Lloyd N. Ferguson CaliforniaState University Los Angeles. 90032
Cancer will strike more than 665,000 and kill over 380,000 Americans in 1975. One in four of us will die from i t unless the situation can be improved ( I ) . I t is probable that each of us has had a close relative die of cancer and we read everyday in the paper of a well-known person who has succumbed to cancer. Although cancer mortality is second to heart disease, the latter is leveling off, whereas cancer is steadily increasing. The agony of cancer patients and the heartaches and financial burden t o families add to the dread of cancer. Help is needed from many sources to conquer this giant. This paper is written to draw the attention of chemists, that they might become interested in some phase of this mammoth problem and be motivated to contrihute their special expertise where it can be most effective.
Cancer How can chemists help?
Figure 1. Some aromatic carcinogens.
The Problem
Cancer is a collection of diseases of which there are over 100 forms and each must be studied separately to find the optimum therapeutic treatment. There are four major modalities used in treating cancer: (1) surgery, which cannot he applied when the disease is spread throughout the body; (2) radiation therapy, which damages normal as well as cancerous tissue; (3) chemotherapy which often produces very unpleasant and sometimes dangerous side effects;' and (4) immunotherapy-the manipulation of immune response, which is still in its infancy. With over a billion dollars a year being spent globally on cancer research, there is obviously much being published on the subject. Therefore, it is difficult to select a preferred bibliography for such a prolific field. As an introduction, one could refer to a recent general book on cancer, one on carcinogens, and one on cancer chemotherapy. T o learn about the latest research developments, one could scan through some of the "advances" series or official journals of the National Cancer Institute, the American Cancer Society, the American Association for Cancer Research, or World Health Organization (2). Chemical Carcinogens (3)
Little is known about what causes normal cells to turn malignant; however, i t is well recognized that chemicals and radiation can produce cancer (4). Evidence is accumulating that certain viruses may induce some forms of cancer (5). Even chemically inert materials such as gold, asbestos, and plastics can do so upon prolonged irritation of tissue. Tests for chemical carcinogenic activity are usually done on mice, rats, or other animal species, take an average of 19 months, and cost thousands of dollars for each substance. Much research is being done t o find quicker methods of detecting carcinogens, some involving in uitro methods (6). The majority of recognized carcinogens or carcinogen precursors consist of polycyclic aromatics, amines and azo dyes, biological alkylating agents, or antibiotics (7). Polycyclic Aromatics (Fig. I): The first compounds shown experimentally t o produce cancer were polynuclear aromatic hydrocarbons and related heterocyclics in the
' Mast commonly, blood infections, anemia, diarrhea, vomiting,
nausea, baldness, or surface ulcerations. 888 / Journal of ChemicalEducaNon
Figure 2. Some carcinogenicalkylating agents early 1930's. This was the result of a search for the substances responsible for the skin cancer of workmen in long contact with soot and tars. Biological Alkylating Agents (Fig. 2): Many compounds capable of alkylating proteins and nucleic acids have carcinogenic activity. Even simple compounds such as dioxane (8) or the halogen compounds methyl iodide or benzyl chloride are carcinogenic in animals and therefore warrant caution when used in the laboratory. This is the view of the Environmental Protection Agency in its curtailment of the production of vinyl chloride and the chlorinated hydrocarbon pesticides. Aromatic Amines and Azo Compounds (Fig. 3): Bladder cancer has long been an occupational disease of those involved in the industrial uses of aromatic amines. Most of the carcinogens in the list designated hy the U S . Dept. of Labor as being "toxic and physically harmful" are amines (9). 2-Acetylaminofluorene 4-Aminobiphenyl Benzidine and its salts 3.3'-D~chlorobenzidineand its salts 4-Dimethylaminoazobenzene a-ando-Naphthylamine
4-Nitrobiphenyl N-Nitrosodimethylamine 8-Propiolactane Bis-(Chloromethyl) ether Methyl chloromethyl ether
4.4'-Methylenebis-(2-chloraniline) Ethyleneimine
N-Nitroso Compounds (Fig. 4): Most N-nitroso derivatives of amines and a i d e s are powerful carcinogens in several species (10).
