Antitumor activity of platinum(II) complexes with histamine and radioiodinated histamine in a transplantable murine adenocarcinoma model.
OBJECTIVE
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 (PtCl(2)Hist, PtCl(2)[(125)I]Hist, PtCl(2)[(131)I]Hist, PtCl(2)Hist/PtCl(2)[(125)I]Hist and PtCl(2)Hist/PtCl(2)[(131)I]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 x ca. 0.5.MTD(Pt) up to Day 13 of the treatment). Experiment 3 included long-term concomitant multidose treatment with higher single doses (9x0.9-0.4.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 PtCl(2)Hist, PtCl(2)Hist/PtCl(2)[(131)I]Hist, and PtCl(2)Hist/PtCl(2)[(125)I]Hist, respectively. Significant (P<.05) prolongations of median survivals (MS) were found in Experiment 2 following the treatment with higher single doses of PtCl(2)Hist and PtCl(2)His/PtCl(2)[(125)I]Hist (Ratio MS(tr)/MS(con) ca. 1.4). A slightly less potent activity was observed for PtCl(2)Hist/PtCl(2)[(131)I]Hist, and no survival improvement was found for the groups treated mostly with the radiation (PtCl(2)[(125)I]Hist and PtCl(2)[(131)I]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.


CONCLUSIONS
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.
Garnuszek
Piotr
P
Department of Radiopharmaceuticals, National Medicines Institute, 00-725 Warsaw, Poland. pgarnuszek@il.waw.pl
Karczmarczyk
Urszula
U
Maurin
Michał
M
D000230:Adenocarcinoma / Q000473:pathology / Q000532:radiotherapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D006632:Histamine / Q000737:chemistry / Q000627:therapeutic use*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000532:radiotherapy*; D020714:Maximum Tolerated Dose; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D019275:Radiopharmaceuticals; D006632:Histamine