Prognosis for fludarabine therapy of chronic lymphocytic leukaemia based on <i>ex vivo</i> drug response by DiSC assay

Bosanquet, Andrew G.; Johnson, Stephen A.; Richards, Sue

doi:10.1046/j.1365-2141.1999.01516.x

Cited by 35 publications

(33 citation statements)

References 31 publications

(43 reference statements)

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“…A model for these pathways of cell death induction by nucleoside analogues is shown in Figure 14. The further elucidation of these signaling events is warranted, especially in view of the impressive clinical activity of these compounds and the deleterious consequences when resistance to nucleoside analogues arises (Bosanquet and Bell, 1996;Bosanquet et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Adenine deoxynucleotides fludarabine and cladribine induce apoptosis in a CD95/Fas receptor, FADD and caspase-8-independent manner by activation of the mitochondrial cell death pathway

et al. 2004

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The adenine deoxynucleosides cladribine (2CdA) and fludarabine (FAraA) are DNA-damaging agents that interfere with DNA repair and induce apoptosis in nonproliferating lymphoid cells. Although both drugs are clinically used for the treatment of indolent lymphoproliferative diseases, the pathways of apoptosis induction remain largely unknown. In the present work, we demonstrate that both drugs induce apoptosis independently of death receptor signaling but activate the mitochondrial cell death pathway. To dissect the signaling pathways, we employed Jurkat cells either deficient for FADD or caspase-8 or overexpressing Bcl-2. In Bcl-2 overexpressing cells, apoptosis and cytochrome c release were blocked whereas processing of caspase-9, -3 and -8 was partially inhibited. In contrast, neither the deficiency of FADD or caspase-8 nor the interference with death receptor signaling by neutralizing anti-CD95/Fas antibodies affected cell death. Inhibitor experiments revealed that caspase-8 is processed by caspase-3-like caspases. Moreover, cytochrome c release and processing of caspase-9 and -3 occurred to an equal extent in wild-type FADD -/-and caspase-8 -/-Jurkat cells. Likewise, apoptosis induction by cladribine or fludarabine was not hampered upon inhibition of caspase-8 in MOLT-3 and MOLT-4 cells or overexpression of a dominantnegative FADD mutant in BJAB cells. Thus, we conclude that apoptosis induced by nucleoside analogues is independent from death receptor signaling as well as from a proposed direct effect on APAF-1, but rather follows the mitochondrial signaling pathway of cytochrome c release and subsequent processing of caspase-9 and -3.

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Section: Discussionmentioning

confidence: 99%

Adenine deoxynucleotides fludarabine and cladribine induce apoptosis in a CD95/Fas receptor, FADD and caspase-8-independent manner by activation of the mitochondrial cell death pathway

et al. 2004

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“…[8][9][10]23 Patients treated with assay-sensitive drugs are eight times more likely to respond to treatment than those treated with assay-resistant drugs. 10 In a study of breast cancer patients, it was concluded that clinicians managed patients with a highly treatable disease on the basis of age rather than physiological status, thereby worsening the prognosis for older patients.…”

Section: Figurementioning

confidence: 99%

“…24 CLL is eminently treatable and DiSC assay guided therapy can make economic sense; life could be extended for £1470 per life year gained, 25 and expensive and toxic therapy that is highly unlikely to be effective can be avoided. 8 Although studies have shown a significantly greater prevalence of severe and lethal toxicity in elderly lymphoma patients treated with intensive chemotherapy regimens, 26 age alone should not be the determining factor in modifying treatment in CLL. Cancer treatment in the elderly is remarkably safe when the co-morbid conditions are also treated.…”

Section: Figurementioning

confidence: 99%

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Ex vivo assessment of drug response by differential staining cytotoxicity (DiSC) assay suggests a biological basis for equality of chemotherapy irrespective of age for patients with chronic lymphocytic leukaemia

Bosanquet

2000

Leukemia

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With a mean age at diagnosis for chronic lymphocytic leukaemia (CLL) of 65 years, development of optimal therapeutic regimens has been hampered by the advanced age of patients. In general, because of comorbidity older patients are not treated with the intent of achieving a complete response and so do not attain the quality of response of younger patients and do not survive as long. We have investigated whether or not ex vivo cellular sensitivity to cytotoxic drugs could be an underlying biological basis for this age differential in response and survival by comparing ex vivo drug response with age in untreated CLL patients. Cells from 365 untreated CLL patients aged 31.1-87.1 years (average 65.3 years) were tested for drug response by differential staining cytotoxicity (DiSC) assay with a panel of 10 drugs. An average of 280 results (range 196-361) obtained for each drug was compared with patient age. For chlorambucil, cyclophosphamide, prednisolone, vincristine, doxorubicin, epirubicin, fludarabine, cladribine and methylprednisolone, no relationship was found between ex vivo drug response and age (r Ͻ 0.12). For pentostatin, a possible but very weak relationship (r = 0.18; n = 210; P = 0.06) was found. We conclude that cellular sensitivity to cytotoxic drugs does not support the differential treatment of older and younger CLL patients. Leukemia (2000) 14, 712-715.

