Victor D. Warner

Potential Carcinogens from Steroid Hormones and Diethyl Stilbesterol (DES): Chemical Relationships between Breast, Ovarian and Prostate Cancers

With the exception of certain environmental causes of cancer like sun and occupational exposure (asbestos), many malignancies result from smoking, alcohol or dietary factors and others may be due to endogenous factors. While a large amount of research has focused on exogenous carcinogens both environmental and dietary, much less has been devoted to potential endogenous cancer initiators. In part, this stems from disbelief that naturallyoccurring compounds in man are carcinogens. Yet, reactive metabolites of the steroid hormones and related compounds have the potential to transform cellular nucleic acids and thereby initiate precursors to the malignant cell. An example is a potential metabolite of estradiol, which could lead to catechol estrogens, was shown to be as mutagenic as 3-methylcholantrene in 1980. And yet, no further research has been done to determine whether this proposed metabolite occurs in mammalian systems and if it does, whether it is a causative agent in breast or ovarian malignancies. Four important questions are: (1) if such metabolites arise in vivo, will tests show them to be carcinogenic?, (2) is there a dose-response relationship, in their causation of malignancies?, (3) what are the biological mechanisms, by which these compounds arise?, and (4) are these pathways perturbed in breast and prostate cancer patients, leading to excessive accumulation of these mutagens? These are merely four of many questions that must be addressed when examining potential endogenous carcinogens. Increasingly, there appears to be a genetic relationship between breast, ovarian and prostate cancers. Could that connection arise from chemical similarities between carcinogenic initiators derived from steroid hormones, their formation, incorporation into nuclear receptors as well as their rate of hydrolysis? These issues in addition to a clarification of the origin of such endogenous carcinogens will be explored. A testable hypothesis is proposed.

Possible chemical initiators of cognitive dysfunction in phenylketonuria, Parkinson’s disease and Alzheimer’s disease

Though a great deal is known of the pathophysiology of phenylketonuria (PKU), Parkinsons disease (PD) and Alzheimers disease (AD) very little is known regarding possible chemical species responsible for initiating the cascade of events that ultimately cause cognitive dysfunction. Can these be viewed as inborn errors in metabolism, occurring at various stages in the life cycle, analogous to adult onset diabetes? One major deficiency in understanding such conditions is the paucity of information regarding the total metabolic pathway for various amino acids that may be implicated in their causation. For example in PKU, its etiology was reported in 1934 and dietary restriction of phenylalanine proved effective for individuals with unsatisfactory metabolism of phenylalanine. Yet, current phenylalanine metabolism does not take into account fully the multiple biochemical pathways operating whose role is preventing burdensome accumulations of intermediates that can contribute to morbidity and toxicity. The same may apply for metabolism of tyrosine in PD and methionine in AD. Especially important, are the presence of labile and reactive chemical species which may be causative agents in protein alteration, misfolding and the creation of prions in neurodegenerative diseases, thereby preventing normal protein catabolism and excretion. Though genetic or epigenetic factors must be responsible, the question remains how are these translated into the chemical structures responsible for disease initiation? The purpose of this presentation is to explore potential labile metabolites in those biochemical pathways, which may be contributing factors. Finally it is worth noting, that drug development has been increasingly designed based upon targeting genetic deficiencies. The effectiveness of this approach for the treatment of these neurodegenerative illnesses will be determined in the future.

Alkylamine Salts and Amides: In Vitro Inhibition of S mutans 6715

Our studies with the salts and amides of alkylamines have shown that the undecylenate salts have significant in vitro activity against S mutans No. 6715, suggesting that these agents are worthy of additional evaluation. The attempt to increase activity by combining undecylenic acid with the alkylamines was not successful; however, better attachment to tooth surfaces and/or retention during washing did occur. Our results suggest that the free amino group of alkylamines and the free acid group of undecylenic acid are required for these two classes of agents to demonstrate antibacterial activity.

Carbamimic Acid Ester as an Inhibitor of Streptococcus Mutans Strain 6715

This study was supported, in part, by the Department of Health, Education, and Welfare Grant RR 07143. Received for publication January 12, 1976. Accepted for publication July 9, 1976. * BBL-Gaspack, Baltimore Biological Laboratories, Division of Bioquest, Cockeysville, Md. phenyl) amino]iminomethyl-carbamimidic acid [4] was obtained. Preliminary antibacterial screening indicated that this compound was approximately ten times more active than the nitrogen isostere, Nl-(4. chlorophenyl) -N5-ethylbiguanide acetate [3] (Table). Since the carbamimidic acid derivative

Infections caused by resistant organisms: Could organic arsenic compounds be an effective treatment?

Without question one of the most important medicinal chemistry discoveries of the 20th century was made by Paul Ehrlich and his colleagues, chemist, Alfred Bertheim and bacteriologist, Sahachiro Hata. They ushered in the age of targeted chemotherapy in 1910 with the discovery of the anti-syphilitic organic arsenic agent, arsphenamine or Salvarsan (also known as 606). It was the clinical compound of choice for treating syphilis until penicillin and other antibiotics were introduced clinically in the 1940s. Yet now, more than 100years after its discovery, the precise biochemical mechanism by which this compound eliminates the syphilis spirochete in vivo from humans and animals remains unknown. Other organic arsenic compounds such as melarsoprol and roxarson have been used to treat parasitic infections. More recently, arsenic trioxide has been shown effective in producing remissions and possibly cures in a high percentage of patients with acute promyelocytic leukemia. However, the exact biochemical mechanism by which this clinical result is manifested remains to be determined. The purpose of this publication is to propose a possible mechanism, by which these apparently diverse arsenic compounds function to produce their clinical results and to suggest their potential for the treatment of infections caused by resistant organisms.