Comparison of cytotoxicity and cellular accumulation of polynuclear platinum complexes in L1210 murine leukemia cell lines

Roberts, John D.; Peroutka, John; Beggiolin, G.; Manzotti, C.; Piazzoni, L.; Farrell, Nicholas

doi:10.1016/s0162-0134(99)00137-3

Cited by 67 publications

(75 citation statements)

References 7 publications

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“…This compound shows a generally higher potency than cisplatin and a substantially different pattern of response in the cell line panel of the NCI (Manzotti et al 2000). Activity is retained or even enhanced in cell lines and human tumour xenografts with acquired or intrinsic resistance to cisplatin (Roberts et al 1999;Perego et al 1999aPerego et al , 1999bManzotti et al 2000) including p53-mutant xenografts (Pratesi et al 1999), confirming the ability to overcome different mechanisms of cisplatin resistance. Surprisingly, transfection of cells lacking p53 function with the wild-type p53 gene reduces their sensitivity to BBR3464, the contrary of the effect on cisplatin sensitivity.…”

Section: Dinuclear and Trinuclear Complexesmentioning

confidence: 96%

“…Whereas BBR3464 has been found to produce a higher portion of interstrand cross-links than cisplatin in plasmid DNA (Brabec et al 1999), the reverse has been observed in DNA isolated from pre-exposed tumour cells (Roberts et al 1999;Perego et al 1999b). However, the interstrand cross-links formed by BBR3464 persist longer than those induced by cisplatin and are therefore considered less susceptible to repair.…”

Section: Dinuclear and Trinuclear Complexesmentioning

confidence: 99%

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Tumour-inhibiting platinum complexes—state of the art and future perspectives

Jakupec

Galanski

Keppler

2003

Reviews of Physiology, Biochemistry and Pharmacology

380

349

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Thirty years after the onset of the first clinical studies with cisplatin, the development of antineoplastic platinum drugs continues to be a productive field of research. This article reviews the current preclinical and clinical status, including a discussion of the molecular basis for the activity of the parent drug cisplatin and platinum drugs of the second and third generation, in particular their interaction with DNA. Further emphasis is laid on the development of third generation platinum drugs with activity in cisplatin-resistant tumours, particularly on chelates containing 1,2-diaminocyclohexane (DACH) and on the promising and more recently evolving field of non-classic ( trans- and multinuclear) platinum complexes. The development of oral platinum drugs and drug targeting strategies using liposomes, polymers or low-molecular-weight carriers in order to improve the therapeutic index of platinum chemotherapy are also covered.

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Section: Dinuclear and Trinuclear Complexesmentioning

confidence: 96%

Section: Dinuclear and Trinuclear Complexesmentioning

confidence: 99%

Tumour-inhibiting platinum complexes—state of the art and future perspectives

Jakupec

Galanski

Keppler

2003

Reviews of Physiology, Biochemistry and Pharmacology

380

349

View full text Add to dashboard Cite

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“…2 The incorporation into the linker backbone of charge and hydrogen-bonding capacity dramatically increases the DNA affinity and affects the charge/lipophilicity balance as well as increasing the distance between the two platinum-DNA binding coordination spheres. All of these features may contribute to contribute to differentiating DNA binding, cellular uptake, and antitumor activity within the polynuclear platinum family itself (1,17,18).…”

mentioning

confidence: 99%

Conformation, Recognition by High Mobility Group Domain Proteins, and Nucleotide Excision Repair of DNA Intrastrand Cross-links of Novel Antitumor Trinuclear Platinum Complex BBR3464

Zehnulova

Kašpárková

Farrell

et al. 2001

Journal of Biological Chemistry

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The new antitumor trinuclear platinum compound [{trans-PtCl(NH 3 ) 2 } 2 -trans-Pt(NH 3 ) 2 {H 2 N(CH 2 ) 6 NH 2 } 2 ] 4؉ (designated as BBR3464) is currently in phase II clinical trials. DNA is generally considered the major pharmacological target of platinum drugs. As such it is of considerable interest to understand the patterns of DNA damage. The bifunctional DNA binding of BBR3464 is characterized by the rapid formation of long range intra-and interstrand cross-links. We examined how the structures of the various types of the intrastrand crosslinks of BBR3464 affect conformational properties of DNA, and how these adducts are recognized by high mobility group 1 protein and removed from DNA during in vitro nucleotide excision repair reactions. The results have revealed that intrastrand cross-links of BBR3464 create a local conformational distortion, but none of these cross-links results in a stable curvature. In addition, we have observed no recognition of these crosslinks by high mobility group 1 proteins, but we have observed effective removal of these adducts from DNA by nucleotide excision repair. These results suggest that the processing of the intrastrand cross-links of BBR3464 in tumor cells sensitive to this drug may not be relevant to its antitumor effects. Hence, polynuclear platinum compounds apparently represent a novel class of platinum anticancer drugs acting by a different mechanism than cisplatin and its analogues.The trinuclear compound [{trans-PtCl(NH 3 ) 2 } 2 -transPt(NH 3 ) 2 {H 2 N(CH 2 ) 6 NH 2 } 2 ] 4ϩ ( Fig. 1) is currently in phase II clinical trials. The compound, designated as BBR3464, is the lead representative of an entirely new structural class of DNAmodifying anticancer agents based on the poly(di,tri)nuclear platinum structural motif (1-3). In phase I trials, objective partial responses in pancreatic and lung cancers as well as melanoma were observed (4, 5). These results suggest the potential for genuinely complementary clinical anticancer activity of BBR3464 in comparison to cis-diamminedichloroplatinum(II) (cisplatin).

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“…12,13 In recent years, several Pt(II) compounds with trans configuration have been developed and reported to be active in vitro in different cancer cell lines, although none has entered phase III clinical trials. [14][15][16][17] Other platinum compounds with cis conformations have also been synthesized and studied as cancer therapeutics. Among these, satraplatin, an orally administered low toxicity platinum analog, demonstrated limited activity as a single agent in metastatic breast carcinoma and while still under investigation, failed in its initial development against prostate cancer;…”

Section: Resultsmentioning

confidence: 99%