Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “CYCLOPHOSPHAMIDE”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,585 records · Page 88Linked to original sources
PubMed1992

Progression and remission of renal disease in the Lupus Nephritis Collaborative Study. Results of treatment with prednisone and short-term oral cyclophosphamide.

OBJECTIVE: To describe the clinical course of severe lupus nephritis and to identify the risk factors for progression to renal failure among patients treated with prednisone and short-term courses of low-dose oral cyclophosphamide. DESIGN: Ancillary analyses of data from the Lupus Nephritis Collaborative Study (LNCS). SETTING: University hospital medical centers (14). PATIENTS: The 86 patients who participated in the LNCS (mean follow-up, 136 weeks [2.6 years]) and a subgroup of 63 patients with follow-up of more than 48 weeks (mean follow-up, 160 weeks [3.1 years]). MEASUREMENTS: Initial clinical and pathologic features, response to therapy within 48 weeks, and subsequent clinical events, including development of renal failure. MAIN RESULTS: Renal failure developed in 18 patients (21%). An observed elevation in serum creatinine concentration was the only initial feature predictive of subsequent renal failure. Mean (+/- SD) initial serum creatinine levels were higher in patients who subsequently developed renal failure (244 +/- 134 mumol/L [2.76 +/- 1.52 mg/dL] compared with 163 +/- 103 mumol/L [1.85 +/- 1.17 mg/dL]; P = 0.007). The risk for renal failure was higher among patients with initial serum creatinine levels greater than 106 mumol/L (1.2 mg/dL) (29% compared with 6.5%; P = 0.014). Response to therapy (defined as resolution of initial serum creatinine elevations within 48 weeks) refined the prognosis based on initial serum creatinine determinations. The risk for subsequent renal failure was higher among patients who failed to respond to therapy within 48 weeks (30% compared with 0%; P = 0.015). By comparison, 9% of patients with normal initial serum creatinine levels progressed to renal failure after 48 weeks. CONCLUSIONS: Initial serum creatinine levels and responses to initial therapy with prednisone and short-term cyclophosphamide, as used in the LNCS, can guide further therapy. Patients with normal initial serum creatinine levels or resolution of initial serum creatinine elevations within 48 weeks have a low risk for renal failure and may not require long-term treatment with cyclophosphamide.

Administration, Oral↗
PubMed1998

[A case of protein-losing gastroenteropathy in association with mixed connective tissue disease which was successfully treated with cyclophosphamide pulse therapy].

A 47-year-old man had been given a diagnosis of mixed connective tissue disease (MCTD) on 1987 when he had presented with Raynaud's phenomenon, polyarthralgia, sclerodactyly, and a high titre of anti-RNP antibody. Once his symptoms had improved following the administration of prednisolone orally and the treatment was discontinued since 1995. He noticed dyspnea and chest pain in February 1997. The bilateral pleural effusion was pointed out in the local hospital and he was admitted to our hospital in March 1997 for further examination. In addition to pleural effusion and ascites, laboratory studies revealed hypoalbuminemia and low serum levels of complements. Renal and liver function tests were normal and the urine gave a trace test for protein. The presence of protein loss in the gut was confirmed by an elevated alpha 1-antitrypsin clearance and 99mTc-albumin scintigraphy showing abnormal radioactivity in the gastrointestinal tract. Although endoscopic examination showed no abnormal findings macroscopically and gastrointestinal biopsies revealed nonspecific inflammation only, immunofluorescent studies demonstrated deposits of C 3, C 4 and IgG in the stomach, colon, and pleura. These findings supported the pathogenesis that immune deposits in tissues caused protein-losing gastroenteropathy (PLGE) in MCTD. Intravenous administration of cyclophosphamide started since July 1997, while the high-dose corticosteroid therapy including methylprednisolone pulse therapy were not effective. Hypoalbuminemia and low serum levels of complements improved remarkably and the pleural effusion and ascites disappeared after cyclophosphamide pulse therapy four times monthly. Cyclophosphamide pulse therapy should be considered as a possibly effective treatment for PLGE in association with collagen disease resistant to corticosteroid therapy.

