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PubMed1999

Cyclophosphamide, cytosine arabinoside and TBI as a conditioning regimen for allogeneic bone marrow transplantation in patients with leukemia.

This is a prospective study designed to determine the toxicity, efficacy and antileukemic effect of high-dose cytosine arabinoside (ara-C), cyclophosphamide and total body irradiation (TBI) as a myeloablative regimen prior to allogeneic bone marrow transplantation for patients with hematologic malignancies. Fifty-eight patients with hematologic malignancies were treated with cyclophosphamide, high-dose ara-C and total body irradiation (TBI) followed by allogeneic bone marrow transplantation. Fifty patients had good prognosis disease and eight had poor prognosis disease. Cyclosporine and short-course methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. The conditioning regimen consisted of ara-C 3000 mg/m2 twice a day x six doses on days -7, -6, and -5; cyclophosphamide 1800 mg/m2 on days -4 and -3; and TBI 1400 cGy midline dose at 5 cGy/min in eight total fractions administered twice a day on days -4, -3, -2, and -1. The bone marrow was infused on day 0 (zero). Toxicity related to the conditioning regimen was comparable to that reported with other conditioning regimens, except for diarrhea which appears to be more frequent. The actuarial survival at 1 year was 69% (58-82) and at 5 years was 54% (42-69) with the numbers in parentheses representing the 95% confidence interval of the Kaplan-Meier estimate. After a median follow-up of 28 months, 31 of 58 (53%) patients are alive without evidence of disease. Only four of the 58 patients (7%) have relapsed. Cyclophosphamide, ara-C and TBI is a safe and effective myeloablative regimen for patients with leukemia. The overall relapse rate in our study was 7% with a median follow-up of 28 months and appears to be lower than relapse rates reported in other series. This is probably due to the added antileukemic effect of ara-C. This regimen should be compared with other myeloablative regimens in a controlled study.

Adolescent↗

PubMed2003

G-CSF alone vs cyclophosphamide plus G-CSF in PBPC mobilization of patients with lymphoma: results depend on degree of previous pretreatment.

We performed a randomized study to compare 'G-CSF alone' (administered at dose of 10 mcg/kg/day) and 'cyclophosphamide plus G-CSF' (cyclophosphamide at dose of 4 g/m(2) and G-CSF at dose of 10 microg/kg/day), as PBPC mobilization schedules in 52 patients with NHL or HD. Randomization was stratified according to the amount of previous chemotherapy (< or =2 and >2 lines of previous chemotherapy). Mean CD34+ cell peak in P.B., mean 'Total CD34+ cells' harvested and percentage of patients successfully mobilized, in the group mobilized with 'G-CSF alone' vs the group mobilized with 'cyclophosphamide plus G-CSF', were: 35.3 x 10(6) vs 45.8 x 10(6)/l (P=0.3), 5.4 x 10(6) vs 6.8 x 10(6)/kg (P>0.9) and 50 vs 61% (P=0.4). No differences were observed in the stratum of less pretreated patients. However, in the stratum of patients who had previously received more than two lines of chemotherapy, CD34+cell peak (P=0.05) and percentage of successful mobilization (P=0.01) were higher when 'cyclophosphamide plus G-CSF' was used. Using logistic regression, both age and mobilization with 'G-CSF alone' were significantly associated with a low CD34+ cell peak in P.B. However, in the stratum of less pretreated patients, only age was significantly associated with this risk.

Adult↗

PubMed2006

Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis. A randomized controlled trial.

