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Carcinogenesis from the standpoint of view of molecular geometry and synergism: Relevance of oxygen and magnesium
Medical Hypotheses
11:
177-184, 1983
CARCINOGENESIS FROM THE STANDPOINT OF VIEW OF MOLECULAR SYNERGISM: RELEVANCE OF OXYGEN AND MAGNESIUM Ernest Maly, Institute of Gerontology,
GEOMETRY AND
901 01 Malacky, Czechoslovakia
ABSTRACT An attempt at a unified exp anation of carcinogenesis, comprising physical, chemical and vira agents which are mutually synergistic involves the idea that cant nually replicated partially denatured chromosomal DNA carries the cancer genetic information. The evidence is circumstantial to date. While interactions and reactions of various heterogeneous chemical agent s and absorption of radiant energy are detrimental to the helicity of the DNA, the interactions of magnesium and oxygen seem to be beneficial and thus may protect against cancer. Mechanisms for the damaging effects of various carcinogenic agents as well as for the protective effects of magnesium and oxygen are proposed. The increasing probability of cancer with age could be due to the cumulative actions of diverse carcinogenic agents. Some experimental results in vitro which are relevant to this hypothesis are discussed.
INTRODUCTION When looking for an effective paper chromatographic solvent system for polycyclic hydrocarbon mixtures occurring in high temperature tar (l), the author of this paper had to deal with the polarity and thus with the Those considerations led to a classconfiguration of these molecules. ification of the polycyclic hydrocarbons, from the standpoint of view The carcinogenic hydrocarbons conform to specific of carcinogenicity. molecular dimensions and configurations (2,3) (figure 1), which may fit into DNA steric structures (figure 2). Steric interactions leading to local denaturations were proposed (2,3). The synergism of tar and absorption of quanta of radiant energy at certain wavelengths which has been known since the 'twenties, hinted at the idea that a higher energy of the chromosomal DNA, in the form of a local denaturation of the DNA macromolecules, replicated continually, could be in the form in which cancer genetic information is carried (2). The metastable structures, once acquired, could result in an abridged duplication time of the DNA, leading to accelerated mitoses (2), so explaining increased DNA content in cancerous cells (4,5). A renaturation of an ;f;;zted site of the DNA thus ought to be preceded by duplication. polymerase able to synthesize altered bond angles was found (6).
177
0%
‘,
=I -
’
8
7
Figure 1.
12
16
n
IL
3. 3,4_benzofluoranthene; 7. Dimethylamino1. 3,4-benzopyrene; 2. Azuleno-5,6,7-c,d-phenalene; 10. 5-methyl-1,2_benzoanthracene; 9. 1,2_benzoanthracene; azobenzene; 8. Dimethylaminostilbene; 11. 5,10-dimethyl-1,2_benzoanthracene; 12. 3-methylcholanthrene; 13. 3,4_benzophenanthrene; 14. 5-methyl-3,4_benzophenanthrene; 15. P-nor-steranthrene; 16. 1,2,3,4_dibenzopyrene.
L
3
6
POLYCYCLIC
HYDROCARBONS
The simplest models for studies on the interactions of carcinogenic molecules with DNA are the polycyclic hydrocarbons. The effective part of a planar contour in a carcinogenic hydrocarbon may be delimited by a right triangle, both its legs being 4.6 angstrom long. An example is 3,4-benzopyrene, containing the benzanthrone configuration (3, figure 1, I). Other types are those containing a 1,2_benzoanthracene configuration, II (3, figure l), or the 3,4_benzophenanthrene configuration, III (figure 1). The active part of I and II could fit into the outer half of the inter-step space of the right-handed helical up staircase, if the steric contours of the DNA are so regarded. The plane of the polycyclic hydrocarbon would be perpendicular to the purine or pyrimidine plate, the edge tending towards or under the desoxyribose and phosphate bond geometry (figure 2). Carcinogenicity is enhanced through the combination of the contours I and II as in the 3-methyl-cholanthrene (figures 1 and 2). The third type could clasp the bond sugar-base. Its carcinogenicity is enhanced when combined with I, as in 1,2,3,4_dibenzopyrene. The steric interaction of a carcinogenic molecule could cause deformations of bond lengths and anglesandloosenthehydrogen bonds of the base pairs. Other carcinogenic molecules may be sterically equivalent even after conjugation with glucuronic acid, or sulphuric acid, as are the aromatic amines, or after metabolism, yielding the alkylation agents.
