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

Abstract

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...

Enhanced radiosensitivity in experimental tumours following erythropoietin treatment of chemotherapy-induced anaemia

“…(Siddik et al, 1987). The data on carboplatin-induced anaemia obtained in the present study are in good accordance with observations made by other investigators (Siddik et al, 1987;Ohno et al, 1993), describing a dose-dependent induction of anaemia with carboplatin doses between 40 and 60 mg kg-'. Although Siddik et al (1987) concluded that internal haemorrhaging as a result of thrombocytopenia causes the carboplatin-induced anaemia, no signs of severe bleeding were observed in the present study.…”

Nephroprotective Effects of Carvedilol and Curcuma longa against Cisplatin-Induced Nephrotoxicity in Rats

“…Furthermore, decreased TEC and Hb by cisplatin may be the attributing factor for decreased level of PCV in present study. Mild thrombocytopenia is one of the consequences of hematological toxicities by cisplatin 16 , however; the observations in the present study are not in agreement with above report. This might be due to reversible appearance of thrombocytes to the normal levels by 18 days or inability of cisplatin to suppress platelets at dose (7.5 mg/kg) used in present study.…”

Fever-range whole body hyperthermia increases the number of perfused tumor blood vessels and therapeutic efficacy of liposomally encapsulated doxorubicin

“…Previous work by others has evaluated whole body hyperthermia (WBH) protocols in which the patient is brought to relatively hot systemic temperatures (e.g. greater than 41.5 C) in combination with various chemotherapeutic agents [30][31]; however, clinical gain was limited by increased chemotherapy-induced toxicity [32]. As a result, Bull and co-workers pioneered a milder (i.e.…”