Q
CONH*
I
I
/"\
HaC
NO
NO
N-Methyl-Nnitropaurea
N-nitro so^
pipetidine
mvNHNOz I + H,C,-N=N--C,HH I
I 0-
N
'H,
Figure 3. Some carcinogenic amines and am dyes.
Miscellaneous Carcinogens (Fig. 5): Carcinogens are known with a wide variety of structures. The aflatoxins ( l l ) , for example, are among the most potent carcinogens known. Some pyrrolizidine alkaloids occurring in Senecio plants are strong liver carcinogens. Compounds of heryllium, arsenic, yttrium, selenium, and cadmium, with the latter heing the most powerful, are sources of cancer in laboratory animals (12). The radioactive salts, of course, are carcinogenic owing to their radioactivity. Mechanism of Chemical Carcinogenesis About the only feature the carcinogens have in common is their ease of heing converted in uiuo to strong electrophiles. One mechanism of carcinogenesis is thought to involve the reaction of these electrophiles with biological nucleophiles such as proteins and nucleic acids, to block the latter from carrying out their regular metabolic functions. Most chemical carcinogens must be changed in uiuo to become oncogenic. This is done primarily by oxidizing enzymes known collectively as microsomal mixed-function oxygenases. They are found in most cell types but particularly in liver and kidney tissues where foreign chemicals accumulate. Amines are generally hydroxylated (13) and hydrocarbons converted to K-region oxides (14).
N-Nitroso and halogen compounds may he activated enzymatically to free radical or polar electrophiles.
Chemists in particular can help elucidate the mechanism of carcinoeenesis. The aromatic hvdrocarbons and m i n e s bind covaLntly with proteins. In the case of the hydrocarbons, attachment indeed is a t the K-region (15). However, the structure of the critical "active" species is not clear. Some work indicates that i t is not the K-region epoxide itself which reacts with DNA in uiuo (16);some work favors a carbocation (17), whereas other work suggests that a cation-radical is the significant intermediate in the carcinogenic step (18). Although there are exceptions, K-region oxides usually are more active than the respective hydrocarbons. For instance, phenanthrene is not carcinogenic hut its K-region oxide is carcinogenic. Recent studies (19) on the differences in behavior of carcinogenic K-region and inactive non-K-region arene-oxides suggests that (1) the former have much greater reactivity toward nucleophiles,
N 'O
Amyethane
Figure 4. S o m e carclnqlenic N-nlroso a army compounds.
Isoniazid Pmnethanol Inorganic and organic compounds of nickel
x N Supinidine (8 fragment of pymlizidine alkaloids)
Figure 5. Some miscellanecup carcinogens
(2) give trans diols with water whereas non-K-region oxides give phenols, and (3) K-region epoxides rearrange more readily to the respective ketones. There is not a good correlation between the binding of the aromatic hydrocarbons to DNA and their carcinogenic activity (201,although there are quantitative correlations of carcinogenecity with hydrophobicity, K-region electrophilicity, and charge-transfer complex forming ability (21). One notion is that the hydrocarbon enters the cell as a hydrocarbon, forms a loose molecular complex with a cellular component, and is activated through oxygenation by a hydroxylase enzyme (22). Extensive studies with aromatic m i n e s show that they are enzymatically N-hydroxylated (13) and the latter induce tumors via cationic or free radical species (23). In this connection, a convenient assay method for the electrophilic reactivity of the N-arylacethydroxamic acids of the arylamines has been developed (24). Thus, a variety of types of research is needed on the mechanism of chemical carcinogenesis. Chemotherapy (25) The use of drugs