Until recently, intravenous cyclophosphamide pulses with oral corticosteroids were regarded standard therapy for proliferative lupus nephritis (LN). Azathioprine, a less toxic alternative, was never proven to be inferior. In the first Dutch lupus nephritis study (enrollment between 1995 and 2001), we randomized 87 proliferative LN patients to either cyclophosphamide pulses (750 mg/m(2), 13 pulses in 2 years) combined with oral prednisone (CY) or to azathioprine (2 mg/kg/day in 2 years) combined with intravenous pulses of methylprednisolone (3 x 3 pulses of 1000 mg) and oral prednisone (AZA). After a median follow-up of 5.7 years (interquartile range 4.1-7.2 years), doubling of serum creatinine was more frequent in the AZA group, although not statistically significant (relative risk (RR): 4.1, with 95% confidence interval (95% CI): 0.8-20.4). Relapses occurred more often in the AZA group (RR: 8.8, 95% CI: 1.5-31.8). Creatinine and proteinuria at last visit did not differ between the two treatment arms. Moreover, 88.4% of the patients in the AZA arm were still free of cyclophosphamide treatment. During the first 2 years, the frequency of remission was not different, but infections, especially herpes zoster virus infections (HZV) were more frequent in the AZA group. Parameters for ovarian function did not differ between the two groups. In conclusion, in this open-label randomized controlled trial, cyclophosphamide was superior to azathioprine with regard to renal relapses and HZV. At last follow-up, there were no differences in serum creatinine or proteinuria between the two groups. However, since our study lacked sufficient power, longer follow-up is needed to reveal putative differences.

Administration, Oral↗

PubMed1997

Stem cell mobilization in resistant or relapsed lymphoma: superior yield of progenitor cells following a salvage regimen comprising ifosphamide, etoposide and epirubicin compared to intermediate-dose cyclophosphamide.

We analysed the factors influencing the efficacy of peripheral blood stem cell (PBSC) collection in patients with lymphoma. Sixty-six patients underwent initial PBSC collection following mobilization with chemotherapy plus recombinant granulocyte colony-stimulating factor (300 microg/d). Patients were mobilized with one of two chemotherapy regimens, either cyclophophamide (3 g/m2 or 4 g/m2) (n = 50) or ifosphamide, etoposide and epirubicin (IVE; n = 16). The target of collecting > 2.0 x 10(6) CD34+ cells/kg was achieved in 43/66 (65%) patients with a median of two apheresis procedures. The IVE plus G-CSF mobilization regimen gave a significantly higher median yield of CD34+ cells (8.62 x 10(6)/kg) compared with cyclophosphamide plus G-CSF (3.59 x 10(6)/kg) (P = 0.045). The median yield of CD34+ cells per leukapheresis was almost twice as high in patients receiving IVE (1.94 x 10(6)/kg) compared to cyclophosphamide (1.03 x 10(6)/kg) (P = 0.035). In a univariate analysis of the factors affecting mobilization, the subtype of lymphoma (high-grade NHL) and the mobilization regimen were the only factors associated with high CD34+ cell yield. However, in a multivariate analysis of factors affecting mobilization including age, lymphoma subtype, previous chemotherapy and radiotherapy, only the use of the IVE protocol was predictive of a high yield of CD34+ cells. In 13 patients undergoing a second mobilization procedure the use of IVE was associated with a significantly higher yield of CD34+ cells compared to cyclophosphamide; three patients who failed cyclophosphamide plus G-CSF mobilization were able to proceed to transplantation following successful mobilization with IVE + G-CSF. These results demonstrate that IVE is a highly effective mobilization regimen which is superior to cyclophophamide and has the benefit of being effective salvage therapy for lymphoma patients.

Adult↗

PubMed2003

Localized non-Hodgkin's lymphoma with B-cell histology: cure without cyclophosphamide? A report of the United Kingdom Children's Cancer Study Group on studies NHL 8501 and NHL 9001 (1985-1996).

