Inhibitory effects of anti‐tumor platinum compounds on DNA, RNA and protein syntheses in mammalian cells <i>in vitro</i>

Harder, Harold C.; Rosenberg, Barnett

doi:10.1002/ijc.2910060207

Cited by 363 publications

(120 citation statements)

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“…Thrombocytopenia and bone marrow hypocellularity were more severe in rats receiving carboplatin, with and without WBH, than in rats given cisplatin, with and without WBH. Although severe thrombocytopenia appeared to be doselimiting for the combination of carboplatin with WBH, similar TERs of about 2 were estimated for both carboplatin The cytotoxicity of platinum compounds is generally thought to be based on reaction of the platinum molecule with nucleophilic sites on the DNA (Harder & Rosenberg, 1970). With the combination of cisplatin and hyperthermia the enhancement of cytotoxicity may be due partly to increased drug uptake in tissues , increased DNA cross-link formation (Meyn et al, 1980), alteration in drug metabolism (Zakris et al, 1987), and inhibition of DNA repair by heat (Meyn et al, 1979).…”

Section: Discussionmentioning

confidence: 88%

Haematological toxicity of carboplatin and cisplatin combined with whole body hyperthermia in rats

Ohno¹,

Strebel²,

Stephens³

et al. 1993

Br J Cancer

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Summary Acute haematological toxicity induced by cis-diammine-1,1-cyclobutane dicarboxylate platinum (II) (carboplatin) and cis-diamminedichloroplatinum (II) (cisplatin) in combination with whole body hyperthermia (WBH) (2 h at 41.5°C) was examined using a F344 rat model. The thermal enhancement ratios (TERs) of drug-mediated thrombocytopenia, anaemia and leukopenia were determined from the dose-response curves of the nadir values of the peripheral platelet, RBC and WBC counts. Carboplatin produced profound depression of platelet counts which was over three-fold greater than cisplatin (14% vs 51% of the control), while the decrease in WBC and RBC counts induced by carboplatin did not differ significantly from those observed with cisplatin. These carboplatin or cisplatin-mediated haematological toxicities were significantly enhanced by WBH. The depth of decrease in platelet, RBC and WBC counts induced by the maximum tolerated dose (MTD) of carboplatin (30 mg kg-1) combined with WBH was identical to that induced by the MTD of carboplatin (70 mg kg-') alone. The TERs of carboplatin-mediated thrombocytopenia, anaemia and leukopenia were 2.0, 2.8 and 1.9, respectively. The thermal enhancement of cisplatin mediated haematological toxicity was similar to that of carboplatin, with TERs of 1.8 for thrombocytopenia, 2.4 for anaemia and 1.9 for leukopenia. These data, demonstrating thermal enhancement of cisplatin or carboplatin-mediated haematological toxicity, must be taken into account in the clinical application of the combination thereapy of platinum and WBH.Hyperthermia has been shown to increase the cytotoxicity of cisplatin (Hahn, 1979;Barlogie et al., 1980), a chemotherapeutic agent commonly used for wide spectrum of human malignancies (Durant, 1980;Zwelling, 1987). At normal temperature, the clinical use of cisplatin is limited by severe toxicity to several normal tissues, especially the kidney, the gastrointestinal tract, and the bone marrow (Rose et al., 1982;Von Hoff et al., 1979). Simultaneous application of cisplatin during WBH produces unacceptable renal toxicity in humans as well as in experimental animals (Gerard et al., 1983;Bull, 1984;Mella et al., 1987). Our previous studies demonstrated that administration of cisplatin combined with WBH caused a 3-fold increase in renal injury, resulting in a limited therapeutic gain of this combined modality .Carboplatin is a new platinum complex with a similar spectrum of antitumour activity as cisplatin (Wagstaff et al., 1989). The major advantage of carboplatin is that it produces minimal or no nephrotoxicity. The dose-limiting toxicity of this analog is myelosuppression, mainly in form of thrombocytopenia (Harrap et al., 1980;Calvert et al., 1982;Wiltshaw, 1985). As observed with cisplatin, the cytotoxicity of carboplatin was also enhanced when combined with hyperthermia in vitro (Cohen & Robbins, 1987;Xu & Alberts, 1988 The purpose of this study is therefore, to examine the severity of thrombocytopenia, anaemia and leukopenia induced by carboplatin or cisplatin...