to treat cancer made its debut in the 1940's, and there was an induction period before cancer chemotherapy was widely practiced. There are about 45 anticancer drugs for medical practice on the approved list of the US. National Cancer Institute with about 10 more agents in the clinical stage and another 30 in preclinical testing (26). Antitumor agents can be placed into four classes: (1) alkylating agents, (2) antimetabolites, (3) antibiotics, and (4) miscellaneous. The objective of cancer chemotherapy is to destroy selectively all malignant cells by means of chemicals. Only a few significant therapeutically exploitable differences between normal and cancer cells have been found. Most drugs in current use inhibit cell division by interfering in one way or another with the synthesis or use of nucleic acids or during the subsequent mitoses (27). The response to drugs deValume 52, Number ll, November 1975 / 889
ci-
,cH>CHCHCI
+
NH
KC'
H,CO.SO-ICH2),4SO,CH,
'CH~H;CI
B U S U I ~ ~ ~
Nitrogen mustard NiCH&H&i)I I
I
Cyclophosphamide (Cytoran or CTXI
NH? Meiphalan. L-PAM or Sarcalysin CKOH
C/O
(IFNf/ I N
oiv'
HO
\CH,CH?CI
Cyelohexylchloroethyinitrosourea (CCNUI
Nf-CO-N
/No 'CH,
Streptorotocin
I
CHOH
haapidin (Two Soviet Drugs)
Figure 6. Some alkylating anticancer drugr.
pends upon the percentage of tumor cells initiating DNA replication per unit time. Thus, most of the drugs act on fast growing cells, normal as well as cancer cells. Alkylating Agents (Fig. 6): Most of the alkylating drugs are nitrogen mustards, ethylenimines, or alkanesulfonates (28). They react with the nucleophilic hydroxyl, amino, carhoxylate, mercapto, or imidazole groups of proteins and nucleic acids. In spite of much work in this area, the mechanism of action of "alkylating drugs" is not clear (29). Polar bonds in the alkylating agents readily cleave to generate a carbocation transition state
be seen that here is a fertile field for mechanistic studies of nncleophilic substitution under very complex conditions. The high degree of reactivity of these simple alkylating drugs leads to indiscriminate reactions with cellular nucleophiles and, consequently, they lack maximal therapeutic indices. A variety of compounds which appear to exert their cytotoxic activity via alkylation, particularly of thiol groups, have been isolated from natural sources (32). Owing to their special stereochemical and molecular structures (proper balance between lipophilic and hydrophilic character), they offer hope of exhibiting greater specificity in the alkylation of critical biological nucleophiles. Here, the natural product chemist can have the pleasure of structure determination and, more so, meet the challenge of synthesizing analogs with optimum therapeutic activity. The nitrosoureas represent a relatively new class of anticancer agents with a broad spectrum of antitumor activity and with little cell cycle dependency (33). They offer some promise as being effective against hrain tumors because of their ahility to cross the blood hrain harrier. Antimetabolites (Fig. 7): Antimetabolites are structurally related analogs mistakenly taken up hy a cell and when inside, the antagonists interfere with the normal metabolism of the cell. Various suhstances are needed by the cell to form nucleic acids for proliferation. Hence, many purines and nucleosides have antitumor activity (34). Antibiotics (Fig. 8): Many of the antibiotic cancer drugs were discovered outside the U S . These compounds may act a t various points in the sequence of DNA to RNA to protein hut most bind to the DNA molecule. There is in-
Dru~
Metabolite
Aminopterin, R = H. G = NH, Methotrexste (MTX). R = CH,. G = NH,
6-Mercaptopurine (6MPl OH
or possibly react via neighboring group participation.
