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Inter- and Intratumoral Disposition of Platinum in Solid Tumors after Administration of Cisplatin

Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 [W. C. Z.]; Departments of Medicine [W. C. Z., M. J. E.] and Pharmacology [M. J. E., J. L. E.], School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; Program of Molecular Therapeutics and Drug Discovery [W. C. Z., A. C. G., M. J. E., D. R. H., B. J. D., A. G., E. G. Z., E. J., J. L. E.] and Biostatistics Facility [D. M. P.], University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213; and Department of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, 1066 CX The Netherlands [J. H. M. S., D. P.]

One possible explanation for variable tumor response within a single patient may be related to delivery of chemotherapeutic agents to the tumors. Microdialysis was used to evaluate inter- and intratumoral disposition of unbound platinum (Pt) after cisplatin administration to mice bearing B16 murine melanoma tumors or H23 human NSCLC xenografts. Before i.v. dosing with cisplatin (3 or 10 mg/kg), microdialysis probes were placed into the right and left sides of each tumor, and serial extracellular fluid (ECF) samples were collected for 2 h. After microdialysis, tumor samples were obtained at each probe site to measure total Pt and Pt-DNA adducts. In a separate study, serial plasma samples (n = 3 mice/time point) were obtained between 5 min and 2 h. Unbound Pt in tumor ECF and plasma and total Pt in tumor homogenates were measured by flameless atomic absorption spectrophotometry. Pt-DNA adducts in tumor samples were measured via ³²P-postlabeling. Area under the plasma (AUC_P) and tumor ECF (AUC_ECF) concentration-time curves of unbound Pt were calculated. Factor VIII expression was measured by immunohistochemistry in tumor samples. After administration of 3 or 10 mg/kg of cisplatin to mice bearing B16 tumors, there was a proportional increase in AUC_PL with dose; however, there was not a proportional increase in AUC_ECF. There was a relatively high (30-fold) inter- and low (2.5-fold) intratumoral variability in AUC_ECF. AUC_ECF correlated better with Pt-DNA adduct formation than did total Pt concentration in tumors. There was no relationship between Factor VIII expression and Pt exposure in tumors. The variable penetration of Pt from plasma into tumor ECF may be associated with variable response of tumors.

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