Chlorambucil vs. combined chlorambucil-corticosteroid therapy in chronic lymphocytic leukemia

Han, Tao; Ezdinli, Ediz Z.; Shimaoka, Katsutaro; Desai, Dinesh V.

doi:10.1002/1097-0142(197303)31:3<502::aid-cncr2820310303>3.0.co;2-7

Cited by 124 publications

(43 citation statements)

References 12 publications

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“…Typical dose-response curves are shown for Chl in from the dose-response curves which gave a scatter of results in accordance with clinical experience of response (Desai et al, 1970;Han et al, 1973;Liepman & Votaw, 1978;Oken & Kaplan, 1979;Sawitsky et al, 1977) success of the assay was 100%, and this included repeat assays of the previous 3 patients whose cells were non-viable after 4 days in culture. Assays were often performed on cells taken from the same patient on consecutive visits to the hospital.…”

Section: Drug Concentrationsfor Use In Vitrosupporting

confidence: 61%

An assessment of a short-term tumour chemosensitivity assay in chronic lymphocytic leukaemia

Bosanquet¹,

Bird²,

Price³

et al. 1983

Br J Cancer

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Summary A 4-day tumour sensitivity assay of potential use in predicting tumour response to cytotoxic drugs has been investigated in patients with chronic lymphocytic leukaemia. The method comprised isolation of white cells from peripheral blood, drug exposure and incubation'for 4 days. Drug-induced tumour cell kill was assessed by differential staining of dead and live cells such that the latter could be morphologically identified, with subsequent calculation of tumour cell viability. Concentrations of drug for use in the assay were chosen for chlorambucil (2jugmlP1), 4-hydroperoxy-cyclophosphamide (2ygml1)--which was used in vitro in place of cyclophosphamide-prednisolone (0.5 pg ml-') and vincristine (0.

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Section: Drug Concentrationsfor Use In Vitrosupporting

confidence: 61%

An assessment of a short-term tumour chemosensitivity assay in chronic lymphocytic leukaemia

Bosanquet¹,

Bird²,

Price³

et al. 1983

Br J Cancer

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“…As early studies in patients with B-cell chronic lymphocytic leukemia (B-CLL) showed that addition of prednisone to chlorambucil augmented response rate but not median survival, glucocorticoids are not generally a standard component of initial therapy for patients with B-CLL (1,2). Nonetheless, two studies of high-dose glucocorticoid therapy have suggested that glucocorticoids can be of clinical benefit to a subset of patients with treatment-refractory B-CLL (3, 4).…”

mentioning

confidence: 99%

Phosphodiesterase 4 Inhibitors Augment Levels of Glucocorticoid Receptor in B Cell Chronic Lymphocytic Leukemia but Not in Normal Circulating Hematopoietic Cells