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“…Although earlier laboratory assays based on drug-induced growth inhibition (e.g. H 3 *-thymidine incorporation, clonogenic) have consistently failed to provide clinically relevant information, newer methods that incorporate cell-death measures as surrogates of drug-induced apoptosis have been shown to correlate with response, time to progression, and survival in human haematologic and solid tumours (Bosanquet et al, 1999;Cortazar and Johnson, 1999;Nagourney et al, 2000Nagourney et al, , 2003. The realisation that most chemotherapeutic agents exert their cytotoxic effects through apoptosis (Reed, 1999) supports the use of cell-death assay in the study of topotecan's antitumour activity in human neoplasms.…”

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confidence: 99%

Ex vivo analysis of topotecan: advancing the application of laboratory-based clinical therapeutics

et al. 2003

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Topotecan is currently approved for relapsed small-cell lung cancer and ovarian cancer. Topotecan's efficacy in the second-line setting and novel mechanism of action suggest broad antitumour activity. We utilised a clinically validated, cell-death, ex vivo assay in human tumour explants to examine the activity profile of topotecan alone and in combination with other antitumour agents. Serial dilutions of topotecan alone and in combination with other cytotoxic agents were applied to biopsy specimens of non-small-cell lung cancer (NSCLC) and breast, colon, and prostate cancers. Dose -response curves were interpolated to provide 50% lethal concentrations (LC 50 ). The degree of synergy (by median effect) and normalised Z-scores (raw scores converted to relative activity distributed around the mean) were then computed. Single-agent activity was observed for topotecan in all four tumour types. In 57 chemotherapy-naive specimens, NSCLC revealed the highest activity, demonstrated by the lowest LC 50 value (0.2670.06 mg ml À1 ; P ¼ 0.002). Overall, previously treated and chemotherapy-naive specimens revealed no significant differences in mean LC 50 's. Synergy was observed for several combinations, including topotecan plus cisplatin in prostate and for topotecan plus 5-fluorouracil in breast cancers. The Z-score analyses conducted suggest activity for previously unexplored drug regimens, including topotecan plus 5-fluorouracil, vinorelbine, and mitomycin-C in NSCLC and breast cancer. Phase II studies are underway to determine the degree to which these ex vivo findings will translate into improved clinical results. Topotecan, a semisynthetic, water-soluble derivative of camptothecin, is an inhibitor of topoisomerase I (Kingsbury et al, 1991). This derivative is more stable, has increased solubility, a shorter half-life, and decreased toxicity compared with its parent compound (Verweij et al, 1993;Burke and Mi, 1994;Rothenberg, 1997). Topoisomerase I is a nuclear enzyme that relieves torsional strain on supercoiled DNA and creates single-strand breaks during DNA replication. Topotecan prevents topoisomerase I from repairing the cleaved DNA, which results in double-stranded DNA breaks and eventually apoptosis. The unique mechanism of action of topotecan and lack of clinical crossresistance with other antineoplastic compounds suggest that topotecan has the potential for broad antitumour activity.The activity of topotecan has been demonstrated in several open-label, randomised phase II and III trials. Currently, topotecan is approved for the treatment of relapsed small-cell lung cancer (SCLC) (Eckardt et

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Prognosis for fludarabine therapy of chronic lymphocytic leukaemia based on ex vivo drug response by DiSC assay

Cited by 35 publications

References 31 publications

Adenine deoxynucleotides fludarabine and cladribine induce apoptosis in a CD95/Fas receptor, FADD and caspase-8-independent manner by activation of the mitochondrial cell death pathway

Adenine deoxynucleotides fludarabine and cladribine induce apoptosis in a CD95/Fas receptor, FADD and caspase-8-independent manner by activation of the mitochondrial cell death pathway

Ex vivo assessment of drug response by differential staining cytotoxicity (DiSC) assay suggests a biological basis for equality of chemotherapy irrespective of age for patients with chronic lymphocytic leukaemia

Ex vivo analysis of topotecan: advancing the application of laboratory-based clinical therapeutics

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