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Section: Discussionmentioning

confidence: 88%

Haematological toxicity of carboplatin and cisplatin combined with whole body hyperthermia in rats

Ohno¹,

Strebel²,

Stephens³

et al. 1993

Br J Cancer

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“…Some of these complexes are also very potent broad-spectrum antitumour agents. Indeed, it is considered that Pt" complexes inhibit DNA synthesis by direct interaction with the nucleic acid (Harder & Rosenberg, 1970). In addition, it has been found that this interaction depends on heterocyclic base composition MiUard, Macquet & Theophanides, 1975), guanine being the preferred site of attack, at least at low complex/DNA ratios, and induces localized conformational changes in DNA (Munchausen & Rahn, 1975;Tamburro, Celotti, Furlan & Guantieri, 1977).…”

Section: Introductionmentioning

confidence: 99%

Structure and activity relationships of platinum complexes related to antitumour activity: the crystal and molecular structure of trans-dichlorobis (cyclohexylamine)platinum(II)

Zanotti¹,

Prà²,

Bombieri³

et al. 1978

Acta Crystallogr Sect B

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Crystals of trans-dichlorobis(cyclohexylamine)platinum(II), PtCI2(C6HIINH2)2, are orthorhombic, space group Pbcn, with four molecules in a cell of dimensions a = 26.170 (9), b = 6.673 (2) and c = 9.002 (4) ./k. Intensity data were collected on a four-circle diffractometer with Mo K~ radiation. The structure was solved by the heavy-atom method and refined by full-matrix least squares to a final conventional R value of 0.041 for 1131 observed reflections. The Pt atom configuration is square-planar with the N and C1 atoms in trans positions. The cyclohexyl ring assumes a chair-like conformation.

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“…In mammalian, as well as in bacterial cells, DNA is the preferential target for Pt compounds. For cis-Pt(NH3)2CI2 this interaction results in lesions that selectively block DNA replication (4,5). In this respect, cis-Pt compounds behave similar to other drugs such as alkylating and radiomimetic agents.…”

mentioning

confidence: 99%

Base-pair substitution hotspots in GAG and GCG nucleotide sequences in Escherichia coli K-12 induced by cis-diamminedichloroplatinum (II).

Brouwer¹,

Putte²,

Fichtinger-Schepman³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

114

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Cell killing and mutation induction by cis-and trans-Pt(NH3)2Cl2 in Escherichia coli were examined by studying forward mutagenesis in the lad gene in cells with different repair capacities. Survival experiments showed that repair-proficient cells were slightly more sensitive for the cis isomer than for the trans isomer, whereas repair-deficient RecA and UvrB cells were extremely sensitive only for the cis compound. cis-Pt(NH3)2CI2 induced mutagenesis in both wild-type cells and RecA cells but not in UvrB cells; whereas no detectable mutagenesis was induced by treatment with the trans compound. Examination of the nature of the mutations induced by cis-Pt(NH3)WCI2, by. using the Lad system, revealed that base-pair substitutions leading to nonsense mutants are only induced in wild-type cells, suggesting that the intact products of both the uvrB and the recA gene are necessary for the repair responsible for this type of mutagenesis. Investigation ofthe nonsense mutants reveals that 70% ofthese mutations result from GC --TA or GC --AT substitutions at sites where the guanine is part of a GAG or GCG sequence. These results are discussed in relation to existing theories on the interaction between Pt compounds and DNA. A model for Pt-DNA adducts, leading to base-pair.substitutions, is proposed.About a decade ago, Rosenberg et aL (1) reported that cisPt(NH3)2CI2 shows antitumor activity against sarcoma 180 and leukemia L1210, whereas trans-Pt(NH3)2C12 is ineffective.Since then it has been shown that several other cis Pt(II) and cis Pt(IV) compounds exhibit antitumor activity (2, 3). In mammalian, as well as in bacterial cells, DNA is the preferential target for Pt compounds. For cis-Pt(NH3)2CI2 this interaction results in lesions that selectively block DNA replication (4, 5). In this respect, cis-Pt compounds behave similar to other drugs such as alkylating and radiomimetic agents.In vitro, cis-Pt(NH3)2C12 binds to bases in DNA, and the order of binding affinity has been shown to be guanine>ad-enine>cytosine>>thymine, with a strong preference for the N-7 position of guanine (6). Monofunctional binding to a single base is unlikely to be the principal lesion through which cisPt(NH3)2CI2 exerts its antitumor activity because, at equitoxic doses, more of the inactive trans compound is bound to DNA (7). Therefore, specific bifunctional binding of cis-Pt(NH3)2CI2 to DNA is thought to be responsible for its antitumor activity.For the bifunctional mode of action, several models have been proposed such as intrabase chelation at the 0-6 and N-7 positions of guanine (6,8), interstrand crosslinking between the N-7 positions of guanines in opposite strands (3,7,9), and intrastrand crosslinks between two, presumably adjacent, guanines in the same strand (10-12).In bacteria (13-17), as well as in eukaryotic cells (18)(19)(20), a correlation between mutagenicity and antitumor activity ofseveral Pt compounds has been found, suggesting that lesions leading to mutation events can also be responsible for antitumor activity. Several...

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Inhibitory effects of anti‐tumor platinum compounds on DNA, RNA and protein syntheses in mammalian cells in vitro

Cited by 363 publications

References 10 publications

Haematological toxicity of carboplatin and cisplatin combined with whole body hyperthermia in rats

Haematological toxicity of carboplatin and cisplatin combined with whole body hyperthermia in rats

Structure and activity relationships of platinum complexes related to antitumour activity: the crystal and molecular structure of trans-dichlorobis (cyclohexylamine)platinum(II)

Base-pair substitution hotspots in GAG and GCG nucleotide sequences in Escherichia coli K-12 induced by cis-diamminedichloroplatinum (II).

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