We have examined the outcome for children treated on two consecutive United Kingdom Children's Cancer Study Group studies of localized B-cell non-Hodgkin's lymphoma (NHL). The first study (NHL 8501; 1985-1989) included cyclophosphamide in the treatment regimen at a total cumulative dose of 4 g/m2 whereas the regimen in the succeeding study (NHL 9001; 1990-1996) did not include cyclophosphamide. Ninety children with confirmed B-cell NHL were treated in the two studies (NHL 8501, n = 33 and NHL9001, n = 57). With a median follow-up of 7.5 years, overall survival for localized B-cell NHL did not differ between the two regimens with observed 3-year survivals of 94%[95% confidence interval (CI) 80-98%] and 89% (95% CI 79-95%) respectively (P = 0.47). There was also no difference in the event-free survival between children treated on regimen NHL 8501 and NHL 9001 [91% (95% CI 76-97%) vs 84% (95% CI 73-92%) after 3 years; P = 0.34]. Although the difference in the number of failed remissions between NHL 8501 and 9001 (0/33 vs 6/57) approached statistical significance (P = 0.08, Fisher's exact test), there was no overall statistical difference between the treatment failures on either regimen (P = 0.34). Substantial long-term survival can be achieved for many children with localized B-cell NHL without the use of cyclophosphamide. Further studies are needed to identify whether all clinical or histopathological subgroups will benefit equally from the omission of cyclophosphamide.

Adolescent↗

PubMed1996

Bladder augmentation in the prevention of cyclophosphamide-induced haemorrhagic cystitis in the rat model.

OBJECTIVE: To evaluate the effects of cyclophosphamide on the bowel mucosa of the rat and to determine whether urothelium can be protected from the effects of haemorrhagic cystitis which can occur after treatment with cyclophosphamide. MATERIALS AND METHODS: Thirty Sprague-Dawley rats were divided into three groups, 10 undergoing a control (sham) operation, 10 an ileal bladder augmentation and 10 a colonic bladder augmentation. Each rat underwent the appropriate surgical procedure and after a recovery period of 2 weeks, was injected with cyclophosphamide. Urine specimens were collected 24 h after the injection and analysed for gross and microscopic haematuria. The rats were killed humanely 48 h after injection and the bladders examined for haemorrhage, oedema, attenuation, inflammation and erosion. RESULTS: None of the 20 augmented rats developed gross haematuria and only four developed microscopic haematuria, compared with the control rats where six of 10 developed gross haematuria and nine developed microscopic haematuria. In addition, the control rats had moderate to severe haemorrhage, oedema and attenuation compared with only mild changes in the augmented rats. This protection was significant for both the bowel mucosa and urothelium. CONCLUSIONS: It is possible that the administration of cyclophosphamide in patients with urinary diversion carries little risk of haemorrhagic cystitis. We propose that this protective mechanism is secondary to a substance secreted by the intestinal mucosa that may bind acrolein and render it inactive. Alternatively, this may be secondary to the production of mucus and its ability to coat and protect the epithelium.

Animals↗

PubMed2001

High-dose paclitaxel in combination with doxorubicin, cyclophosphamide and peripheral blood progenitor cell rescue in patients with high-risk primary and responding metastatic breast carcinoma: toxicity profile, relationship to paclitaxel pharmacokinetics and short-term outcome.

We assessed the feasibility and pharmacokinetics of high-dose infusional paclitaxel in combination with doxorubicin, cyclophosphamide, and peripheral blood progenitor cell rescue. Between October 1995 and June 1998, 63 patients with high-risk primary [stage II with >or= 10 axillary nodes involved, stage IIIA or stage IIIB inflammatory carcinoma (n = 53)] or with stage IV responsive breast cancer (n = 10) received paclitaxel 150-775 mg/m(2)infused over 24 hours, doxorubicin 165 mg/m(2)as a continuous infusion over 96 hours, and cyclophosphamide 100 mg kg(-1). There were no treatment-related deaths. Dose-limiting toxicity was reversible, predominantly sensory neuropathy following administration of paclitaxel at the 775 mg/m(2) dose level. Paclitaxel pharmacokinetics were non-linear at higher dose levels; higher paclitaxel dose level, AUC, and peak concentrations were associated with increased incidence of paraesthesias. No correlation between stomatitis, haematopoietic toxicities, and paclitaxel dose or pharmacokinetics was found. Kaplan-Meier estimates of 30-month event-free and overall survival for patients with primary breast carcinoma are 65% (95% CI; 51-83%) and 77% (95% CI; 64-93%). Paclitaxel up to 725 mg/m(2) infused over 24 hours in combination with with doxorubicin 165 mg/m(2) and cyclophosphamide 100 mg kg(-1) is tolerable. A randomized study testing this regimen against high-dose carboplatin, thiotepa and cyclophosphamide (STAMP V) is currently ongoing.