Cyclophosphamide↗
PubMed1976

Cyclophosphamide and CCNU in the treatment of inoperable small cell carcinoma and adenocarcinoma of the lung.

Two hundred and fifty-eight patients with small cell carcinoma and 185 patients with adenocarcinoma were centrally randomized to receive either cyclophosphamide (1000 mg/m2 every 3 weeks) iv or cyclophosphamide (700 mg/m2 every 3 weeks) iv plus CCNU (70 mg/m2 every 6 weeks) orally. Those patients who were initially treated with the single agent were then treated with CCNU (130 mg/m2 every 6 weeks) at the time of cyclophosphamide failure. Objective tumor regression occurred more frequently with the combination regimen in patients with small cell carcinoma (43% vs 22%, P = 0.002), but no difference in response rates was apparent in patients with adenocarcinoma. In both cell types patients survived somewhat longer following treatment with the combination. The overall incidence of severe toxicity was equal for the two regimens in both cell types; however, the therapeutic index of the combination was superior to that of the single agent in small cell carcinoma. Severe drug toxicity was more frequent in small cell carcinoma patients with extensive disease, and survival was reduced in both cell types with extensive disease. Survival was better for ambulatory patients in both cell types and women survived longer than men. In women with small cell carcinoma, ambulatory status also was associated with a higher incidence of tumor regression. In patients with small cell carcinoma those who had prior lung surgery survived longer than those without prior surgery. Previous radiation therapy was associated with a reduced incidence of objective regression in men with small cell carcinoma. In both cell types patients with tumor regression lived longer than nonresponders; however, objective disease stability was associated with improved survival only in patients with adenocarcinoma. Stratification in future studies should consider extent of disease, performance status, sex, and prior therapy.

Adenocarcinoma↗
PubMedDate not supplied

Adjuvant sequential dose-dense doxorubicin, paclitaxel, and cyclophosphamide (ATC) for high-risk breast cancer is feasible in the community setting.

PURPOSE: This study evaluated the feasibility, when given in the community, of dose-dense, sequential ATC (doxorubicin, paclitaxel, cyclophosphamide) as adjuvant therapy for breast cancer with four or more metastatic axillary lymph nodes. PATIENTS AND METHODS: Patients were recruited after definitive breast cancer surgery if four or more axillary nodes were involved by metastatic cancer and if distant metastases were not present on computed tomographic scan or bone scan. Forty patients received doxorubicin, 90 mg/m2 every 14 days for three cycles; paclitaxel, 250 mg/m2 every 14 days for three cycles; and cyclophosphamide, 3 g/m2 every 14 days for three cycles with filgrastim support. Chemotherapy was administered by the referring physician. RESULTS: Mean dose intensity was 99% for doxorubicin, 96% for paclitaxel, and 99% for cyclophosphamide. Grade 3 toxicities included mucositis (13%), nausea/vomiting (10%), neuropathy (13%), and myalgia/arthralgia (10%). Thirteen patients had neutropenic fever. One patient developed acute leukemia. Three relapses have occurred. Ninety percent of patients are alive and disease-free at a median follow-up of 24 months. DISCUSSION: ATC can be administered in the community at full doses with acceptable toxicity. Preliminary efficacy data suggest that this high-dose, intensively scheduled regimen warrants comparison with standard therapy for high-risk patients.

Adult↗
PubMed1999

The chemistry of the metabolites of cyclophosphamide.

This is primarily an overview of the spontaneous (non-enzymatic) chemistry of the metabolites of cyclophosphamide, viz., cis- and trans-4-hydroxycyclophosphamide, aldophosphamide (and its hydrate), iminophosphamide, phosphoramide mustard, acrolein, and chloroethylaziridine. A brief description of detoxification products obtained through enzyme catalyzed reactions appears. Included as the historical basis for the development of cyclophosphamide is the chemistry of nitrogen mustards. Among the topics covered are: perturbations to metabolite distributions and half-lives effected by buffer, structure, pH and nucleophiles; effects of pH on mechanism; alkylation versus P-N bond hydrolysis; the influence of nucleophiles on alkylation product distributions; the influence of substituents on alkylation rates; and preactivated forms of cyclophosphamide as metabolite precursors (4-hydroperoxycyclophosphamide and mafosfamide). A review with 66 references.

