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Suppression of tumor promotion by inhibitors of poly(ADP)ribose formation
1Institute of Environmental Medicine, New York University Medical Center, New York 10016.
Abstract:
Tumor promoters, such as phorbol esters or hormones, cause many biological effects which may contribute to the expression of cancer. The mechanism of cancer expression may have a common theme. One method of learning about this common mechanism is the identification of chemicals that interfere with tumor development. That there is actually a common theme between very different substances, such as inflammatory skin tumor promoters and estradiol causing breast cancer, was shown by the fact that both skin and breast cancers are suppressed by the same agents, e.g., protease inhibitors and retinoids. In addition to skin and breast, protease inhibitors suppress colon, bladder, and liver cancers. The substances that crossed over in suppressing many varieties of cancer were found to inhibit oxygen radical formation by tumor promoter-activated neutrophils and ras oncogene expression in NIH 3T3 cells. Poly(ADP)ribose polymerase (PADPR polymerase) may serve as the connecting link between oxygen radicals that cause its activation and oncogene expression. PADPR polymerase is inhibited by retinoids, antioxidants, and some protease inhibitors. Benzamide, an inhibitor of PADPR polymerase, is also a chymotrypsin inhibitor which suppresses oxygen radical formation by tumor promoter-activated neutrophils. The inhibition of PADPR polymerase causes the expulsion of some oncogenes from NIH 3T3 cells at definite times after oncogene transfection. Further work is required to find what are the contributions of PADPR polymerase to tumor promotion and of its inhibitors to suppression of oncogene expression.
Insights
Protease inhibitors and retinoids suppress various cancers by inhibiting oxygen radical formation and oncogene expression. Poly(ADP)ribose polymerase (PADPR polymerase) links these processes, with its inhibitors showing promise in cancer suppression.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Tumor promoters like phorbol esters and hormones contribute to cancer development through various biological effects.
- A common mechanism underlying cancer expression suggests shared pathways across different cancer types.
- Identifying chemicals that interfere with tumor development is crucial for understanding cancer mechanisms.
Purpose of the Study:
- To identify common mechanisms in cancer expression and discover agents that suppress diverse tumor types.
- To investigate the role of specific chemical agents in inhibiting tumor promoter-activated neutrophils and oncogene expression.
- To explore the potential link between oxygen radicals, Poly(ADP)ribose polymerase (PADPR polymerase), and oncogene expression in cancer.
Main Methods:
- Investigated the suppressive effects of protease inhibitors and retinoids on skin, breast, colon, bladder, and liver cancers.
- Assessed the inhibition of oxygen radical formation by tumor promoter-activated neutrophils by specific agents.
- Examined the suppression of ras oncogene expression in NIH 3T3 cells and the role of PADPR polymerase.
Main Results:
- Protease inhibitors and retinoids demonstrated cross-over efficacy in suppressing multiple cancer types.
- Identified agents that inhibit oxygen radical formation and ras oncogene expression.
- Demonstrated that Poly(ADP)ribose polymerase (PADPR polymerase) activation by oxygen radicals may link to oncogene expression, and its inhibition by retinoids, antioxidants, and protease inhibitors can lead to oncogene expulsion.
Conclusions:
- A common theme exists in cancer expression, targetable by agents like protease inhibitors and retinoids.
- Poly(ADP)ribose polymerase (PADPR polymerase) activation by oxygen radicals is a potential key mediator in tumor promotion and oncogene expression.
- Inhibitors of PADPR polymerase, including retinoids and protease inhibitors, show potential for cancer suppression by affecting oncogene expression.