Adult↗

PubMed2001

Salvage chemotherapy with high-dose leucovorin (LV) and 48-hour continuous infusion (CI) of 5-fluorouracil (5-FU) in combination with conventional doses of cyclophosphamide (CPM) in patients with metastatic breast cancer (MBC) pretreated with anthracycline and taxanes.

The purpose of this study was to evaluate the activity and tolerance of high-dose leucovorin (LV) and infusional 5-fluorouracil (5-FU) in combination with conventional doses of cyclophosphamide (CPM) as salvage chemotherapy in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. 41 patients (median age 59 years) with MBC refractory or resistant to anthracyclines and taxanes were enrolled. The patients' performance status (WHO) was 0 in 10 patients (24%), 1 in 22 (54%), and 2 in 9 (22%). 30 (73%) patients had received 2 or more prior chemotherapy regimens. Cyclophosphamide (600 mg m(-2)) was given i.v. bolus on day 1 and LV (500 mg m(-2) d(-1)) as a 2-h infusion followed by 5-FU (1.5 g m(-2) d(-1)) over a 22 h c.i. for 2 consecutive days. Cyclophosphamide was administered every 28 days while 5-FU/LV every 14 days. In an intention-to-treat analysis, complete response (CR) was achieved in 2 (4.9%) patients and partial response (PR) in 9 (22%) (overall response rate 26.9%; 95% CI: 13.27-40.39%). Stable disease (SD) and progressive disease (PD) were observed in 9 (22%) and 21 (51%) patients, respectively. The overall response rate was 6% and 40% in patients with primary and secondary resistance to anthracyclines/taxanes, respectively (P = 0.047). The median duration of response and the median time to disease progression was 8 and 9.5 months, respectively. The median overall survival was 13 months and the probability for 1-year survival 51%. Grade 3/4 neutropenia occurred in 9 (22%) patients and 4 (9%) patients developed grade 3/4 thrombocytopenia. Non-haematological toxicity was mild. There were no cases of febrile neutropenia, toxic deaths or treatment-related hospital admissions due to toxicity. The combination of high-dose 5-FU/LV with conventional doses of cyclophosphamide is a well tolerated and effective salvage regimen in patients with MBC heavily pretreated with both anthracyclines and taxanes.

Adolescent↗

PubMed1993

[Cyclophosphamide bolus therapy in lupus nephritis].

A pilot study of 21 patients (17 women; 4 men; mean age 35 [18-59] years), randomized into two groups, was undertaken to test how many cycles of intravenous pulse cyclophosphamide administration were required in lupus nephritis to achieve remission. It was planned that patients randomized to group A should be treated for 3 months, those in group B for over 12 months. In the first cycle the cyclophosphamide dosage was 500 mg/m2, in the subsequent cycles, 4 weeks apart, it was raised by 250 mg/m2 to a maximum of 1,000 mg/m2, if the WBC count was over 2,000/microliters. Three women in group B gave up treatment prematurely after 5-8 cycles, because a remission had occurred. In group A only one patient went into remission after only three cycles. Of the total of 18 patients in both groups whose data could be evaluated, 15 achieved remission after an average of 7.3 cycles and a cumulative total cyclophosphamide dosage of 9.3 g. The disease progressed in two patients, one died. No recurrence has so far been observed after a follow-up period of 1-41 months. Three patients had infections and two had developed leukopenia as side effects. Pulse cyclophosphamide has thus been shown to be an effective treatment in lupus nephritis, but it must be continued for more than 3 months.

Adolescent↗

PubMed1975

Carcinoma of the urinary bladder in patients receiving cyclophosphamide.

