Tyrphostin 4-nitrobenzylidene malononitrile reduces chemotherapy toxicity without impairing efficacy

• Published in: Cancer research (Chicago, Ill.) Vol. 58; no. 11; pp. 2397 - 2403
• Main Authors: NOVOGRODSKY, A, WEISSPAPIR, M, PATYA, M, MESHORER, A, VANICHKIN, A
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.06.1998
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - adverse effects; Apoptosis - drug effects; Biological and medical sciences; Bone Marrow - drug effects; Chemotherapy, Adjuvant; Cisplatin - adverse effects; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Doxorubicin - adverse effects; Drug Interactions; Enzyme Inhibitors - pharmacology; Female; Humans; Intestine, Small - drug effects; Kidney - drug effects; Lung Neoplasms - pathology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental - pathology; Nitriles - pharmacology; Pharmacology. Drug treatments; Protective Agents - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Tumor Cells, Cultured; Tyrphostins; Antineoplastic agent; Lewis lung carcinoma; Carcinoma; Toxicity; Spontaneous; Tumoral tissue; Fibrosarcoma; Doxorubicin; Secondary effect; Platinum II Complexes; Lung disease; Drug combination; Sarcoma; Respiratory disease; Rodentia; Tolerance; Malignant tumor; In vitro; Cisplatin; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Anthracyclins
• ISSN: 0008-5472; 1538-7445

In mice, 4-nitrobenzylidene malononitrile (AG1714), which belongs to the tyrphostin family, reduced toxicity induced by doxorubicin and cisplatin without impairing their antitumor efficacy. AG1714 reduced mortality induced by doxorubicin and cisplatin. It prevented, in a dose-dependent manner, cisplatin-induced nephrotoxicity as assessed by measurement of serum creatinine and blood urea nitrogen levels. The protective effect of AG1714 was most pronounced on its administration 2 h before cisplatin. AG1714 also prevented doxorubicin-induced myelosuppression as assessed by the scoring of bone marrow nucleated cells and colony-forming units. Cisplatin-induced small intestinal injury was also protected by AG1714 as assessed by histopathological analysis. In vitro, AG1714 reduced cisplatin-induced apoptosis in a murine fibroblastic cell line (A9) and did not affect doxorubicin-induced apoptosis of B-16 melanoma cells. In contrast to its protective effect against mortality and injury of normal tissues induced by chemotherapy, AG1714 did not impair its antitumor activity and in some tumor models enhanced it. This was evident by using the murine tumors B-16 melanoma, Lewis lung carcinoma, and methylcholanthrene-induced fibrosarcoma and the human tumors SK-28 melanoma and human ovary carcinoma xenografts in nude mice. Experiments in which low and high doses of cisplatin and doxorubicin were administered to tumor-bearing mice demonstrated that AG1714 reduced mortality of high-dose chemotherapy and increased its therapeutic index. AG1714 could provide a novel, useful tool to improve chemotherapy by allowing dose intensification.