A
Falic acid. R = H, G = OH
Adenine OH
OH
I
I
H urseii
H 5-Fluomuracii i5~FU)
Ftorsfur (a Soviet drug)
Thus, many of the drugs have two carhons between nitrogen and the halogen or have the aziridine ring. In this case, they are more active when the strained ring is attached to an electron-withdrawing group. This led to the use of TEPA
There is little correlation between the in vitro alkylation activities (toward 4-(p-nitr0benzyl)-p~ridine)~ and cytotoxicity but the alkylating activity plus carbamoylating activity (reactivity toward lysine-"C) sometimes correlates with the therapeutic index of a series of drugs (31). I t can This compound is often used to assess the alkylating activity of a substance. See Ref. (30). 690 / Journal of ChemicalEducaiion
NH,
Nf,
I
I
Cytosine arabinoside
Cytidine
Figure 7. Some antimetabolic cancer drugs and their metabolite analogs.
Mitornycin C
(X = NH,,
Y = OCH,. Z = H) (a Japanese drug)
H~HCI Adriamycin (an 1talisn drug)
Figure 9. Miscellaneousanticancer drugs
Variomycin . A (a Soviet drug)
Figure 8. Some antlblotic Eancer dryls
tense international interest in Adriamycin, which has the widest spectrum of clinical activity of any known compound. Miscel1aneou.s Agents (Fig. 9): Hormonal compounds are among the oldest of anticancer drugs. Male hormones are used against breast cancer and female hormones for treating prostate cancer. A large number of plant extracts exhibit antitumor activity and several have reached the clinical or medical practice stage. Manv metal chelates or comolexes exhibit cvtotoxicitv. One of the most potent, hroad spectrum antitumor agents of this t w e is cis-dichlorodiamino~latinum(Fie. 9) which is in clinical trials (35). Several analogs a& m k e potent and less toxic in in uiuo and in oitro rec clinical tests. One is the cyclohexylamine complex (36) and another is a group of Dvrimidine com~lexes137). In contrast to the stronelv c y t ~ o n i cplatinum~complexes,palladium analogs have fittle activity (38). The mainland Chinese have antimony complexes of EDTA in clinical trials (39) in which activity appears to depend on the ahility of the chelates to inhibit the incorporation of zinc into tumor cells. Gallium nitrate is another inorganic compound to reach clinical trials in the US. (40). Thus, inorganic coordination chemists can play an active role in cancer chemotherapy. The Soviets have found that hindered phenols, which produce stable free radicals because of steric hindrance to dimerization (41), make good anticancer agents and are undergoing clinical trials (42a). The free radical character of cancer tissue not onlv orovides a notential avenue for treatment hut also offers possible means of early detection of cancer cells (426). There are increased electron s ~ i n resonance (esr) signalsobserved for the plasma of cancer patients (43) and animal cancer tissue (44). Cancerous tissue is normally recognized by histological
a
examination. I t is heralded, however, by certain biological changes, such as the presence of tumor-produced hormonal peptides, tumor-associated antigens (45), increases in plasma mucoproteins (46) and mucopolysaccharides (47), and lower calcium ion concentrations. Accordingly, cancer detection methods are being explored which involve, among others, the measurement of these biological constituents, of potassium isotope ratios (48), and by nmr spectroscopy (49). For instance, the concentration of potassium ions in cancer cells is twice that in normal cells. Water molecules are less rigidly hound and this is reflected in the shapes of the nmr signals (48, 50). Thus, there is need for physical chemists to develop some of these methods for early detection of cancer, not only to tell the physician when treatment is needed but to let him know when it is safe to discontinue the administration of drugs. Present Status The major criterion for the success of the chemotherapy program is the number of patients to achieve normal life expectancy who would otherwise have died from cancer. In this respect, we might note that prior to the 1940's, five of six women with diaanosable uterine cancer died within a year, but today 95%of such patients can be cured by drugs. In 1947, leukemia victims had only %-month life expectancy whereas now, over half can expect at least a five-year survival. There are ten human cancers which are highly responsive to chemotherapy and 50% of these patiengshould achieve normal life expectancy (51). However, these successes do not include the major