Animals↗
PubMed1999

[The comparison of the effectiveness of treatment of multiple sclerosis relapse with high doses of methylprednisolone, alpha-24 corticotropin and cyclophosphamide].

The effectiveness of treatment was compared in groups of patients with definite multiple sclerosis (MS) given respectively: methylprednisolone, alpha-24 corticotropine and cyclophosphamide combined with corticotropine. Clinical improvement was assessed by means of the expanded disability status scale (EDSS). The significant results were noted in patients treated with methylprednisolon and corticotropine combined with cyclophosphamide (1.5 in EDSS) for the first time, when compared to subsequent treatment. Within the patients in a more advanced stage of the disease, undergoing subsequent treatment, those given corticotropine displayed the best improvement (1.5 in EDSS), but without statistical significance. The authors suggest methylprednisolone or corticotropine combined with cyclophosphamide are the most effective immunosuppressive treatment in the initial phase of MS.

Adult↗
PubMed1999

Apparent cyclophosphamide (cytoxan) embryopathy: a distinct phenotype?

Cyclophosphamide (CP) is an alkylating agent widely used in treating cancer and autoimmune disease. CP is classified as a pregnancy risk factor D drug and is teratogenic in animals, but population studies have not conclusively demonstrated teratogenicity in humans. Six isolated reports of prenatally exposed infants with various congenital anomalies exist, but to date no specific phenotype has been delineated. The purpose of this report is to document a new case of in utero CP exposure with multiple congenital anomalies and to establish an apparent CP embryopathy phenotype. The mother had systemic lupus erythematosus and cyclophosphamide exposure in the first trimester. She also took nifedipine, atenolol, clonidine, prednisone, aspirin, and potassium chloride throughout pregnancy. The infant had growth retardation and multiple anomalies including microbrachycephaly, coronal craniosynostosis, hypotelorism, shallow orbits, proptosis, blepharophimosis, small, abnormal ears, unilateral preauricular pit, broad, flat nasal bridge, microstomia, high-arched palate, micrognathia, preaxial upper limb and postaxial lower limb defects consisting of hypoplastic thumbs, and bilateral absence of the 4th and 5th toes. Chromosomes were apparently normal. The reported cases of in utero exposure to cyclosposphamide shared the following manifestations with our patient: growth deficiency, developmental delay, craniosynostosis, blepharophimosis, flat nasal bridge, abnormal ears, and distal limb defects including hypoplastic thumbs and oligodactyly. We conclude that (a) cyclophosphamide is a human teratogen, (b) a distinct phenotype exists, and (c) the safety of CP in pregnancy is in serious question.

Abnormalities, Multiple↗
PubMed1999

The addition of interferon or high dose cyclophosphamide to standard chemotherapy in the treatment of patients with multiple myeloma: phase III Eastern Cooperative Oncology Group Clinical Trial EST 9486.

