Platinum Agents and Secondary Myeloid Leukaemia: Two Cases Treated Only With Platinum‐based Drugs

Philpott, Nicola J.; Elebute, Modupe; Powles, R; Treleaven, J; Gore, Martin; Dainton, Melissa; Min, Toon; Swansbury, G. J.; Catovsky, Daniel

doi:10.1046/j.1365-2141.1996.d01-1716.x

Cited by 21 publications

(9 citation statements)

References 15 publications

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“…The telomeric portion of the MLL bcr is a preferred target for specific cleavage resulting from higher-order chromatin fragmentation during apoptosis and therefore would be a preferred target region for chromosomal translocations caused by this mechanism. Of note, there are several reports of patients with t-AML characteristic of t-AML associated with topo II inhibitor therapy (a short latency period, monocytic phenotype, and MLL translocations) whose chemotherapeutic regimens did not incorporate topo II inhibitors but who were instead treated with chemotherapeutic drugs such as alkylating agents or antimetabolites (20,32,46), which can induce apoptosis. While these t-AML cases may in fact be de novo leukemias, an alternate explanation would be that a chemotherapeutic agent which does not target topo II, but which can induce apoptosis, had caused the translocation.…”

Section: Discussionmentioning

confidence: 99%

DNA Cleavage within the MLL Breakpoint Cluster Region Is a Specific Event Which Occurs as Part of Higher-Order Chromatin Fragmentation during the Initial Stages of Apoptosis

Stanulla

Wang

Chervinsky

et al. 1997

Molecular and Cellular Biology

170

163

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A distinct population of therapy-related acute myeloid leukemia (t-AML) is strongly associated with prior administration of topoisomerase II (topo II) inhibitors. These t-AMLs display distinct cytogenetic alterations, most often disrupting the MLL gene on chromosome 11q23 within a breakpoint cluster region (bcr) of 8.3 kb. We recently identified a unique site within the MLL bcr that is highly susceptible to DNA double-strand cleavage by classic topo II inhibitors (e.g., etoposide and doxorubicin). Here, we report that site-specific cleavage within the MLL bcr can be induced by either catalytic topo II inhibitors, genotoxic chemotherapeutic agents which do not target topo II, or nongenotoxic stimuli of apoptotic cell death, suggesting that this site-specific cleavage is part of a generalized cellular response to an apoptotic stimulus. We also show that site-specific cleavage within the MLL bcr can be linked to the higher-order chromatin fragmentation that occurs during the initial stages of apoptosis, possibly through cleavage of DNA loops at their anchorage sites to the nuclear matrix. In addition, we show that site-specific cleavage is conserved between species, as specific DNA cleavage can also be demonstrated within the murine MLL locus. Lastly, site-specific cleavage during apoptosis can also be identified at the AML1 locus, a locus which is also frequently involved in chromosomal rearrangements present in t-AML patients. In conclusion, these results suggest the potential involvement of higher-order chromatin fragmentation which occurs as a part of a generalized apoptotic response in a mechanism leading to chromosomal translocation of the MLL and AML1 genes and subsequent t-AML.Nonrandom chromosomal aberrations, particularly chromosomal translocations, are frequently found in association with a wide spectrum of malignancies, most prominently leukemias and lymphomas (9,14,47). The available evidence suggests that these nonrandom chromosomal translocations are often causal events leading to malignant transformation (2, 40). However, the molecular mechanisms which cause these translocations remain largely unknown.In many cases, a powerful argument can be made that these translocations are the result of mistakes in normal V(D)J recombinase activity (4, 60). These arguments are based on identification of features that resemble normal V(D)J recombinase activity, such as cryptic heptamer sequences, nontemplated N-region nucleotide addition, and exonucleolytic deletion of germ line nucleotides at the translocation breakpoints (4, 60). Other factors that have been implicated in the generation of nonrandom translocations include homologous recombination events between Alu elements (52) and exposure to DNA-damaging agents (35,36). It has been recognized for some time that DNA-damaging cancer chemotherapeutic agents, such as the topoisomerase II (topo II) inhibitor etoposide (36) and the alkylating agent melphalan (35), can cause chromosomal translocations. For instance, phytohemagglutinin-stimulated peripheral blood ly...