ON THE INTERACTION OF OXYGEN WITH DNA The absorbance changes at 259 nm of native, or weakly denatured, or denatured DNA were studied; 2.66 x 10-6 M calf thymus DNA solution (Flukka) in 2 x 10m2 M hydrogen peroxide as well as 2.66 x 10-6 M aqueous DNA solution in distilled water were used. The DNA solutions and the blanks were exposed to temperatures of 25-lOOoC, and cooled suddenly, the test tubes being submerged into melting ice. The difference in absorption was maximal after twelve minutes exposure to 60°C (figure 3). The Tm in hydrogen peroxide (full line curve in figure 4) was found to be 76oC, being increased by 26OC compared to that in distilled water (dashed curve in figure 4). The aqueous DNA solution subjected to denaturation at 9OoC for twenty minutes, and left overnight at room temperature, and resubjected to the described procedure with H202, exhibited no difference in absorption as compared to that in water. The UV spectra were run on a Perkin-Elmer-Visible-NIR spectrophotometer with silica cells, a 10 mm path-length being employed. This phenomenon could be explained from the standpoint of molecular geometry assuming that the hydrogens of the guanine-cytosine base pairs are the sites of interaction. The electro-negative 02 set free from H 02 could bridge over the spacing between them, as a transition state igure 2). The spacing between Nl at guanine and Nl at cytosine is (T. The spacing between one H at N6 in cytosine, and one 2.86 angstrom(18). of the two H at N2 in guanine could be a little more than 1.32 + 2 x 0.3 angstrom, taking the bond angles into consideration. The bond length between the two 0 of 02 is 1.32 angstrom and the bond radius of 0 is 0.66 angstrom. The secondary valence forces may be interrupted due to a protracted temperature over 400C and 02 can be expelled, as is seen in figure 3. The presence of oxygen at that site may contribute to the 179
A \ Figure 2. A. Possible interaction of magnesium, oxygen, 3,4-benzopyrene, 3-methylcholanthrene and potassium with DNA. A fragment of DNA drawn according to Calbiochem sale pamphlet. B. Possible interaction of 3,4_benzophenanthrene type with DNA.
W
a ts ) 0.2 The time effect Figureupon 3. the difference in chromicity of the DNA solution exposed to 60°C, both in istilled water and in 2 x lo-P M hydrogen peroxide.
G t z 0
01
1
I
I
/'
& 0
0
0 .-/
/ r( T I s
\ 1
1 10
'1 'I \ 1 15
TIME, MINUTES
180
I
I /\
_
2 0
1
I 20
-f25
-
-
20
30
40
50
60
70
80
90 100 fEW$RATut?E PC)
Figure 4, The denaturation of the DNA both in water (dashed curve) and in hydrogen peroxide (full curve).
--1~~
. .
3paCcrllO
ml
2
,rc--------*
Figure 5. The increase in Cl' in the DNA solution bubbled with vinyl chloride; through denatured DNA (upper full curve), through DNA solution in distilled water (middle dashed curve), through potassium nitrate solution (partly dashed and partly dotted middle curve) and through hydrogen peroxide or magnesium nitrate (bottom dashed and dotted line).
181
protection of the DNA against thermal and other denaturation. Once denatured, the DNA is n&ot capable of any interaction with oxygen anymore, in contrast with Warburg's view (7). The preliminary suggestion (8) seems to be confirmed. In this manner, all agents which remove oxygen for a long time from tissue such as respiratory poisons, arsenic, anemia, pressure of foreign bodies and scars under the epithelium, may result in the cancer cell development.
MAGNESIUM Magnesium seems to be antagonistic to agents causing denaturation of the DNA and to be cancer prophylactic (9,10,11,12,13). When in the form of a polyvalent MgDNA salt, the DNA's helicity may be protested by the electrostatic forces of MgL+. On the other hand, the MgL+ bond radius cannot bind the two neighbouring phosphate groups in one polynucleotide chain once local bond deformation has occurred. The normal spacing between the two nearest phosphate groups of one polynucleotide chain is about 7 angstrom (18). The straight P-0-+Mgt-O-P bond length is about 7.88 angstrom, which fits into the DNA sturcture, when taking the One would expect that the denatured segments bond angles into account. of the DNA are unable to bind the divalent cations, but can still bind Magnesium content was found to be reduced in cancerous the univalent. tissues, and in addition the potassium content increased (15), both being the cations of the cell nucleus. Some cations like Co, or Cr, could influence adversely the helicity of the DNA (14).
