title: Intraperitoneal cisplatin with regional hyperthermia in advanced ovarian cancer: pharmacokinetics and cisplatin-DNA adduct formation in patients and ovarian cancer cell lines.
abstract: The purpose of this study was to investigate the influence of hyperthermia on cisplatin pharmacokinetics and DNA adduct formation. The latter was investigated both in tumour cell lines in vitro and in tumour cells and buccal cells from cancer patients. The patients had advanced ovarian carcinoma and were entered into a phase I study for cytoreductive surgery followed by hyperthermia in combination with intraperitoneal cisplatin administration. The cisplatin-DNA modifications in vivo and in vitro were studied by an immunocytochemical method with the polyclonal antiserum NKI-A59. The patient samples for pharmacokinetic determinations were analysed by flameless atomic absorption spectrometry. In vitro, the combination of hyperthermia and cisplatin enhanced cell killing compared with either treatment alone, such that the cisplatin-resistant ovarian cell line A2780/DDP became almost as sensitive as the parent A2780 cell line (resistance factor reduced from 30 to 2 at the IC50). In addition, increased cisplatin-DNA adducts were observed in the resistant cell line after the combined treatment compared with cisplatin alone. A good correlation was found between nuclear staining density and surviving fraction for all groups, indicating that the DNA adducts generated are an important determinant of toxicity and that the mechanism by which hyperthermia enhances kill is by increasing adduct levels. In the patients, the ratio of drug concentration in the peritoneal perfusate compared with that in plasma was found to be approximately 15, indicating a favourable pharmacokinetic ratio. Cisplatin-DNA adduct formation in tumour cells from patients was higher than in buccal cells, reflecting this higher drug exposure, i.e. local plus systemic versus systemic only. In addition, the tumour cells but not buccal cells were exposed to hyperthermia. The higher number of tumour adducts also suggests that a favourable therapeutic ratio could be achieved. Platinum-DNA adduct formation was found to decrease with distance from the surface of the tumour nodules. However, at a distance of 3-5 mm, the nuclear staining density levels were still measurable and higher than in buccal cells. In conclusion, the combined pharmacokinetic and adduct data in patients support the advantages of the intraperitoneal route for drug administration, and the addition of heat.
authors.affiliation: Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: P J
authors.initials: PJ
authors.lastname: van de Vaart
authors.forename: N
authors.initials: N
authors.lastname: van der Vange
authors.forename: F A
authors.initials: FA
authors.lastname: Zoetmulder
authors.forename: A R
authors.initials: AR
authors.lastname: van Goethem
authors.forename: O
authors.initials: O
authors.lastname: van Tellingen
authors.forename: W W
authors.initials: WW
authors.lastname: ten Bokkel Huinink
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: H
authors.initials: H
authors.lastname: Bartelink
authors.forename: A C
authors.initials: AC
authors.lastname: Begg
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002945:Cisplatin / Q000008:administration & dosage* / Q000378:metabolism* / Q000493:pharmacokinetics; D003131:Combined Modality Therapy; D018736:DNA Adducts / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D007263:Infusions, Parenteral; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D004273:DNA, Neoplasm; C057270:cisplatin-DNA adduct; D002945:Cisplatin