Estimation of the haematological toxicity of minor groove alkylators using tests on human cord blood cells

Ghielmini, Michele; Bosshard, Giovanna; Capolongo, Laura; Geroni, M. C.; Pesenti, Enrico; Torri, Valter; D’Incalci, Maurizio; Cavalli, Franco; Sessa, Cristiana

doi:10.1038/bjc.1997.155

Cited by 29 publications

(14 citation statements)

References 21 publications

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“…The non-alkylating MGB PNU 151807 appears to be insensitive to the presence of MMR proteins. This is, in our opinion, an interesting finding, due to the high preclinical anti-tumour activity and the relatively low haematological toxicity shown for this compound (D'Alessio et al, 1994;Ghielmini et al, 1997), and makes it a good future candidate for the treatment of tumours responsive to MGB but presenting alterations in the MMR pathway. As a collateral result we observed that CDDP-resistant cell lines, CP70 and MCP1, are crossresistant to PNU 151807.…”

Section: Discussionmentioning

confidence: 93%

Mismatch repair deficiency is associated with resistance to DNA minor groove alkylating agents

et al. 1999

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Mismatch DNA repair deficiency is associated with resistance to certain major groove alkylating agents including methylating agents and cisplatin. We have now studied the relevance of mismatch repair alterations to the cytotoxicity induced by drugs which alkylate N3 adenines in the minor groove of DNA. We have used the mismatch repair defective human colocarcinoma cell line HCT-116 which has a mutation in the hMLH1 gene, and a subline where hMLH1 expression is restored by chromosome 3 transfer (HCT-116+ch3). We have tested three alkylating minor groove binders (tallimustine, carzelesin and CC1065) and one non-covalent minor groove binder (PNU 151807). The HCT-116+ch3 subline was more sensitive than the parental line to the treatment with the three alkylating minor groove binders, while the non-alkylating compound had a similar activity in both cell lines. Further support for mismatch repair being involved in sensitivity of the minor groove alkylators is that two cisplatin-resistant sublines of the human ovarian adenocarcinoma cell line A2780 (A2780/CP70 and A2780/MCP-1) are defective in hMLH1 expression and are more resistant to these agents than the parental mismatch repair proficient cells. Furthermore, the restoration of hMLH1 activity in the A2780/CP70 cell line, by introduction of chromosome 3, was associated with an increased sensitivity to the three alkylating minor groove binders. Again, the non-covalent minor groove binder was equally effective in mismatch repair deficient and proficient clones. The data indicate that mismatch repair deficiency mediated by loss of hMLH1 expression is associated not only with drug-resistance to major groove binders, but also to minor groove binders. However, loss of mismatch repair does not mediate resistance to the non-covalent minor groove binder PNU 151807. © 1999 Cancer Research Campaign

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Section: Discussionmentioning

confidence: 93%

Mismatch repair deficiency is associated with resistance to DNA minor groove alkylating agents

et al. 1999

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“…An in vitro therapeutic index reported by Ghielmini and others, can be calculated by comparison of the IC 50 of DTLIL3 on sensitive leukemic CFC with that of normal CFU-GM. [37][38][39] In these studies, we observed an in vitro index of 4-12, where values greater than 1 would suggest selective toxicity towards malignant progenitors. In comparison, when conventional chemotherapeutic agents including doxorubicin, melphalan and cytarabine have been tested in similar assays, 37-39 the indices obtained were Ͻ5.…”

Section: Discussionmentioning

confidence: 99%

Diphtheria toxin fused to human interleukin-3 is toxic to blasts from patients with myeloid leukemias