cancer killers such as breast, colon, or lung cancer. For example, the median qurviva1 rate of all luna cancer ~ a t i e n t sfrom diaenoses t o death remains less than six months (52). Recent techniques for more effective use of our present arsenal of drugs are (1) to combine chemotherapy with sureerv andlor radiation t h e r a ~ v153). For instance. it was reeenily reported in the national press that the use of L-PAM (Fig. 6) immediately following a simple mastectomy for breast cancer is more effective than a radical mastectomy. In the past, drugs were usually administered when cancers had reached the inoperable stage, when chemotherVolume 52, Number 11. November 1975 / 691
apy itself has little chance of success. The second change in practice is to administer several drugs together, schematically chosen on a basis of having different sites of action, different times of action in the cell cycle, or different host resistances. Approaches to Explore
Until we can desien the structure " with hieh " orobahilitv . of an effective drug, we will have to continue the program of the National Cancer Institute of testing most organic and prospective inorganic compounds available -now over 30.000 substances annuallv for a total of auuroximatelv (26). Thus, t h e - ~ screens ~ l 45'0,000 in the past 18 comnounds submitted hv the scientific community, others espekally synthesized, fkrmentation products, extracts of plants from all over the world (541, and extracts of marine animals (55,56) and insects (56). What is needed is a good guide or rationale for planning the structure of an effective &otoxic agent. here are several approaches used presently for the strategic design of potential antitumor agents. Quantitative Structure-Activity Relationships (QSAR) (57)
These techniaues fall into two cateeories: (1) those which attempt to correlate physiochemical properties of a family oi molerules with their bioactivitv, and (2) statistical merhods for ranking substructure contributions to biological activity. In the first group are the widely used Hansch method (58) and Free-Wilson model (59), and in the second category are the so-called pattern recognition method (60) and molecular orbital (61) and quantum chemical treatments (62). These are areas where chemists in particular can make a contribution. Extensive use has been made of linear free energy equations in recent years t o correlate the hioactivity of chemicals (63). Although the number of cases in which a highly therapeutic drug has been synthesized and developed on the basis of QSAR is very small, the application of this approach should markedly increase in the near future for two reasons. One reason is the recent improvement in the techniques and secondly, there is greater awareness of the promise offered by this approach. When the Hansch method is applied to the nitrosoureas, for example, it predicts that for optimal therapeutic properties, the nitrosourea should have a log P value ( P = partition coefficient between l-octanol and water) in the range -1.5 to -0.5 (64). when steric and electronic effects are neglected. Following this prediction, a cyclohexyl group in the active drug CCNU (Fig. 6) was replaced by a carbohydrate moiety t o h x e a s e itswater solubility. The product is indeed more active and less toxic than CCNU (65). I t is not known, however, whether this is due to the greater hydrophilic character of the compound or because the sugar fragment serves as an effective carrier to the tumor cells. In spite of the great promise and value of the QSAR correlation treatments, they offer little aid in finding new structural types with antitumor activity. They are useful for optimizing previously recognized "lead" structures but do not generate new leads. The quantum chemical techniques, on the other hand, provide a potential tool for learning more about drug-receptor site interactions, such as the enereetics of the reactions, conformations and charge distributions necessary for maximum interaction, molecular sites of reactivitv, and mechanism of reaction itself (62). The 45 drugs now in use represent some 30 different classes. Obviously many new structural variations should be explored. A wide variety of molecular types should be investigated, including oxygen, phosphorus, and sulfur heterocycles, coordination compounds, nucleocides, etc. Some of the structural types exhibiting a range of antitumor activity have been reviewed recently (66). 692 / Journal of
Chemical Education
.
.
..