BACKGROUND: Interferon (IFN) has demonstrated activity in the treatment of patients with multiple myeloma. A previous Eastern Cooperative Oncology Group (ECOG) study suggested that the rates of complete response (CR) and survival were increased with a regimen that alternated IFN with chemotherapy. The current study was designed to evaluate the effect of adding alternating cycles of IFN or early intensification with high dose cyclophosphamide (HiCy) to the VBMCP regimen for the treatment of multiple myeloma patients. METHODS: From February 1988 to May 1992, the ECOG entered previously untreated patients with active multiple myeloma on a study in which they were randomized to VBMCP (vincristine 1.2 mg/m(2) administered intravenously [i.v.] on Day 1, BCNU 20 mg/m(2) i.v. on Day 1, melphalan 8 mg/m(2) administered orally [p.o.] on Days 1-4, cyclophosphamide 400 mg/m(2) i.v. on Day 1, and prednisone 40 mg/m(2) p.o. on Days 1-7; 5-week cycles) or VBMCP + rIFN(alpha2), the latter given at 5 Mu/m(2) 3 times a week starting on Day 22 of each 6-week cycle after 2 initial cycles of VBMCP. Patients younger than 70 years were also randomized to a third treatment that substituted cyclophosphamide 600 mg/m(2) i.v. on Days 1-4 and prednisone 100 mg/m(2) p.o. on Days 1-4 for cycles 3 and 5 of VBMCP (VBMCP + HiCy). Treatment was continued for 2 years. RESULTS: Of the 653 patients entered, 628 were eligible for the study. All were evaluated for response. With median follow-up for surviving patients of 54 months, the median survival duration was 42 months-1 year longer than usually reported for melphalan combined with prednisone. A comparison of the three regimens revealed no significant difference in the rates of survival or objective response (OR). However, CRs were increased among patients treated with VBMCP + rIFN(alpha2) compared with VBMCP alone (18% vs. 10%, P = 0.03). Patients treated with VBMCP + rIFN(alpha2) had a longer response duration than patients treated with VBMCP alone (30 vs. 25 months, P = 0.035). There was a greater response rate with the IFN regimen among elderly patients (OR and CR = 67% and 31%, respectively) and patients with immunoglobulin A (IgA) myeloma (OR and CR = 83% and 29%, respectively). Severe infections were seen as often with VBMCP as with VBMCP + rIFN(alpha2) (13% vs. 15%), but they were more frequent with VBMCP + HiCy (25%). CONCLUSIONS: VBMCP + rIFN(alpha2) yields a higher rate of CR and a longer response duration than VBMCP alone but appears to make no difference in the rates of overall response or survival compared with VBMCP or VBMCP + HiCy. The superior ability of VBMCP + rIFN(alpha2) induction therapy to produce CR and more durable responses, as well as its activity in older patients and in those with IgA myeloma, suggest that this therapy has important biologic activity in myeloma and merits further clinical investigation.

Adult↗
PubMed1999

Chemotherapy with etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone in patients with refractory cutaneous T-cell lymphoma.

BACKGROUND: This Phase II study was undertaken to assess the efficacy and toxicity of chemotherapy with etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone (EPOCH regimen) in patients with advanced, refractory cutaneous T-cell lymphoma (CTCL). METHODS: Fifteen patients were treated with a 96-hour continuous infusion of etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone, followed by granulocyte-colony stimulating factor support and trimethoprim/sulfamethoxazole prophylaxis. The median age of the patients was 53 years (range, 17-82 years). Six patients had Sézary syndrome (SS), four patients had visceral involvement, and four patients had anaplastic large cell morphology, three with Ki-1 (CD30) positivity. All patients had disease that was refractory to prior chemotherapy or electron beam irradiation and eight of these patients had received cyclophosphamide, doxorubicin, vincristine, and prednisone. Seven patients had received prior interferon therapy and nine patients had received fludarabine and/or 2-CDA. RESULTS: After a median of 5 cycles (range, 1-9 cycles), 4 patients achieved a complete response (27%) and 8 patients achieved a partial response (53%) for an overall response rate of 80% (95% confidence interval, 52-96%). Three patients with visceral involvement, two of three patients with anaplastic large cell morphology, and one patient with human T-cell lymphoma virus leukemia/lymphoma did not respond. All 12 responders had improvement in skin disease; 2 of 6 patients with SS had complete disappearance of circulating Sézary cells. The median progression free survival was 8.0 months (range, 3-22 months). After a median follow-up of 11.4 months (range, 2-56+ months), the median patient survival was 13.5 months. Grade 3 or 4 hematologic toxicity occurred in 8 patients (61%); 5 of these 8 patients had febrile neutropenia. Six patients developed staphylococcal bacteremia, two patients had disseminated herpes infection, and one patient had Pneumocystis carinii pneumonia. Grade 3 neurotoxicity occurred in one patient. Two patients had a significant decrease in left ventricular ejection fraction and one patient had supraventricular tachycardia. CONCLUSIONS: EPOCH chemotherapy has a high response rate with acceptable toxicity in patients with advanced and refractory CTCL.

Administration, Oral↗
PubMed1999

In vitro evaluation of fludarabine in combination with cyclophosphamide and/or mitoxantrone in B-cell chronic lymphocytic leukemia.