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Section: Discussionmentioning

confidence: 99%

DNA Cleavage within the MLL Breakpoint Cluster Region Is a Specific Event Which Occurs as Part of Higher-Order Chromatin Fragmentation during the Initial Stages of Apoptosis

Stanulla

Wang

Chervinsky

et al. 1997

Molecular and Cellular Biology

170

163

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“…Development of MDS in one patient eleven months after the therapy, the first noted case of possible treatment related leukemia following JM-216 therapy, supports the hypothesis of stem cell damage. Presence of complex karyotype (including 7q-, an abnormality typically associated with prior chemotherapy related leukemia/MDS) in our patient and existence of reports describing higher incidence of secondary leukemia following cisplatin and carboplatin therapy in ovarian cancer favors this conclusion [25,26]. The cause and significance of lymphopenia in majority of patients during the treatment phase is also not clear even though it has been reported in other studies evaluating estrogen, corticosteroids, suramin and mitoxantrone in HRPC [27][28][29].…”

Section: Discussionmentioning

confidence: 58%

Phase II study of oral bis (aceto) ammine dichloro (cyclohexamine) platinum (IV) (JM-216, BMS-182751) given daily x 5 in hormone refractory prostate cancer (HRPC)

et al. 2005

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JM-216 is an orally bioavailable platinum compound with activity against many tumor models. The objective of this study was to determine the safety profile and anti-tumor activity of JM-216 in patients with hormone refractory prostate cancer (HRPC) when given orally daily x 5 days. In this open label phase II study JM-216 was administered orally at the dose of 120 mg/m2/d for 5 days every 4 weeks. Patients continued on the therapy until evidence of disease progression or intolerable toxicity developed. Dose escalation and de-escalation were allowed according to patient's tolerance. Thirty-nine patients were enrolled onto the study and received a total of 155 courses (median 2, range 1-16) of JM-216. Dose delays (77% of courses) and dose reductions (31% of courses) were common and were mainly due to myelosupression. Treatment was discontinued in 5 patients due to treatment related toxicities. One patient developed myelodysplastic syndrome 11 months after the start of treatment. The most frequent grade III or higher adverse events included thrombocytopenia (54%), neutropenia (52%), anemia (24%) nausea (13%), vomiting (16%) and diarrhea (28%). PSA response was assessed in 32 patients, 10 (26%) had partial response, 14 (36%) had stable disease while PSA progression was seen in 8 (21%) patients. Of 20 (54%) patients with measurable disease two patients had a documented partial response. Although JM-216 had moderate activity in HRPC when given on daily basis for 5 days, it is associated with significant treatment related toxicities in this patient population.

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“…None of the five cases of t-AML published aftercisplatin or carboplatin-monotherapy have shown a typical alkylator type cytogenetic alteration, [2,4,14] indicating that platin-derivatives alone may induce topoisomerase II inhibitor type t-AML.…”

Section: Discussionmentioning

confidence: 99%

Secondary leukaemia after cure for locally advanced NSCLC

et al. 2004

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Platinum Agents and Secondary Myeloid Leukaemia: Two Cases Treated Only With Platinum‐based Drugs

Cited by 21 publications

References 15 publications

DNA Cleavage within the MLL Breakpoint Cluster Region Is a Specific Event Which Occurs as Part of Higher-Order Chromatin Fragmentation during the Initial Stages of Apoptosis

DNA Cleavage within the MLL Breakpoint Cluster Region Is a Specific Event Which Occurs as Part of Higher-Order Chromatin Fragmentation during the Initial Stages of Apoptosis

Phase II study of oral bis (aceto) ammine dichloro (cyclohexamine) platinum (IV) (JM-216, BMS-182751) given daily x 5 in hormone refractory prostate cancer (HRPC)

Secondary leukaemia after cure for locally advanced NSCLC

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