et al. 2000

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Leukemic blasts from patients with acute phase chronic myeloid leukemic and refractory acute myeloid leukemia are highly resistant to a number of cytotoxic drugs. To overcome multi-drug resistance, we engineered a diphtheria fusion protein by fusing human interleukin-3 (IL3) to a truncated form of diphtheria toxin (DT) with a (G 4 S) 2 linker (L), expressed and purified the recombinant protein, and tested the cytotoxicity of the DTLIL3 molecule on human leukemias and normal progenitors. The DTLIL3 construct was more cytotoxic to interleukin-3 receptor (IL3R) bearing human myeloid leukemia cell lines than receptor-negative cell lines based on assays of cytotoxicity using thymidine incorporation, growth in semi-solid medium and induction of apoptosis. Exposure of mononuclear cells to 680 pM DTLIL3 for 48 h in culture reduced the number of cells capable of forming colonies in semi-solid medium (colony-forming units leukemia) у10-fold in 4/11 (36%) patients with myeloid acute phase chronic myeloid leukemia (CML) and 3/9 (33%) patients with acute myeloid leukemia (AML). Normal myeloid progenitors (colony-forming unit granulocytemacrophage) from five different donors treated and assayed under identical conditions showed intermediate sensitivity with three-to five-fold reductions in colonies. The sensitivity to DTLIL3 of leukemic progenitors from a number of acute phase CML patients suggests that this agent could have therapeutic potential for some patients with this disease. Leukemia (2000) 14, 576-585.

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“…Considering that some of the latter compounds were associated with unexpected clinical haematologycal toxicity, and that from studies on haematologycal precursors maintained in vitro it appears that PNU 151807 had a much lower toxicity and a higher therapeutic index than tallimustine (Ghielmini et al, 1997), PNU151807 or analogues of it could represent an interesting clinical alternative to alkylating minor groove binders. Figure 7 Effect of PNU 151807, tallimustine (tall.)…”

Section: Discussionmentioning

confidence: 99%

“…A series of other distamycin derivatives was synthesized and tested for anti-tumour activity and bone marrow toxicity: one possessing a favourable therapeutic index (i.e. high anti-tumour activity with relatively low bone marrow toxicity) was the α-bromoacryloyl derivative of distamycin A (PNU 151807) (D'Alessio et al, 1994;Ghielmini et al, 1997). We report here the characterization of the interaction of this new compound with DNA and studies on its mechanism of action.…”

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confidence: 99%

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α-Bromoacryloyl derivative of distamycin A (PNU 151807): a new non-covalent minor groove DNA binder with antineoplastic activity

Marchini¹,

Cirò²,

Gallinari³

et al. 1999

Br J Cancer

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Summary PNU 151807 is a new synthetic α-bromoacryloyl derivative of distamycin A. In the present study we investigated the DNA interaction and the mechanism of action of this compound in parallel with the distamycin alkylating derivative, tallimustine. PNU 151807 possesses a good cytotoxic activity in in vitro growing cancer cells, even superior to that found for tallimustine. By footprinting experiments we found that PNU 151807 and tallimustine interact non-covalently with the same AT-rich DNA regions. However, differently from tallimustine, PNU 151807 failed to produce any DNA alkylation as assessed by Taq stop assay and N3 or N7-adenine alkylation assay in different DNA sequences. PNU 151807, like tallimustine, is able to induce an activation of p53, and consequently of p21 and BAX in a human ovarian cancer cell line (A2780) expressing wild-type p53. However, disruption of p53 function by HPV16-E6 does not significantly modify the cytotoxic activity of the compound. Flow cytometric analysis of cells treated with equitoxic concentrations of PNU 151807 and tallimustine showed a similar induction of accumulation of cells in the G2 phase of the cell cycle but with a different time course. When tested against recombinant proteins, only the compound PNU 151807 (and not tallimustine or distamycin A) is able to abolish the in vitro kinase activity of CDK2-cyclin A, CDK2-cyclin E and cdc2-cyclin B complexes. The results obtained showed that PNU 151807 seems to have a mechanism of action completely different from that of its parent compound tallimustine, possibly involving the inhibition of cyclin-dependent kinases activity, and clearly indicate PNU 151807 as a new non-covalent minor groove binder with cytotoxic activity against cancer cells.

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Estimation of the haematological toxicity of minor groove alkylators using tests on human cord blood cells

Cited by 29 publications

References 21 publications

Mismatch repair deficiency is associated with resistance to DNA minor groove alkylating agents

Mismatch repair deficiency is associated with resistance to DNA minor groove alkylating agents

Diphtheria toxin fused to human interleukin-3 is toxic to blasts from patients with myeloid leukemias

α-Bromoacryloyl derivative of distamycin A (PNU 151807): a new non-covalent minor groove DNA binder with antineoplastic activity

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