Hemorrhagic cystitis is a common side effect of cyclophosphamide therapy not observed with other alkylating agents. In five patients receiving cyclophosphamide by mouth for prolonged periods with large cumulative dosage urinary-bladder tumors fatal to four and requiring cystectomy in the lone survivor developed. These observations strongly suggest chemical carcinogenicity of this drug in the production of these tumors. Increasingly, cyclophosphamide is being used for non-neoplastic disease. These circumstances suggest careful follow-up observation of patients in whom hemorrhagic cystitis from this drug develops for evidence of bladder cancer, as well as restraint in use of cyclophosphamide for non-neoplastic diseases if alternative therapy is available.

Administration, Oral↗

PubMed1983

Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide.

Fifty-one patients with acute nonlymphocytic leukemia (16 with end-stage disease, 17 in second or third remission or in early relapse, and 18 in first remission) were given infusions of HLA-identical sibling marrow after cytoreduction with high doses of busulfan and cyclophosphamide. Actuarial two-year survival rates were 0 per cent, 29 per cent, and 44 per cent, respectively. Twelve patients are still alive and in remission after 327 to 1488 days, with 10 surviving beyond two years. Acute graft-versus-host disease and viral pneumonia were the major causes of death. Leukemic cells failed to clear in one patient with end-stage disease, and a relapse with meningeal leukemia occurred in another. Only one other relapse was seen--in a patient given a transplant during a third remission. Survival was favorably affected by younger age and transplantation during first remission. We conclude that high-dose chemotherapy with busulfan and cyclophosphamide, followed by allogeneic-marrow transplantation, can produce long-term remission of acute leukemia. Chemotherapy with high-dose busulfan and cyclophosphamide before transplantation provides an effective alternative to cyclophosphamide and total-body irradiation before transplantation for the treatment of acute nonlymphocytic leukemia.

Acute Disease↗

PubMed1996

Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer.

BACKGROUND: Chemotherapy combinations that include an alkylating agent and a platinum coordination complex have high response rates in women with advanced ovarian cancer. Such combinations provide long-term control of disease in few patients, however. We compared two combinations, cisplatin and cyclophosphamide and cisplatin and paclitaxel, in women with ovarian cancer. METHODS: We randomly assigned 410 women with advanced ovarian cancer and residual masses larger than 1 cm after initial surgery to receive cisplatin (75 mg per square meter of body-surface area) with either cyclophosphamide (750 mg per square meter) or paclitaxel (135 mg per square meter over 24 hours). RESULTS: Three hundred eighty-six women met all the eligibility criteria. Known prognostic factors were similar in the two treatment groups. Alopecia, neutropenia, fever, and allergic reactions were reported more frequently in the cisplatin-paclitaxel group. Among 216 women with measurable disease, 73 percent in the cisplatin-paclitaxel group responded to therapy, as compared with 60 percent in the cisplatin-cyclophosphamide group (P = 0.01). The frequency of surgically verified complete response was similar in the two groups. Progression-free survival was significantly longer (P < 0.001) in the cisplatin-paclitaxel group than in the cisplatin-cyclophosphamide group (median, 18 vs. 13 months). Survival was also significantly longer (P < 0.001) in the cisplatin-paclitaxel group (median, 38 vs. 24 months). CONCLUSIONS: Incorporating paclitaxel into first-line therapy improves the duration of progression-free survival and of overall survival in women with incompletely resected stage III and stage IV ovarian cancer.

Adult↗

PubMed2004

Intravenous cyclophosphamide for lupus nephritis in Thai children.

