Antitumor activity of platinum(II) complexes with histamine and radioiodinated histamine in a transplantable murine adenocarcinoma model

Abstract 

Purpose

Antitumor activity of the dichloroplatinum(II)–histamine complexes labeled with I-125 or I-131 was investigated in a transplantable murine adenocarcinoma (MA) model.

Methods

The tumor model was obtained in C3H/W female mice after subcutaneous inoculation of the tumor cells derived from the mice bearing a mammary tumor of spontaneous origin. Antitumor activities of the platinum-histamine complexes were investigated in three independent experiments, which differed in applied doses of preparations (PtCl₂Hist, PtCl₂[¹²⁵I]Hist, PtCl₂[¹³¹I]Hist, PtCl₂Hist/PtCl₂[¹²⁵I]Hist and PtCl₂Hist/PtCl₂[¹³¹I]Hist), treatment schedules as well as stages of the disease progress in the animals used. Experiment 1 included long-term, multidose treatment with low single doses (treatment duration 31–32 days; 8–10 doses of ca. 0.25∙MTD_Pt each). Experiment 2 included short-term, multidose treatment with higher single doses (4×ca. 0.5∙MTD_Pt up to Day 13 of the treatment). Experiment 3 included long-term concomitant multidose treatment with higher single doses (9×0.9–0.4∙MTD_Pt up to Day 33).

Results

The long-term treatment with the platinum-histamine preparations revealed inhibiting activity on the tumor growth and size in comparison to control groups. The most intensive and significant antitumor effects were observed for the radioactive complexes. The tumor growth delay factors (GDFs) observed in Experiment 1 were 0.4, 0.7, and 1.2 for PtCl₂Hist, PtCl₂Hist/PtCl₂[¹³¹I]Hist, and PtCl₂Hist/PtCl₂[¹²⁵I]Hist, respectively. Significant (P<.05) prolongations of median survivals (MS) were found in Experiment 2 following the treatment with higher single doses of PtCl₂Hist and PtCl₂His/PtCl₂[¹²⁵I]Hist (Ratio MS_tr/MS_con ca. 1.4). A slightly less potent activity was observed for PtCl₂Hist/PtCl₂[¹³¹I]Hist, and no survival improvement was found for the groups treated mostly with the radiation (PtCl₂[¹²⁵I]Hist and PtCl₂[¹³¹I]Hist). The intensive and long-term concomitant scheduling of the radioactive platinum–histamine complexes labeled with I-125 and I-131 (Experiment 3) resulted in a significant inhibition of the tumor growth (GDF=1.9) and survival prolongation of the tumor-bearing mice (MS_tr/MS_con=1.5, P=.023). The treatment-related toxicity was mild.

Conclusion

An enhancement of the antitumor activity due to the multidose concomitant treatment with a combination of cytotoxic/cytostatic dichloroplatinum(II)–histamine and the attached iodine radionuclides was shown in the murine model of experimental neoplasm.

Keywords: Dichloroplatinum(II)–histamine, Iodine radioisotopes/therapeutic use, Chemoradiotherapy, Experimental neoplasm, C3H mice, Treatment outcome