Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-12-17
2004-07-27
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S004000, C549S027000
Reexamination Certificate
active
06767919
ABSTRACT:
BACKGROUND OF THE INVENTION
Despite advances in the discovery of antitumor agents, cancer remains a disease with very poor prognosis. Substances displaying in vitro and in vivo anticancer activity are continuously reported in the literature, but only a scant number of those substances go past a phase II clinical trial. Moreover, the cure rates of drugs for the treatment of cancers are unacceptably low, and the side effects of these drugs are severe. The toxic effects of the drugs on the cancer tissues only marginally exceed their toxic effects on normal, healthy cells of the body that should be protected from the effects of the drugs. Moreover, that high failure rate of potential anticancer agents arguably can be traced to the lack of methods to ascertain and to design into, in advance, control of secondary effects, specificity, and high target-tissue activity in human subjects. A design process is needed to design into candidate compounds all the requirements for the drug delivery system and anticancer effectiveness. That goal is achieved by the present invention.
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 for 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.
Modem anticancer drug development began with the recognition that some poison gas exposures in WWI actually had anticancer side effects. The process of anticancer drug development began at this point with the mostly random procedure of searching through known toxins to determine through exposure if the given toxin had differential toxicity that would aid in the control or cure of cancer. The approach centered on the discovery of “single moiety” compounds.
In the 1930s, more complex compounds were developed so designed as to divide the function of the anticancer agent into two parts, or two moieties on the same compound, wherein one moiety would serve to concentrate the drug in the cancer cell or tissue and the second moiety would serve to destroy the cancer cells wherein the compound concentrated. A fundamental advance in this area was the elucidation of chemical entities with tumor tissue selectivity. Early reports on such selectivity were made for the dye Nile blue by Lewis, et al. in
Cancer Res
. 9:736, 1949, a report that prompted the modification of this benzophenoxazine to incorporate a toxin such as a nitrogen mustard as an integral part of the molecule (Sen, et al. in Int.
Union against Cancer Acta
, 26, 774 (1960)). Those attempts at modification of a tumor tissue selective agent with a toxic moiety met with limited success. It has been presumed that the failure of such approaches is due to intrinsic modification of the tissue selectivity of the parent compound with the addition of the toxic moiety. The cause of the failure, however, is more fundamental and is shared by other drug delivery concepts, in particular, the concept of anticancer prodrugs.
Beginning in the early 1950s, the two-moiety drug design approach of a concentrating moiety and a toxic moiety was modified to the two-moiety “prodrug” design, wherein one moiety served to modify or “mask” or “cap” the toxicity of the second toxic moiety of the drug compound until the drug entered the cancer cells. At this point, a chemical reaction, generally intended to be with enzymes specific to the cancer cells, would remove the mask or cap moiety so that the toxic moiety would kill the cancer cells. Again, the prodrug anticancer delivery concept has had limited success.
Both the concept of drugs that combine a concentrating moiety together with a toxic moiety and the concept of prodrugs that are to be metabolized preferentially in cancer tissues suffer from the problems that arise out of the nature of cancer itself: cancer cells and tissues are not foreign biological organisms having a chemistry distinct from normal tissue. These tissues are, in the case of human cancers, human tissues. The normal and neoplastic tissue have essentially the same chemistry; that is, for the most part, both consist of the same chemical molecules and in similar concentrations.
In 1980, Evan Harris Walker in
Perspectives in Biology and Medicine, Spring Issue
, 424-438, (1980) argued that the prodrug concept and the combination of toxin with concentrator concept fail because of the fundamentals of the pharmacokinetics of drug delivery. The time course of the drugs depends on their metabolic uptake and elimination rates. If the rates are lower for the cancer cells than for the normal cells, the drugs will appear to concentrate. That is to say, after a sufficient lapse of time, the drugs will have been metabolized and eliminated out of the normal tissues while still being in significant concentrations in the cancer cells and tissues. This will be the case even though the total amount of drug delivered to both normal and cancer cells may be essentially the same. The problem of achieving an effective anticancer drug was not one of achieving differential concentration, or of having the drug be activated by enzymes in the cells, but rather one of being able to suppress the toxicity of the drug in the normal cells and tissues until the differential concentration of the drug had become favorable.
In order to take advantage of the drug concentration differential between normal and cancer tissue, Walker in
Perspectives in Biology and Medicine, Spring Issue
, 424-438, (1980) proposed a design procedure consisting of two drugs, a prodrug and an “activation” drug. Both the prodrug (that had a design limited to a toxin plus a cap or mask moiety) and the activation drug were to be designed so as to have little or no toxic or other effect on the body (i.e., to be substantially biologically inert) if administered alone. However, in combination, these two compounds would react in the body to produce a compound toxic to the cells wherein it was produced. These two drugs were to be administered sequentially with a time delay between their introduction to allow for the normal cells to metabolize and eliminate the prodrug out of the body before the activation drug was administered. At that point in time—after a time delay for differential delivery of the drug—differential concentration of the prodrug would have been achieved. Removing the masking or capping moiety of the prodrug at that time—when the prodrug would be differentially concentrated in the cancer tissues—would then result in delivery of high levels of the included anticancer toxin. In this way, anticancer toxins would be delivered to cancer cells and tissues without harm being done to normal cells and tissues.
Prodrugs of the type proposed by Walker were designed and synthesized by the present inventors. One of these was a 5-fluorouracil-N-glucoside, which can be activated by the enzyme &bgr;-glucosidase. After designing a prodrug of this type, the inventors of the present disclosure found that a more complex prodrug and activation drug system would be needed to provide all the requirements for a selective and effective anticancer pharmaceutical. In particular, the present inventors found that the prodrug and activation design of this type also had limitations in that the differential concentration achievable within the limits of that design was not sufficiently high. In other words, the differential concentration effect due entirely to differential diffusion with no added moiety to enhance the concentration differential proved to be inadequate. A more complex drug system was needed and it was found that a process for the development of the drug system would be required.
SUMMARY OF THE INVENTION
The present disclosure covers an assemblage containing chemicals and chemical moieties, a process for the detailed design
Blumenthal Steven L.
Palomino Eduardo
Walker Evan Harris
Frommer William S.
Frommer & Lawrence & Haug LLP
Kuzmich Sandra
Lambkin Deborah C.
Walker Cancer Research Institute, Inc.
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