B-chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of long-lived CD5(+) B lymphocytes. We have analyzed the effect in vitro of the combination of fludarabine with cyclophosphamide and/or mitoxantrone on cells from 20 B-CLL patients. Mafosfamide, the active form of cyclophosphamide in vitro, increased the cytotoxicity of fludarabine in all of the patients studied and produced a significant synergistic effect (P <.01) after 48 hours of incubation. The addition of mitoxantrone to this combination increased the cytotoxic effect in cells from 8 patients, but in the remaining 12 patients no significant increase was observed. The effect of fludarabine and mafosfamide was dose-dependent. Mafosfamide and fludarabine had a synergistic effect in inducing apoptosis of B-CLL cells as determined by DNA staining with propidium iodide and analysis of phosphatidylserine exposure. Mafosfamide significantly increased the apoptosis induced by fludarabine on CD19(+) cells (P =.007), but not on CD3(+) cells (P =. 314). Cell viability was correlated with a decrease in Mcl-1 levels and an increase in p53 levels. These results support that fludarabine in combination with cyclophosphamide and/or mitoxantrone can be highly effective in the treatment of B-CLL.

Adult↗
PubMed1975

Survival of mice with metastatic osteosarcoma treated by cyclophosphamide or radiotherapy.

Dunn osteosarcoma cells injected i.v. into tumor-free isogeneic C3H/He mice resulted in artificial pulmonary metastases, which were treated by cyclophosphamide (100 mg/kg/day i.p. for 3 days) or single thoracic X-ray doses of 1500 rads either 1 or 14 days after tumor cell injection. Compared to untreated controls, reduction in lung colony number and increase in life-span for the 1-day metastases were 56 and 46% for radiated mice, and 100 and greater than 367% for cyclophosphamide-treated mice. Corresponding values for 14-day metastases were 42, 26, 85, and 98%, respectively. Nine of 44 mice bearing 1-day metastases treated by cyclophosphamide are surviving greater than 340 days after treatment. Both treatments resulted in the extension of life-span and reduction of the number of lung colonies, and, in both modalities, there was a reduced antitumor effectiveness when treatment was withheld until the disease was more advanced.

Animals↗
PubMed2000

Oral estramustine and cyclophosphamide in patients with metastatic hormone refractory prostate carcinoma: a phase II study.

BACKGROUND: Nearly all cases of metastatic prostate carcinoma progress, after hormonal ablation, to a hormone refractory status. To the authors' knowledge no standard chemotherapy for patients with hormone refractory prostate carcinoma (HRPC) exists. In a prospective study, the efficacy and toxicity of an oral combination of estramustine and cyclophosphamide were evaluated. METHODS: Between March 1996 and April 1998, 32 consecutive patients (median age 74 years; range, 53-84 years) with metastatic HRPC were treated with oral estramustine (10 mg/kg/day) and oral cyclophosphamide (2 mg/kg/day) for 14 days every 28 days. Inclusion criteria were previous complete androgen blockade, antiandrogen withdrawal evaluation, and clinical or biochemical disease progression. Response assessment was based on a decrease > or =50% in the prostate specific antigen (PSA) level associated with improvement (or no worsening) in Eastern Cooperative Oncology Group (ECOG) performance status (PS) and relief of bone pain (if present). RESULTS: All patients were evaluable for efficacy and toxicity. PSA levels decreased by at least 50% in 14 patients (43.7%) (95% confidence interval, 26.5-60.9), remained stable in 12 patients (37.5%), and rose in 6 patients (18.8%). ECOG PS was 0 in 5 of 14 patients, improved from 1 to 0 in 7 patients, and remained unchanged in 2 patients. Bone pain, present in 8 of 14 patients, disappeared in 7 and was partially relieved in 1. The median duration of response was 30 weeks (range, 8-88+ weeks). An objective partial response was obtained in two cases. Toxicity was mild and mainly gastrointestinal (World Health Organization [WHO] Grade 1). No cases of WHO Grade 3-4 hematologic toxicity occurred. CONCLUSIONS: The oral combination of estramustine and cyclophosphamide appears to be safe and effective in patients with HRPC. In responding patients its use shows a clinical benefit in terms of improvement of ECOG PS and pain control.