THE ANTIALKYLATING
EFFECT OF OXYGEN AND MAGNESIUM
One can expect that the alkylation of guanine at Nl or N2, and of cytosine at N6 as well as of thymine at Nl will cause an irreparable local denaturation of the DNA macromolecule. Model experiments with vinyl chloride as a carcinogenic agent in vitro were carried out. Vinyl chloride was made to interact with DNA, when 8 ml of pure gas at 1 atm were bubbled and recycled for one hour through 15 ml of calf thymus (Flukka) n x 8 x 10-6 M aqueous DNA solution, where n=1,2,4,6; pH was about 5.8, at 37OC. The increase in Cl- was a measure of the alkylation according to the equation: RNH t ClHC=CH2
= RN-CH=CH2
t H+Cl-
The inorganic chlorine was determined nephelometrically. The results are shown in figure 5. The middle dashed curve belongs to the experiNo increase in Cl- was noticed as against the ments in pure water. gassed solution, when the distilled water was replaced by 1.94 x 10-l M hydrogen peroxide (bottom dashed and dotted line in figure 5). The increase in Cl- was highest when the denatured DNA solution without peroxide was gassed (upper full curve in figure 5). Vin 1 chloride was bubbled through 10-2 M magnesium 10-$ M potassium nitrate, under the same conditions
nitrate, and (21). The results are shown in figure 5. There was no increase in Cl- in magnesium nitrate (the bottom dashed and dotted line). The increase in Cl182
in potassium nitrate was similar to that in pure water (the middle partly dashed and partly dotted line). It is to be expected that the free NH groups will be more reactive with vinyl chloride than those forming the hydrogen bonds, which are interrup ted in a denatured DNA. Thus, a synergism of an alkylating agent and abnormal temperature may be suggested in vivo. Oxygen and magnesium could stabilize the bond lengths and angles of the DNA. Furthermore, oxygen may repulse the electronegative chlorine moiety of the alkylating molecule. The relative turbidities were measured with a Pulfrich nephelometer: 20 mm path length,green filter and comparing glass No 4 were employed. Cl- was determined according to the calibration curve carried out in presence of the calf thymus DNA. The concentrations 1 - 6 mg DNA/100 ml in standard solution influenced the turbidities to the same extent.
VIRAL AND VARIOUS OTHER CARCINOGENIC Segments of the DNA virus (6) or double be metastable. The (17) and in the DNA between viruses and
AGENTS
synthesized on the single strand RNA oncogenic stranded linear DNA adenovirus template (16) could internucleotide spacings in RNA are 3.0 angstrom double helix are 3.4 anstrom (18). Synergism chemical agents is also known.
The carcinogenicity of some forms of asbestos, synergistic with 3,4benzopyrene (19) could be explained as a partial thermal denaturation of the chromosomal DNA. A thermal isolation of the cell nucleus owing to these particles in the environmental plasm and intercellular space could be the result. A coagulation of the proteins surrounding the chromosomal DNA, due to strong tannic materials, could cause a mechanical steric compression and consequently local denaturation of the DNA macromolecule (20). The physical agents could bring about a local denaturation of the DNA directly through an abnormal temperature, or through the absorption of the radiant energy transformed to heat at certain wavelengths. The formation and incorporation of thymine dimer after ultraviolet irradiation ought to lead to a local denaturation of the DNA. The distance of the two plates in the thymine dimer is about 1.54 angstrom.
REFERENCES 1.
Ma19 E. Paper chromatography of tar polycyclic hydrocarbons. Nature 181: 698, 1958. An improved method for determination of Mikrocim. Acta, Wein, 1977; air-borne polycyclic hydrocarbons. I, 429.
2.
Maly E. Pozndmka ku genetickej rakovinnej inform&ii dizoxyribonukleovgch kyselin. A note on cancer genetic information of the DNA. Pracov. 1ekaPstvi 17: 121, 1965. 183
3.
Ma19 E. Kancerogeneze z hlediska molekularni geometrie. Set of abstracts of the second conference "Cemicka karcinogenita 1975". VQzk. iIstavorg. syntez Pardubice - Rybitvt, Czechoslovakia, 1975.
4.
Mellors RC, Keane JP, Jr, Papanicolaou GN. Nucleic acid content of the squamous cancer cell. Science 116: 265, 1952.
5.
Paulette-Vantrell J. DNA content and chromosome number in twentyfive human carcinomas. Oncology 24: 265, 1970.
6.
Temin H, Mizutani S. RNA-dependent DNA polymerase in virions of Rous sarcoma virus. Nature 226: 1211, 1970.
7.
Warburg 0.
8.
Ma19 E. 0 interakcii kysliku s kyselinou dezoxyribonukleovou. On the interaction of oxygen with DNA. Pracov. Lekai%tvS 22: 226, 1970. A preliminary report.
9.
Dubard.
On the origin
of cancer cells.
Magnesie et cancer.
Science 123: 309, 1956.
Bull Acad Med de Paris 79: 309, 1918.
