High-dose cyclophosphamide. An effective treatment for advanced refractory multiple myeloma

Lenhard, Raymond E.; Oken, Martin M.; Barnes, Janet M.; Humphrey, Richard L.; Glick, John H.; Silverstein, Murray N.

doi:10.1002/1097-0142(19840401)53:7<1456::aid-cncr2820530705>3.0.co;2-c

Cited by 55 publications

(27 citation statements)

References 10 publications

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“…Kinetic analyses done in vitro (461, and enhanced anti-BPDE cytotoxicity of 1.7-fold, relative to controls, caused by depletion of intracellular glutathione levels (17) to 10-60% of GST's K, for glutathione (0.1 mM) (22,461, were predictive of recombinant GST .rr + 'S ability to confer resistance to anti-BPDE. Significantly, values of 1.5-fold resistance relative to controls are identical with resistance values to anticancer alkylating agents observed clinically (30,31,58).…”

Section: Discussionsupporting

confidence: 70%

Recombinant glutathione S‐transferase (GST) expressing cells purified by flow cytometry on the basis of a GST‐catalyzed intracellular conjugation of glutathione to monochlorobimane

et al. 1991

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COS cells transiently expressing glutathione S-transferase (GST) m, Ya, or Yb, (human Pi, rat Alpha or Mu, cytosolic classes) were purified by flow cytometry and used in colony-forming assays to show that GST confers cellular resistance to the carcinogen benzoblpyrene (*)-anti-diol epoxide (anti-BPDE). We developed a sorting technique to viably separate recombinant GST+ cells (20%) from the nonexpressing electroporated population (80%) on the basis of a GST-catalyzed intracellular conjugation of glutathione to the fluorescent labeling reagent monochlorobimane (mClB). The concentration of mClB, length of time cells are exposed to mClB, and activity of the expressed GST isozyme determined the degree to which recombinant GST+ cells fluoresced more intensely than controls. On-line reagent addition ensured that all cells were exposed to 25 p M mClB for 3035 s during transit before being analyzed for fluorescence intensity and sorted. The apparent K , for mClB of the endogenous COS cell GST-catalyzed intracellular reaction was 88 pM. Stained GST Ya+ or Yb,+ cells catalyzed the conjugation 2 or 5 times more effectively than GST n+ cells. Enzyme activity in cytosolic fractions prepared from sorted recombinant GST+ cells was 1.8 -+ 0.3-fold greater than that of the control (80 f 4 nmoYmin/mg protein). Upon a 5-fold purification of GST n+ cells in the electroporated population, resistance to anti-BPDE in colony-forming assays increased 5 times, from 1.1-fold (unsorted) to 1.5-fold (sorted) (P <0.001).Key terms: Resistance to carcinogens, reversion of transient expression, COS cells Glutathione S-transferases (GST,3 EC 2.5.1.18) are a family of isozymes that can catalyze the covalent addition of the tripeptide glutathione, present at 0.5-10 mM in mammalian cells (35), to a structurally diverse array of physiological and xenobiotic electrophiles (21,25,32,37,41,52,53). GSTs are ubiquitous in the animal and plant kingdoms (53), and Mannervik (32) has classified the mammalian cytosolic GSTs into three classes (Pi, Alpha, and Mu) based on structural, immunological, and enzymatic properties. Mammalian cytosolic GSTs constitute 1-10% of total cytosolic protein (21) and are composed of two subunits (23-28 kilodaltons each) (32) that dimerize by noncovalent interactions (51). As demonstrated with in vitro kinetic analyses, GSTs can conjugate glutathione to anticancer alkylating agents (2,3,9,49,59) [1606][1607][1608][1609][1610][1611][1612] 1991) and Ublacker et al. (Cancer Res 51: 1783-1788, 1991, based upon in vitro kinetic analyses, support our findings done in whole cells which show that the rat )I and a class GSTs catalyze the conjugation of GSH to monochlorobimane more efficiently than 71 class GSTs.

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Section: Discussionsupporting

confidence: 70%

Recombinant glutathione S‐transferase (GST) expressing cells purified by flow cytometry on the basis of a GST‐catalyzed intracellular conjugation of glutathione to monochlorobimane

et al. 1991

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“…11,12 We employed the combination of CPA and G-CSF to mobilize PBSC, because she had VADresistant disease and high-dose CPA has been shown to be effective in refractory myeloma. 13 However, she developed severe myopericarditis after high-dose CPA. Myocarditis caused by a viral infection should be considered in the differential diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Myopericarditis caused by cyclophosphamide used to mobilize peripheral blood stem cells in a myeloma patient with renal failure

