DEVELOPMENT OF CHEMOTHERAPEUTIC DRUGS

1 Jun

It was Paul Ehrlich who first initiated a systematic screening program in the search for chemo- therapeutic  agents. In his work, the agents were directed toward the treatment of several sys- temic parasitic diseases. Initially, the search for new drugs to be used in the chemotherapy  of cancer followed a similar program. Figure 20.3 lists the stages in the development of drugs to be used in the chemotherapy  of cancer. It should be noted that this formulation  is not unique to cancer chemotherapy, but is also utilized in the development of a variety of other pharmaceuti- cals. At certain stages, as noted in the figure, decisions must be made whether to continue to study a particular drug. Thus, although a large number of compounds  may be selected in the acquisition stage, relatively few survive to make an impact on general medical practice.

Acquisition or selection of the compounds to be tested may be done as a purely random screening of synthetic chemicals or biologicals. The results of this approach have been disap- pointing with respect to the yields of new classes of active compounds. Other approaches, such as rational synthesis and analog development, have been used with good results (cf. Goldin and Carter, 1982). When a compound is known to be somewhat effective in the treatment of neopla- sia in either animal or human systems, closely related compounds with structural modifications of the parent compound are developed for testing. By this mechanism, one may be able to im- prove on the efficacy of the original compound. The development of certain antimetabolites has proceeded on the basis of our knowledge of specific metabolic pathways within the living cell. The development of 5-fluorouracil was one of the prime examples of this method for the selec- tion of compounds used in drug development (cf. Heidelberger, 1975). A third method, one of the most popular for selecting compounds to be screened for activity against neoplastic growth, is the testing of compounds obtained from antibiotic fermentation of beers and plant products. Several highly active compounds have been isolated and characterized from a large number of naturally produced materials that have been screened. Some of these are presently in use. Prod- ucts of such testing have been the taxanes, vinblastine, and the topoisomerase inhibitors.

After selection of the compounds  to be tested, efficacy against neoplasia is analyzed in several systems, usually in the mouse. Originally, the primary system was the L-1210 leukemia in mice, but at present the primary screening system is the P-388 mouse leukemia. The screening procedure currently used at the National Cancer Institute in the United States is outlined in Fig- ure 20.4. A list of other animal neoplasms that have been used as test systems in various screen-

Figure 20.3 Listing of the stages involved  in new drug development  at the National  Cancer Institute. The asterisks designate stages at which decisions are made as to further development of the drug.

Figure 20.4 Outline of the currently employed standard screening design employed at the Division of Cancer Treatment at the National Cancer Institute.

ing programs  is given in Table 20.5. Some of these have been used in the secondary  panel screen, as seen in Figure 20.4. Within the last decade, human neoplasms grown in immunologi- cally deficient animals—for  example, the nude mouse—constitute  a major component  of this secondary panel. In addition, drugs have also been screened for their efficacy in tissue culture systems, a number of which are derived from human cells.

After the evaluation  of a drug in a variety of animal tumor systems, toxicological  and pharmacological  evaluations of the drugs are undertaken (cf. Goldin and Carter, 1982). Purity, physicochemical characteristics (including solubility), and acute toxicity in animals—leading to

Table 20.5 Test Systems for Screening Chemotherapeutic  Drugs

Mouse tumors

Transplantable

Lymphoid leukemia L-1210

Adenocarcinoma  755

Cloudman melanoma (S91) Ehrlich ascites

Hepatoma 129

Lewis lung carcinoma

Osteogenic sarcoma HE 10734

Sarcoma 180

P388 leukemia L5178Y leukemia B16 melanoma LPC1 plasma cell

Primary and transplantable AKR virus leukemia Moloney virus leukemia Rauscher virus leukemia Friend virus leukemia C3H mammary tumor

Rat tumors

Dunning leukemia

Murphy-Sturm  lymphosarcoma

Walker 256

Hamster tumors

Adenocarcinoma  of duodenum Adenocarcinoma  of endometrium Adenocarcinoma  of small bowel Melanotic melanoma

Chicken tumor

Rous sarcoma

Carcinogen-induced tumors in rodents

3-Methylcholanthrene–induced mammary adenocarcinoma Dimethylbenzanthracene-induced mammary adenocarcinoma Dibenzo[a,i]pyrene-induced fibrosarcoma

Tumors in heterologous hosts HS-1 in conditioned rats HEP-3 in conditioned rats

DBA/2 mouse lymphatic leukemia in conditioned hamsters

Human amelanotic melanoma in conditioned hamsters

systemic  and local tissue damage from acute and cumulative  doses—are  determined.  These tests are often extended from rodents to other species, including primates. Usually included in these investigations are specific studies related to the pharmacokinetics of the drugs, including determination of blood and tissue levels, and the metabolism and excretion of the drug (Work- man, 1993).

When all of these studies are completed, clinical trials are initiated in several phases, the first (phase I) being in patients with advanced cancer, usually after all conventional therapeutic measures have failed. The evaluation of drugs in these patients includes a variety of studies on the pharmacology of the drug—its toxicity to the bone marrow, gastrointestinal tract, and other tissues—from which the maximally tolerated dose is determined. In order for a drug to continue to the next phase of clinical trial, an objective response need not necessarily be obtained in these patients. These studies are carried out with a specific protocol approved by the local committee on human experimentation  as well as the National Cancer Institute (Freireich, 1979). The Na- tional Cancer Institute sponsors  a large number of cooperative  clinical trials which, prior to 1988, had more than 30,000 entries (Friedman and Cain, 1990). Today many more such trials are active but face a variety of problems, including their integration into the changing health care delivery system in this country as well as a number of ethical concerns that have emerged from a number of these trials (Durant, 1990). Only a limited number of institutions are allowed to par- ticipate in these studies. If a tolerated dose has a toxicity that is predictable, controllable,  and reversible, the trial of the drug extends into the second phase, which is directed toward determin- ing clinical activity against a variety of cancers in the human. The required and optional panel of neoplasms in human patients against which a potentially useful drug may be tested is given in Figure 20.5. If the efficacy of the drug is shown in phase II trials, then it is finally evaluated in controlled  phase III clinical trials and in combination  with other drugs. The National Cancer Institute officials estimate that fewer than 1 in 15,000 drugs ever reach the final stage of clinical trials. Despite this limited chance of success, over 40 drugs are effective in the treatment of one or more human cancers.

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