OBJECTIVE: To evaluate the efficacy of a 36-month course of intravenous cyclophosphamide therapy for severe lupus nephritis in Thai children between October 1993 and December 2000. METHODS: Intravenous cyclophosphamide combined with oral prednisolone was given for 36 months to patients with systemic lupus erythematosus (SLE) who had severe renal involvement. Serum creatinine (Cr), creatinine clearance (CCr), urinary protein, C3, and complete blood count (CBC) were measured each visit for intravenous cyclophosphamide. Repeated measures ANOVA and Kaplan-Meier survival analysis were used. RESULTS: Of 21 patients enrolled in the study, three died and two were lost to follow-up, leaving 16 patients who completed therapy (13 females and three males) with age at diagnosis 12.1+/-2.3 years (range 7.2-20.6 years). The follow-up period was 6.3+/-2.3 years (range 3.3-13.8 years). Fourteen patients had lupus nephritis WHO classification class IV and two had lupus nephritis WHO classification class II. Hypertension was detected in ten patients. Lowess smoothing curves and repeated measures ANOVA indicated no significant change in Cr and CCr [probability (p) > 0.05)], but significantly increased C3 and haemoglobin and significantly decreased urinary protein and white blood cell count (p < 0.001). Five patients had six episodes of acute renal failure; one died, renal function returned to normal in two patients, two continued to chronic renal failure, and one died of chronic renal failure. The 5-year survival and renal survival were 86.5% and 87.5% (95% CI 55.8-96.5% and 58.6-96.7%), respectively. CONCLUSION: Intravenous cyclophosphamide in severe lupus nephritis in Thai children showed a satisfactory outcome with minimal complications. Further follow-up is needed.

Acute Kidney Injury↗

PubMed1977

Mutagenic activity of major mammalian metabolites of cyclophosphamide toward several genes of Escherichia coli.

Representative intermediates of the major mammalian metabolic pathway of cyclophosphamide, a drug that is not mutagenic as such unless it is metabolically activated, were assayed for their direct mutagenic activity toward a bacterial indicator strain, Escherichia coli 343/113. The compounds tested were 4-hydroperoxycyclophosphamide and the two urinary metabolites, carboxyphosphamide and 4-ketocyclophosphamide. Further, the degradation products of 4-hydroxycyclophosphamide, phosphoramide mustard, acrolein, and nornitrogen mustard, were also tested. The mutagenicity test systems were those used previously to demonstrate the liver enzyme-mediated mutagenic activity of cyclophosphamide in E. coli 343/113: stationary cell suspensions were treated for 180 min at 37 degrees C with different concentrations of the compound under test; the induction of forward mutations from 5-methyltryptophan sensitivity to resistance (MTR) and from galRs18 to gal+ as well as back mutations from arg56 to arg+ was measured by plating aliquots of the treated bacterial population on different selective mutation media. Except for acrolein, all cyclophosphamide metabolites tested are directly mutagenic toward E. coli 343/113. With all substances the highest induced mutation frequency is that of arg+ mutations, followed by gal+ and MTR mutations; this indicates that mostly base-pair substitution type mutations are induced. The mutagenic potential, however, differs greatly between compounds at concentrations between 0.1 and 20mM. The results show that the first step in the mammalian biodegradation of cyclophosphamide gives rise to compounds that are directly mutagenic, and that this mutagenicity is retained and even enhanced through all further metabolic steps to produce the compound of highest mutagenicity, nornitrogen mustard.

Alkylating Agents↗

PubMed1987

Antispermatogenic effects of cyclophosphamide in the Syrian hamster.

Cyclophosphamide is an alkylating antineoplastic drug and has been shown to impair spermatogenesis after chronic exposures. The purpose of this investigation was to determine the effect of cyclophosphamide on sperm production in hamsters following subacute intraperitoneal (ip) exposures. The Syrian hamster, Mesocricetus auratus, aged 10-11 wk, received single daily ip doses for 4 d ranging from 10 to 250 mg cyclophosphamide/kg body weight. Control hamsters received an equivalent volume of phosphate-buffered saline solution. Testis weight, caudal sperm number, and sperm morphology were monitored for 12 wk. Cyclophosphamide failed to induce sperm abnormalities. Testis weight and sperm count were slightly suppressed at wk 1 and 4 before returning to normal at wk 12. This study showed that subacute doses of cyclophosphamide in hamsters did not significantly affect the sperm production as previously reported in other animals.

Animals↗

PubMed1967

Resistance of long-lived lymphocytes and plasma cells in rat lymph nodes to treatment with prednisone, cyclophosphamide, 6-mercaptopurine, and actinomycin D.