Administration, Oral↗
PubMedDate not supplied

Antitumour and antimetastatic effect of genistein alone or combined with cyclophosphamide in mice transplanted with various tumours depends on the route of tumour transplantation.

In the present study we evaluated the antitumour effect of genistein alone, cyclophosphamide alone and as a combined therapy with both agents in mice transplanted with B16F-10 melanoma and Lewis lung cancer cells. The influence of the route of inoculation of the tumour cells on the antitumour and antimetastatic effects of these therapeutics was evaluated. The antitumour effect of genistein in mice with B16F-10 intradermically (i.d.) growing tumours and in mice with LL2 subcutaneous (s.c.) tumours was observed. In addition, its antimetastatic effect (reduction of lung colonies) in mice inoculated intravenously (i.v.) with B16F-10 and in mice with LL2 cells injected either intravenously or subcutaneously was observed. No life span prolongation of mice injected intraperitoneally (i.p.) with B16F-10 cells was observed, either after treatment with genistein alone or with cyclophosphamide alone. The synergistic effect of both agents in combined treatment, when the cells of B16F-10 melanoma were injected i.p., i.v. or i.d. and in a weaker manner when the cells of LL2 cancer were injected s.c., was observed. When LL2 cells were injected intravenously, no additive effect of genistein and CY could be detected. In conclusion, we have described the experimental mouse tumour models in which both the antitumour and antimetastatic effects of genistein alone, CY alone and those of combined therapy with genistein and cyclophosphamide were dependent on the implantation route of the tumour cells.

Animals↗
PubMed1976

[Immunologic competence of T- and B-lymphocytes in tolerance induced by cyclophosphamide].

A study was made of immunological competence of T- and B-lymphocytes of mice subjected to tolerogenic treatment (administration of a massive dose of sheep erythrocytes and cyclophosphamide 7 days before the experiment). The capacity of lymphocytes of tolerant mice to influence the interaction of normal T- and B-lymphocytes was also investigated. This form of tolerance was caused not by T-suppressors, but by a true deficiency of T-cells-helpers (both in the thymus and in the spleen), and partially of B-cells (in the spleen). Some lack of B-cells in the bone marrow was connected with a nonspecific action of cyclophosphamide. Cyclophosphamide is supposed to selectively eliminate cells proliferating in response to the antigen.

Animals↗
PubMed1976

The effect of cyclophosphamide and irradiation on cells which suppress contact sensitivity in the mouse.

Contact sensitivity was produced in mice by painting the skin with picryl chloride and was assessed by the increase in ear thickness following local challenge. Contact sensitivity was passively transferred by immune lymph node and spleen cells taken at 4 days. The mice were then challenged immediately and the reactions read at 24 and 48 hr. Immune lymph node and spleen cells taken at day 8 virtually fail to transfer. Experiment showed that they contain cells which suppress passive transfer. These are demonstrated by mixing approximately equal numbers of 4-day cells, which transfer contact sensitivity, and cells taken at later times and injecting them intravenously into recipients. These 'suppressor cells' can be demonstrated by day 6 and are still present at day 11 after immunization. The precursors of the suppressor cells are sensitive to cyclophosphamide. Irradiation of immune mice 2 days before taking cells also selectively inactivates the suppressor cells. When mice are pretreated with cyclophosphamide before immunization or irradiated 2 days before transfer, the lymph node and spleen cells taken on day 9 after immunization transfer contact sensitivity. In contrast the same number of cells from untreated mice were inactive. This suggests that the cells which mediate passive transfer or their precursors may occur in an inhibited form in lymph nodes and spleen at later times after immunization. These suppressor cells in immune mice differ from the T suppressor cells produced by the injection of picryl sulphonic acid--an agent which causes unresponsiveness: (1) the precursors of the T suppressor cells resist cyclophosphamide; (2) the T suppressor cells are found in mice treated so as to produce unresponsiveness while the other type of suppressor cells occurs in mice immunized for contact sensitivity. However, both types of suppressor cells are selectively inactivated by irradiation as compared with the cells which mediate contact sensitivity and both are able to act on the effector stage of contact sensitivity.

