Chemically Triggered Time Delay Activation Chemotherapy for the Treatment of Cancer

CHEMICALLY TRIGGERED TIME DELAY ACTIVATION CHEMOTHERAPY FOR THE TREATMENT OF CANCER* EVAN HARRIS WALKERS Chemotherapy research in cancer treatment has been largely devoted to the search for drugs providing toxin specificity to destroy neoplastic tissue in the body without exceeding toxic exposure levels injurious to healthy tissues, that is to say, to the search for cytotoxic drugs that concentrate in neoplastic tissues or drugs that metabolize into such toxins . Although major efforts to this end have been made, success has been achieved for only a few cancer types. For most cancer types, success has been quite limited. Extensive data, as discussed below, show that there exist compounds that, while they do not selectively concentrate in malignant neoplastic tissue, do exhibit an overall lower metabolic rate in such tissue; that is, they undergo cytometabolism and removal from cancer cells more slowly than in vital body tissues. Typically such compounds are taken up by neoplastic tissues more slowly (see below) as well, which is, of course, a factor limiting selective concentration in neoplastic tissues and the use of such compounds as drugs or moieties in drug design. The purpose of the present paper is to show the following: 1.Despite the fact that a compound does not concentrate preferentially in neoplastic tissue, if it is metabolized out of neoplastic tissue more slowly than from normal tissue, the neoplastic to normal tissue concentration ratio rises with time. 2.Under the above conditions, the laws of chemical kinetics show that at some time the concentration in the neoplastic tissue will exceed the concentration in all other tissues. It should therefore be clear that, if it is possible to convert the compound to a cytotoxin at a specific time, as by *I thank Dr. Erwin Di Cyan of New York, Dr. James King, Chemical Laboratory, Aberdeen Proving Ground, Maryland, and the late Margaret F. O'Connell for their valuable contributions of information, suggestions, and encouragement in the present research . The paper is dedicated to the memory of Merilyn Ann Zehnder, Margaret F. O'Connell, and Dr. Coy M. Glass of The Johns Hopkins University. tU.S. Army Ballistic Research Laboratory, Aberdeen Proving Ground, Maryland 21005, and The Johns Hopkins University, Baltimore, Maryland 21218.© 1980 by The University of Chicago. 0031-5982/80/2303-0140$01.00 ' 424 I Evan Harris Walker ¦ Chemotherapyfor Cancer the administration of a second drug, neoplastic tissue toxin specificity can be achieved. For example, malignant neoplastic tissues typically have a higher concentration of DNA and RNA than normal tissues, often twice as much [1; 2, see p. 905; 3-13]. Ifone designs a toxin that binds to cell RNA, one may expect to achieve toxin concentrations twice as high in the malignant tissue as in normal tissue. Such factors as high blood flow to vital organ tissue, however, can offset such preferential concentration, with the result that the vital tissues suffer from excessive toxic exposure. However, if a prodrug is used which does not bind to the RNA but does have an affinity to associate with RNA (as in chromatographic separation techniques), diffusion rates from the neoplastic cells will be correspondingly reduced. As pointed out in statement 1 , this means the concentration ratio ofneoplastic to normal cells will rise. According to chemical and diffusion kinetics (see below), this rise will be exponential. Given a sufficient delay time before toxin activation, essentially any desired concentration ratio can be achieved. Attempts to employ the concept of preferential site binding for drug design in the absence of evidence of unique and distinctive chemical processes in malignant tissues [2] should be expected to be less likely to succeed than utilization of the mechanism detailed in the present paper. Chemically triggered time delay toxin activation (TDTA), based on principles 1 and 2 as given above, has the potential of greatly amplifying toxin specificity. The TDTA utilizes two compounds to be administered separately. The first drug (designated as the prodrug below) is a protoxin exhibiting the already mentioned cytometabolic rate differential; the second drug is the toxin-activation agent. Separately both drugs are designed to be nontoxic, but in combination they release an anticancer cytotoxin. Each of the two drugs is administered in large doses (as compared...