The cells of the popliteal lymph nodes of rats were labeled for 4 days after a secondary immunological stimulus. 31 days after the last dose of tritiated thymidine, groups of rats were started on courses of daily, intraperitoneal injections of prednisone, cyclophosphamide, 6-mercaptopurine, or actinomycin D. The initially low doses of these agents were doubled in successive weeks until either lymphoid hypoplasia or death occurred. Rats from each group were killed weekly, and the percentages of persisting, labeled small lymphocytes in the popliteal nodes were determined. Sections of these nodes were examined for persisting, labeled plasma cells. The per cent of lymphocytes labeled increased while the total number of lymphocytes decreased during treatment with prednisone and cyclophosphamide. Prednisone decreased the numbers of long-lived plasma cells, but these cells were preferentially resistant to cyclophosphamide. Neither 6-mercaptopurine nor actinomycin D had an appreciable effect on lymphoid tissues histologically nor on the proportions of labeled, long-lived lymphocytes and plasma cells before causing the deaths of the rats receiving them. These results indicate that long-lived lymphocytes and plasma cells survive treatment with the immunolytic drugs studied, and that long-lived lymphocytes are specifically resistant to prednisone and cyclophosphamide. We believe these results have an application to the attempts to find drugs useful in the treatment of immunologic rejections of organ transplants, and for therapy of autoimmune diseases.

Animals↗

PubMed1976

Genetic control of specific immune suppression. IV. Responsiveness to the random copolymer L-glutamic acid50-L-tyrosine50 induced in BALB/c mice by cyclophosphamide.

Previous reports from our laboratory have demonstrated the stimulation of specific suppressor T cells in genetic nonresponder mice after immunization with the terpolymer of L- glutamic acid, L-alanine, and L-tyrosine (GAT) (1,2) and with the copolymer of L-glutamic acid and L-tyrosine (GT) (3-5). These findings raise two important questions: (a) do the specific suppressor T cells inhibit an antibody response which would otherwise develop in nonresponder mice; and, (b) can specific helper T cells inhibit an antibody response which would otherwise develop in nonresponder mice; and, (b) can specific helper T-cell activity be detected in these animals. Responsiveness appears to be completely dominant over suppression in (responder x suppressor)F(1) hybrids, therefore, we have been unable to detect suppressor cells in these hybrids after conventional immunization with GAT (2). However , using special conditions of antigen administration, GAT helper activity could be demonstrated in nonresponder DBA/1 ("suppressor") mice. Thus, GAT-specific helper activity was not detected in these nonresponder animals after immunization with GAT irrespective of the adjuvant used, but could be stimulated by macrophage-bound GAT or by GAT complexed with methylated bovine serum albumin GAT-MBSA (6). In the current report we have taken advantage of the fact that suppressor T-cell activity is more sensitive to cyclophosphamide treatment than T-cell helper activity (7) to demonstrate the presence of GT-specific helper activity in "nonresponder" BALB/c mice. We describe: (a) the dose of cyclophosphamide and conditions of treatment which inhibits the well-documented stimulation of specific suppressor T cells in BALB/c mice injected with GT previous to immunization with GT-MBSA, and (b) the ability of cyclophosphamide to permit the development of primary PFC responses to GT in these "nonresponder" mice. These cyclophosphamide-induced responses are not characterized by the high levels of antibody detected in genetic responder animals.

Animals↗

PubMed1979

Regulation of specific cell-mediated cytotoxic response against SV40-induced tumor associated antigens by depletion of suppressor T cells with cyclophosphamide in mice.

When cyclophosphamide was administered to mice before immunization with syngeneic SV40 transformed cells, the specific immune response elicited, as was measured by in vitro 51Cr release assay was stronger and lasted longer when compared to the response generated in noncyclophosphamide-treated mice. The augmentation effect of the drug was dependent on cyclophosphamide concentration being optimal at 100 mg/kg and on the time of drug administration in relation to antigen immunization being optimal at 2 d before antigen administration. Transfer of T cells from normal syngeneic mice to drug-treated animals abolished the cyclophosphamide-induced augmentation of immune response. These results implied that cyclophosphamide sensitive T cells suppressed the in vivo generation of specific effector T cells against SV40-induced tumor-associated antigens.

Animals↗