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Hyperthermia (HT) potentiates in vitro cytotoxicity of cisplatin, providing a rationale for HT enhancement of cisplatin effect in vivo. In this study, regional abdominal HT was combined with intraperitoneal (IP) cisplatin in canines to characterize temperature distributions, as well as pharmacokinetics and toxicity of IP cisplatin with and without HT. Cisplatin (65 mg/m2) in normal saline was administered IP with a two-hour dwell time in ten Beagle dogs. Five of the ten dogs were randomly selected to receive concurrent regional microwave-producing HT at approximately 41.5 degrees C (IP) for a 60-minute period. Systemic temperatures in heated animals ranged from 37 degrees C to 40 degrees C; IP temperatures ranged from 39 degrees C to 44 degrees C. Initial IP temperatures ranged from 39 degrees C to 44 degrees C. Initial IP cisplatin concentrations were ten to 22 times greater than serum levels; the IP drug half-lives were 133 +/- 9 minutes and 68 +/- 15 minutes in heated and unheated dogs, respectively (P less than .001). Total concentrations of serum and urine cisplatin did not differ between the heated and unheated controls. The area under the concentration v time curve for free, ultrafilterable cisplatin in serum in units of percent minutes was 40 +/- 8 in heated and 60 +/- 7 in unheated controls (P = .006). Except for transient nausea and vomiting, no evidence of serious toxicity was observed in serum chemistries or histopathologic sections at 21 days post-treatment. Experiments involving in vitro incubation of cisplatin in normal saline were performed as a function of saline temperature; these showed that the amount of reactive cisplatin metabolites formed increased linearly with temperature by approximately 30% from 38 degrees C to 44 degrees C. This study supports the hypothesis that, with IP temperature elevation, there is an increased rate of generation and retention of reactive metabolites of cisplatin in the peritoneal cavity relative to unheated controls. In spite of these differences in pharmacokinetics, no significant toxicity was encountered. This study provides a model for treatment of IP malignancy such as ovarian carcinoma with IP cisplatin and regional HT.
E L Zakris, and
M W Dewhirst, and
J E Riviere, and
P J Hoopes, and
R L Page, and
J R Oleson
December 1993,
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E L Zakris, and
M W Dewhirst, and
J E Riviere, and
P J Hoopes, and
R L Page, and
J R Oleson
January 1991,
European journal of cancer (Oxford, England : 1990),
E L Zakris, and
M W Dewhirst, and
J E Riviere, and
P J Hoopes, and
R L Page, and
J R Oleson
January 1998,
European journal of cancer (Oxford, England : 1990),
E L Zakris, and
M W Dewhirst, and
J E Riviere, and
P J Hoopes, and
R L Page, and
J R Oleson
January 2002,
Anticancer research,
E L Zakris, and
M W Dewhirst, and
J E Riviere, and
P J Hoopes, and
R L Page, and
J R Oleson
July 2003,
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E L Zakris, and
M W Dewhirst, and
J E Riviere, and
P J Hoopes, and
R L Page, and
J R Oleson
September 1993,
British journal of cancer,
E L Zakris, and
M W Dewhirst, and
J E Riviere, and
P J Hoopes, and
R L Page, and
J R Oleson
January 1992,
Journal de gynecologie, obstetrique et biologie de la reproduction,
E L Zakris, and
M W Dewhirst, and
J E Riviere, and
P J Hoopes, and
R L Page, and
J R Oleson
April 1993,
Zhonghua fu chan ke za zhi,
E L Zakris, and
M W Dewhirst, and
J E Riviere, and
P J Hoopes, and
R L Page, and
J R Oleson
November 1983,
World journal of surgery,
E L Zakris, and
M W Dewhirst, and
J E Riviere, and
P J Hoopes, and
R L Page, and
J R Oleson
April 1982,
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