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Antitumor effectiveness of electrochemotherapy with cis-diamminedichloroplatinum(II) in mice.

One of the ways to increase drug delivery into cells and tissues is by a local application of short, intense electric pulses, i.e., electropermeabilization. This approach is used in electrochemotherapy to potentiate antitumor effectiveness of chemotherapeutic drugs. To determine whether electropermeabilization can potentiate antitumor effectiveness of cis-diamminedichloroplatinum(II) (CDDP), electrochemotherapy with CDDP was tested in vitro and in vivo on s.c. SA-1, EAT, and melanoma B16 tumors in mice. Electric pulses were applied to the tumors by percutaneously placed electrodes after i.v. injection of CDDP. Severalfold potentiation of CDDP antitumor effectiveness with electric pulses was obtained, inducing partial or complete responses in tumor growth. Electrochemotherapy was CDDP dose dependent, as well as dependent upon the amplitude of electric pulses. Also important was the sequencing and the interval of CDDP administration, relative to application of electric pulses. Specifically, a good antitumor effect without side effects was obtained with eight electric pulses (electric pulse amplitude, 1040 V; repetition frequency, 1 Hz; pulse width, 100 microseconds; electrode distance, 8 mm; 1300 V/cm) applied 3 min after i.v. injection of 4 mg/kg CDDP. With a higher CDDP dose (8 mg/kg), some long-term complete responses were obtained (14%) on melanoma B16 tumors. Thus, electrochemotherapy with CDDP offers an approach to making chemotherapy with CDDP more effective.