The rationale here is to attach a cytotoxic moiety to a molecule known to localize in certain oreans of the hodv. ~ but n i t For example, drugs known to have C N activity known antitumor activity are structurally modified to give them cytotoxic action without destroying their ability to reach the brain or CNS. Several active drugs contain an amino acid (L-PAM, Fig. 6). steroid (phenesterin) (67), or carbohydrate (streptozotocin, Fig. 6) carrier. Active Molecular Fragment (68)
Often some common structural feature is sought in a group of compounds active against a given cancer. An example is the O-N-0 triangulation observed in some nonalkylating antileukemic agents (69). The presence of this molecular fragment does not mean that a compound must have antileukemic action but a t least this structural moiety can be found in several different classes of antitumor drugs including MTX, Adriamycin, 6-MP, those below, and numerous others. I t is hypothesized that such a structural fragment might assist the in uivo hinding of the drug to one of the pertinent biological receptor sites involved in leukemic genesis. Intercalation Mechanisms
Since several drugs are k n o w to form complexes with DNA, i t is thought that antitumor activity is in some way due to intercalation of planar aromatic structures between base airs of the DNA chain (70). Moreover. i t is observed -that most of these agents are pianar, polyc~clicquinones, or nitrogen heterocyclics with several hydroxyl or methoxyl groups attached. In particular, the hinding characteristics of these compounds with DNA and other bioloeical constituents are b e k g studied. ~~~
-
Vinblastine, R = Me Vincristine, R CHO
-
I t has heen estimated that the distances between two potential alkylating sites in a number of cytoxic drugs (y-lactones, epoxides, N-mustards) are in the range 6.C7.2 A (71). This distance matches the 6.8 & . vertical distance hetween alternate pairs of DNA bases and might be significant. Along this line, some potential antitumor agents have been designed such that the planar portion of a molecule can intercalate between adjacent base pairs in a DNA helix while cationic charged centers in the drug match negative charges on the DNA sugar phosphate backbones (72).
Summary In summation, chemists can help unravel the mechanisms of carcinogenic and cytotoxic actions of chemicals. The most productive route to curative drugs will come when we have an understandine of the mechanisms of action of antitumor drugs. This wzl he facilitated by having a working hvnothesis for the mode of action of a eiven tvDe of drug and is a way in which organic chemists can play a leadineu role. From their ex~eriencewith in uitro reaction mechanisms, they can postulate likely intermediate metabolites and desien ex~erimentsto follow the reaction sequences of drugs. For example, extensive effort is being made to identify the cytotoxic metabolites of CTX (Fig. 6) (731. The total svntheses of several cytotoxic agents with promising therapeutic value need to b e worked-out for a t least three reasons: (1) compounds obtained from natural sources are usually isolated in quantities too small for clinical testing: (2) once the total synthesis of an important active agent has been achieved, analogs may be prepared in search of more effective compounds (74); and (3)drugs can be synthesized containing radioactive isotopes for tracing metabolic pathways (75). Also, drugs need to he synthesized based on promising QSAR predictions. Many of these syntheses would provide interesting and challenging projects. Other chemists are needed t o develop methods for the detection of low concentrations of cancer cells or the presence of neo-cancer cells by physical or biochemical techniaues. it is fairly well established that skin cancers are caused bv uv radiation. and the tvrosine and t w.. p t o.~ h a n eresidues of proteins are suspected of being the principal absorbing units. Either direct radiation uf DNA or DNA-photoproduct interactions could produce changes in nucleic acids to induce cancer cell formation. Steroids, proteins, lipids, or other biological constituents could serve as photosensitizers to trigger tumor growth, not only skin cancer but other types as well. The situation is complex and offers an opportunity for photochemists t o do some creative research (76). Thus, there are many ways in which chemists can use their expertise to help in the war on cancer. This includes organic, inorganic, physical, clinical analytical, pharmaceutical chemists, and biochemists. As in all research, the many bits of negative and positive results will help to guide us through the maze toward success in conquering cancer.
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..
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Acknowledgment The author is grateful to the National Cancer Institute for making accessible much of the information given herein., narticularlv that from outside the U S . However, the --r ~ ~ ~ ~ ~ NCI is not responsible for any errors or misconceptions stated. Support was also provided by the Minority Biomedical Research Support Program of the National Institutes of Health. ~
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