Antitumor, Toxic and Biochemical Properties of Cisplatin and Eight Other Platinum Complexes

The comparative nephrotoxicity of i.v. cisplatin, i.v. carboplatin and six p.o. ammine/amine Pt(IV) dicarboxylates was studied in rodents following single MTD treatments. In mice, i.v. cisplatin caused proteinuria (1 g l-1), glycosuria (16.7 mM) and decreased GFR at 4 days, and histological kidney damage with onset at 6 days. In contrast, mice treated with i.v. carboplatin or p.o. ammine/amine Pt(IV) dicarboxylates had urinary glucose, urinary protein, GFR and kidney histology within the control range. In rats, i.v. cisplatin caused 5-fold elevations in plasma creatinine (188 +/- 33 microM) and urea (30.4 +/- 8.9 mM), a 10-fold fall in creatinine clearance (0.54 +/- 0.31 ml min-1 kg-1), a 25-fold elevation in urine/plasma glucose concentration ratio (3.28 +/- 0.17), a 20% increase in kidney weight (7.9 +/- 0.56 mg gm-1 body weight) and extensive histological damage 4 days after treatment. In contrast, i.v. carboplatin and p.o. JM216 (the lead compound of this series) caused neither abnormalities in renal function nor histological damage in rats. The nephrotoxicity of single MTD treatments of p.o. ammine/amine Pt(IV) dicarboxylate complexes appears less than i.v. cisplatin and comparable to i.v. carboplatin.

Section: Discussionsupporting

confidence: 70%

mentioning

confidence: 99%

Lack of nephrotoxicity of oral ammine/amine platinum (IV) dicarboxylate complexes in rodents

McKeage

Morgan²,

Boxall³

et al. 1993

“…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 in combination with WBH and to determine and compare the thermal enhancement ratios of those haematological toxicities.…”

mentioning

confidence: 99%

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

Ohno¹,

Strebel²,

Stephens³

et al. 1993

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...

“…Such models include the P388 leukaemia, L1210 leukaemia, Lewis lung carcinoma, B16 melanoma, Colon 38 and CD8F1 mammary carcinoma. Our earlier work, which predicted the clinical antitumour activities of the platinum analogues JM8 (carboplatin) and JM9 (iproplatin), exploited predominantly the platinum-sensitive ADJ/PC6 murine plasmacytoma (Harrap et al, 1980;Harrap, 1985). Other workers have generated cisplatin-resistant variants of the L1210 and P388 tumours in attempts to identify novel platinum drugs which might exhibit wider spectra of antitumour activities (Burchenal et al, 1979(Burchenal et al, , 1980.…”

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confidence: 99%

Biological properties of ten human ovarian carcinoma cell lines: calibration in vitro against four platinum complexes

Hills

Kèlland²,

Abel³

et al. 1989

166

Summary Ten human ovarian carcinoma cell lines have been studied as a potential in vitro screen for the development of novel anticancer platinum complexes. Lines have been established and developed both from solid and ascitic tumours, from pretreated and untreated patients, and are available at a range of in vitro passage numbers. The biological properties of the lines were consistent with them being human, epithelial and of ovarian carcinoma origin. Using a tritiated thymidine or leucine uptake method, and a 96 hour continuous drug exposure, the lines have been calibrated against four platinum-containing chemotherapeutic agents: cisplatin, iproplatin, carboplatin and tetraplatin. Striking differences in cytotoxicity were observed across the lines for each agent. Some lines were consistently resistant, others generally sensitive, whereas some showed clear evidence of differential sensitivity to a particular agent. Statistical analysis (Spearman rank correlation) involving the six possible pairings of drugs showed that cisplatin, iproplatin and carboplatin elicit a very similar pattern of response in these lines whereas tetraplatin elicits a completely different response pattern. Similar cytotoxicity values were obtained using a soft agar cloning assay. Results using a tetrazolium dye reduction assay, however, gave somewhat higher and more variable values, particularly with tetraplatin. The thymidine uptake assay will be adopted in further studies on a selected panel of six lines. This panel encompasses the spectra of sensitivities identified for each of the four agents against the original ten lines and may provide a useful screening facility for the development of novel platinum drugs, in that it detects both cell line-determined and structure-determined differences in cytotoxicity.Traditionally, the development of new drugs for the treatment of malignant diseases has relied predominantly on transplantable murine tumour models, such as those used by the National Cancer Institute (NCI) (Frei, 1982;Venditti, 1983). Such models include the P388 leukaemia, L1210 leukaemia, Lewis lung carcinoma, B16 melanoma, Colon 38 and CD8F1 mammary carcinoma. Our earlier work, which predicted the clinical antitumour activities of the platinum analogues JM8 (carboplatin) and JM9 (iproplatin), exploited predominantly the platinum-sensitive ADJ/PC6 murine plasmacytoma (Harrap et al., 1980;Harrap, 1985). Other workers have generated cisplatin-resistant variants of the L1210 and P388 tumours in attempts to identify novel platinum drugs which might exhibit wider spectra of antitumour activities (Burchenal et al., 1979(Burchenal et al., , 1980. Tetraplatin exhibits no cross-resistance in such models and is currently under preclinical development at NCI (Anderson et al., 1986). A recent reappraisal of screening models at the NCI has resulted in the replacement of the in vivo murine panel in favour of a range of in vitro human tumour cell lines representative of the major histological types (Boyd, 1986).Clinical trials using platinum-con...