosphamide metabolite exposure. Increased exposure to toxic metabolites of cyclophosphamide leads to increased liver toxicity and nonrelapse mortality and lower overall survival after hematopoietic cell transplantation.

Adolescent↗