Animals↗
PubMed2000

A phase I and II study of pentostatin (Nipent) with cyclophosphamide for previously treated patients with chronic lymphocytic leukemia.

Purine analogs and alkylating agents are the most active drugs in the treatment of patients with chronic lymphocytic leukemia (CLL). Although fludarabine is the most widely tested purine analog in CLL, myelosuppression has limited its use in combination chemotherapy regimens. Because pentostatin (Nipent; SuperGen, San Ramon, CA), a related purine analog with proven activity in CLL, has less myelosuppression, we postulated that it would prove advantageous and could be more readily combined with alkylating agents. We are conducting a phase I/II trial of combination chemotherapy with pentostatin and cyclophosphamide for previously treated patients with CLL. Patients need to have Rai high-risk disease or "active" intermediate-risk disease. The treatment regimen consists of a fixed dose of pentostatin (4 mg/m2) combined with an increasing dose of cyclophosphamide. We plan to treat cohorts of three patients each at cyclophosphamide dose levels of 600, 900, 1,200, 1,500, and 2,000 mg/m2. Cycles will be repeated every 21 days. If unacceptable toxicity is encountered at one dose level, then three additional patients (total of six patients) will be accrued to that dose level before further dose escalations will be permitted. A second instance of unacceptable toxicity will close that dose level and identify the preceding level as the phase II dose. Additional patients will be accrued to the phase II dose level to better assess response. Supportive measures include the use of granulocyte colony-stimulating factor (5 microg/kg/d) to limit neutropenia. Sulfamethoxazole/trimethoprim will be given as prophylaxis against Pneumocystis carinii pneumonia and acyclovir will be administered as prophylaxis for herpes zoster. Response will be assessed according to standard criteria, and flow cytometry and fluorescent in situ hybridization will be used to assess for minimal residual disease in patients with trisomy 12.

Acyclovir↗
PubMedDate not supplied

Combination therapy with SCH58500 (p53 adenovirus) and cyclophosphamide in preclinical cancer models.

SCH58500 (ACN53) is a replication-deficient, recombinant adenovirus which expresses human p53 tumor suppressor. In preclinical models, SCH58500 has therapeutic efficacy against a wide range of human tumor types containing nonfunctional p53 and it has enhanced activity in combination with many chemotherapeutic drugs. However, the anti-tumor efficacy of SCH58500 combined with the DNA-damaging chemotherapeutic cyclophosphamide has not been previously reported. Cyclophosphamide did not enhance the activity of SCH58500 in three out of four human tumor xenograft models studied. Furthermore, combination therapy with SCH58500 and cyclophosphamide was not any better than single drug treatment in transgenic H-ras mice and in FVB mice bearing syngeneic MidT2-1 tumors. This is in sharp contrast to previous combination studies in these models where SCH58500 had enhanced efficacy when given with the farnesyl protein transferase inhibitor SCH66336, paclitaxel, cisplatin, cisplatin/paclitaxel, or doxorubicin. Further evaluation of this combination is required before it can be recommended for clinical trials in cancer patients.

Adenoviridae↗
PubMedDate not supplied

The presence of HLA-DR B1 shared motif does not influence cyclophosphamide and methotrexate cytotoxicity in rheumatoid arthritis patients.

In the present study we investigated the relation between cyclophosphamide and methotrexate toxicity and the presence of HLA- DR B1 alleles in rheumatoid arthritis patients. Seventy-eight such patients (67 women and 11 men) were observed for 12 months. Eighteen were treated with intravenous cyclophosphamide, 28 with oral methotrexate, and 32 with intramuscular gold salts. The prevalence of this shared motif was higher in the study population than in the healthy controls. However, detailed observations did not demonstrate a relation between particular genotype and drug intolerance. Based on the obtained findings we concluded that HLA-DR B1 typing cannot affect cyclophosphamide or methotrexate tolerance in rheumatoid arthritis patients. However, taking into account the relatively small number of patients expressing single genotype, further studies are recommended.

Adult↗