Yamamoto

Kanda

Matsuyama

et al. 2000

Bone Marrow Transplant

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Summary:Cyclophosphamide (CPA) is widely used for peripheral blood stem cell mobilization, and a dose adjustment of CPA in the presence of renal failure has not been suggested. However, we describe a myeloma patient with renal failure (serum creatinine 4.2 mg/dl, creatinine clearance 11.2 ml/min) receiving CPA 2 g/m 2 for 2 days, who developed unexpectedly severe toxicity, including myopericarditis and prolonged myelosuppression. The serial serum concentrations of CPA metabolites were persistently much higher than those in a myeloma patient with normal renal function. We consider, therefore, that the dose of CPA should be reduced in the presence of severe renal failure when used as high-dose therapy or to mobilize peripheral blood stem cells. Bone Marrow Transplantation (2000) 26, 685-688. Keywords: cyclophosphamide; cardiotoxicity; pericardial effusion; renal failure; myeloma Multiple myeloma is a neoplastic disorder of plasma cells which is considered to be incurable with standard chemotherapy. 1 High-dose chemotherapy followed by hematopoietic stem cell support has resulted in prolonged event-free and overall survival. 2 However, eligibility criteria for highdose chemotherapy protocols generally require patients to have normal vital organ function. Impairment of renal function is one of frequent complications of multiple myeloma and affects the pharmacokinetics of variety of drugs.Cyclophosphamide (CPA) is one of the most useful antineoplastic agents also widely used for peripheral blood stem cell mobilization. However, little information is available about the pharmacokinetics of CPA in renal insufficiency. Bramwell et al reported that the alkylating activity of CPA is influenced more by the wide individual variation in CPA breakdown than by decreased renal function 3,4 and Grochow et al 5 failed to show any correlation between the severity of renal insufficiency and hematopoietic toxicity. Therefore, adjusting CPA doses in the presence of renal insufficiency has not been recommended. 5,6 However, we experienced a myeloma patient with renal failure, who received 4 g/m 2 of CPA for peripheral blood stem cell (PBSC) mobilization and eventually developed severe myopericarditis and prolonged myelosuppression. We present the clinical course and discuss the pharmacokinetics of CPA in renal failure. Case reportA 36-year-old woman with persistent fever was discovered to have Bence-Jones proteinuria, anemia and renal failure with a serum creatinine of 3.1 mg/dl, that rose to 6.5 mg/dl over 2 months. A skeletal survey demonstrated advanced osteolytic lesions. Bone marrow aspiration showed an increase in atypical plasma cells, thus establishing a diagnosis of multiple myeloma, stage IIIB, according to the criteria by Durie and Salmon. Two courses of VAD therapy (vincristine 0.4 mg/body for 4 days, doxorubicin 9 mg/m 2 for 4 days, dexamethazone 40 mg/body for days 1-4, 9-12 and 17-20) resulted in partial response and a decrease in serum creatinine level (from 6.5 mg/dl to 2.9 mg/dl). 7 Because of her young age and the f...

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“…9,10 Furthermore, it has been demonstrated that hematopoietic support is not necessary after HDCYC. 11 As HDCYC has been reported to be efficient in the treatment of refractory MM, 12 we have used it at the dose of 7 g/m 2 , either alone or followed by hematopoietic growth factors (HGF), for PBPC mobilization in 116 patients planned to receive subsequently autologous PBPC transplantation (ABPCT). The aims of this monocentric study were: (1) to evaluate in MM patients the ability of HDCYC to mobilize circulating hematopoietic progenitors and to determine the parameters associated with successful mobilization; and (2) to analyze the predictive factors for hematologic recovery following reinfusion of PBPC after myeloablative treatment in a group of MM patients mobilized with HDCYC.…”

Section: Introductionmentioning

confidence: 99%

Factors affecting both peripheral blood progenitor cell mobilization and hematopoietic recovery following autologous blood progenitor cell transplantation in multiple myeloma patients: a monocentric study

et al. 1998

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The aim of the study was to analyze the factors influencing peripheral blood progenitor cell (PBPC) collection after high-dose cyclophosphamide (HDCYC) (7 g/m 2 ) and hematopoietic recovery after autologous transplantation of HDCYC-mobilized PBPC (ABPCT) in 116 patients with aggressive multiple myeloma (MM). Following HDCYC 74 patients received hematopoietic growth factors (HGF), either G-CSF (n = 19) or GM-CSF (n = 55). All the patients were subsequently planned to undergo ABPCT. PBPC collection was possible for 106 patients. The most important prognostic factor for collection of more than 25 × 10 4 CFU-GM cells/kg and 2 × 10 6 CD34 + cells/kg was the use of HGF (P = 0.002 and 0.009, respectively). Previous use of an alkylating agent, response to treatment before HDCYC, and interval between diagnosis and HDCYC were also significant factors (P = 0.004, 0.025 and 0.001, respectively). The number of CFU-GM cells infused was the most important parameter for rapid and complete hematological recovery after ABPCT (P Ͻ 0.0001). Thus the use of HGF post-HDCYC is the major factor which, associated with reduced time between diagnosis and HDCYC and the use of an alkylating agent, could increase the numbers of hematopoietic progenitors collected, and subsequently improve hematopoietic recovery following ABPCT in MM patients.

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High-dose cyclophosphamide. An effective treatment for advanced refractory multiple myeloma

Cited by 55 publications

References 10 publications

Recombinant glutathione S‐transferase (GST) expressing cells purified by flow cytometry on the basis of a GST‐catalyzed intracellular conjugation of glutathione to monochlorobimane

Recombinant glutathione S‐transferase (GST) expressing cells purified by flow cytometry on the basis of a GST‐catalyzed intracellular conjugation of glutathione to monochlorobimane

Myopericarditis caused by cyclophosphamide used to mobilize peripheral blood stem cells in a myeloma patient with renal failure

Factors affecting both peripheral blood progenitor cell mobilization and hematopoietic recovery following autologous blood progenitor cell transplantation in multiple myeloma patients: a monocentric study

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