Meyers

Taverna

Chaves

et al. 2007

Clinical Cancer Research

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Type 4 cyclic AMP (cAMP) phosphodiesterase (PDE4) inhibitors, a class of compounds in clinical development that activate cAMP-mediated signaling by inhibiting cAMP catabolism, offer a feasible means by which to potentiate glucocorticoid-mediated apoptosis in lymphoid malignancies such as B-cell chronic lymphocytic leukemia (B-CLL). In this study, we show that PDE4 inhibitors up-regulate glucocorticoid receptor (GRa) transcript levels in B-CLL cells but not T-CLL cells or Sezary cells or normal circulating T cells, B cells, monocytes, or neutrophils. Because GRa transcript half-life does not vary in CLL cells treated with the prototypic PDE4 inhibitor rolipram, the 4-fold increase in GRa mRNA levels observed within 4 h of rolipram treatment seems to result from an increase in GRa transcription. Rolipram treatment increases levels of transcripts derived from the1A3 promoter to a greater extent than the 1B promoter.Treatment of B-CLL cells with two other PDE4 inhibitors currently in clinical development also augments GR transcript levels and glucocorticoid-mediated apoptosis. Washout studies show that simultaneous treatment with both drug classes irreversibly augments apoptosis over the same time frame that GR upregulation occurs. Although treatment of B-CLL cells with glucocorticoids reduces basal GRa transcript levels in a dose-related manner, cotreatment with rolipram maintained GRa transcript levels above baseline. Our results suggest that as a result of their unusual sensitivity to PDE4 inhibitor^mediated up-regulation of GRa expression, treatment of B-CLL patients with combined PDE4 inhibitor/glucocorticoid therapy may be of therapeutic benefit in this disease.Glucocorticoids are an important component of standard therapy for several lymphoid malignancies, including multiple myeloma, acute lymphoblastic leukemia, and diffuse large B-cell lymphoma. As early studies in patients with B-cell chronic lymphocytic leukemia (B-CLL) showed that addition of prednisone to chlorambucil augmented response rate but not median survival, glucocorticoids are not generally a standard component of initial therapy for patients with B-CLL (1, 2). Nonetheless, two studies of high-dose glucocorticoid therapy have suggested that glucocorticoids can be of clinical benefit to a subset of patients with treatment-refractory B-CLL (3, 4).Despite frequent responses to glucocorticoid treatment, monotherapy with glucocorticoids is not curative in any lymphoid malignancy, but the mechanisms underlying clinical glucocorticoid resistance remain controversial. Structural alterations in the glucocorticoid receptor (GR) are commonly identified in lymphoid cell lines that have been selected for glucocorticoid resistance by prolonged culture in dexamethasone, but comparable alterations in primary malignant lymphoid cells have been only infrequently reported (5 -9). A detailed analysis of treated B-CLL patients failed to identify abnormalities in either the DNA-or steroid-binding domains of leukemic GRs (10). Nonstructural modifications of ...

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“…The waseiti e eWlecr greater stimulation of DNA cross-linking fThe sensidoled WaLkr and nuclear-protein phosphorylation than TI was doubled. CHL after treatment with the alkylating agent ximum tolerated dose of alone (Wilkinson et al, 1979 proved effective in combination with alkylating agents for the treatment of lymphomas (Jelliffe, 1975) and leukaemias (Han et al, 1973). In these cases the steroid alone is cytotoxic.…”

Section: Resultsmentioning

confidence: 99%

Modulation of the toxicity and antitumour activity of alkylating drugs by steroids

Shepherd¹,

Harrap²

1982

Br J Cancer

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Summary.-The steroids prednisolone and progesterone significantly altered the therapeutic indices of the alkylating agents, nitrogen mustard, melphalan, cyclophosphamide, phenyl acetic mustard and chlorambucil. For nitrogen mustard, chlorambucil and phenyl acetic mustard, prednisolone reduced host toxicity in the rat and enhanced the antitumour effectiveness against alkylating-agent-resistant strains of the Yoshida sarcoma and Walker carcinosarcoma. Progesterone also increased the therapeutic index of chlorambucil in the rat by decreasing its systemic toxicity.Two other alkylating agents, melphalan and cyclophosphamide, exhibited lower therapeutic indices in combination with prednisolone against alkylating-agentsensitive tumours. This was due to the greater host toxicity of the combination than of the alkylating agent alone. In alkylating-agent-resistant tumours, however, a significant increase in growth delay was achieved if prednisolone was combined with the alkylating agent.

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Chlorambucil vs. combined chlorambucil-corticosteroid therapy in chronic lymphocytic leukemia

Cited by 124 publications

References 12 publications

An assessment of a short-term tumour chemosensitivity assay in chronic lymphocytic leukaemia

An assessment of a short-term tumour chemosensitivity assay in chronic lymphocytic leukaemia

Phosphodiesterase 4 Inhibitors Augment Levels of Glucocorticoid Receptor in B Cell Chronic Lymphocytic Leukemia but Not in Normal Circulating Hematopoietic Cells

Modulation of the toxicity and antitumour activity of alkylating drugs by steroids

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