10.
Delbet P. RQle du magnesium dans les phenom&nes biologiques. Monde medical 39: 969, 1929.
11.
Robinet L. Terrains magnesiens et cancer. Haut-Rhin, Bas-Rhin, Moselle Bull assoc franc. Etude can 19: 243, 1930.
12.
Estas P. Rapports du metabolisme avec le cancer du goudron. belge des sciences medicales 1: 189, 1929.
13.
Shear MJ. The role of sodium, potassium, calcium and magnesium in cancer. Amer J Cancer 18: 924-1024, 1933. A review.
14.
Eichhorn GL. Metal ions as stabilizers or destabilizers of the deoxyribonucleic acid structure. Nature 194: 74, 1962.
15.
Moravek V. Biochemie des Rous-Sarkoms der Huner. forsch 35: 626, 1932. Ibid, 36: 529, 1932.
16.
Graham FL, Van der Ebb AJ, Heijneker HL. Size and location of the transforming region in human adenovirus type 5 DNA. Nature 521: 687, 1974.
17.
Langridge R, Gomatos P.
18.
Wilkins NHP. Molecular configuration of nucleic acids. 140: 941, 1963.
19.
Salk R, Vasamae A. Induction of lung tumors in rats by intratracheal instillation of benzo/A/pyrene and chrysotile asbestos. Exper Oncology 2: 88, 1975.
20.
Issekutz B. 1951.
21.
Ma19 E.
The structure of RNA.
Zeitung Krebs-
Science 141: 694, 1963. Science
Gybgyszertan, meregtan es gydgyszren degles.
The unpublished paper.
184
Revue
Budapest
11:
177-184, 1983
CARCINOGENESIS FROM THE STANDPOINT OF VIEW OF MOLECULAR SYNERGISM: RELEVANCE OF OXYGEN AND MAGNESIUM Ernest Maly, Institute of Gerontology,
GEOMETRY AND
901 01 Malacky, Czechoslovakia
ABSTRACT An attempt at a unified exp anation of carcinogenesis, comprising physical, chemical and vira agents which are mutually synergistic involves the idea that cant nually replicated partially denatured chromosomal DNA carries the cancer genetic information. The evidence is circumstantial to date. While interactions and reactions of various heterogeneous chemical agent s and absorption of radiant energy are detrimental to the helicity of the DNA, the interactions of magnesium and oxygen seem to be beneficial and thus may protect against cancer. Mechanisms for the damaging effects of various carcinogenic agents as well as for the protective effects of magnesium and oxygen are proposed. The increasing probability of cancer with age could be due to the cumulative actions of diverse carcinogenic agents. Some experimental results in vitro which are relevant to this hypothesis are discussed.
INTRODUCTION When looking for an effective paper chromatographic solvent system for polycyclic hydrocarbon mixtures occurring in high temperature tar (l), the author of this paper had to deal with the polarity and thus with the Those considerations led to a classconfiguration of these molecules. ification of the polycyclic hydrocarbons, from the standpoint of view The carcinogenic hydrocarbons conform to specific of carcinogenicity. molecular dimensions and configurations (2,3) (figure 1), which may fit into DNA steric structures (figure 2). Steric interactions leading to local denaturations were proposed (2,3). The synergism of tar and absorption of quanta of radiant energy at certain wavelengths which has been known since the 'twenties, hinted at the idea that a higher energy of the chromosomal DNA, in the form of a local denaturation of the DNA macromolecules, replicated continually, could be in the form in which cancer genetic information is carried (2). The metastable structures, once acquired, could result in an abridged duplication time of the DNA, leading to accelerated mitoses (2), so explaining increased DNA content in cancerous cells (4,5). A renaturation of an ;f;;zted site of the DNA thus ought to be preceded by duplication. polymerase able to synthesize altered bond angles was found (6).
177
0%
‘,
=I -
’
8
7
Figure 1.
12
16
n
IL
3. 3,4_benzofluoranthene; 7. Dimethylamino1. 3,4-benzopyrene; 2. Azuleno-5,6,7-c,d-phenalene; 10. 5-methyl-1,2_benzoanthracene; 9. 1,2_benzoanthracene; azobenzene; 8. Dimethylaminostilbene; 11. 5,10-dimethyl-1,2_benzoanthracene; 12. 3-methylcholanthrene; 13. 3,4_benzophenanthrene; 14. 5-methyl-3,4_benzophenanthrene; 15. P-nor-steranthrene; 16. 1,2,3,4_dibenzopyrene.
L
3
6
POLYCYCLIC
HYDROCARBONS
The simplest models for studies on the interactions of carcinogenic molecules with DNA are the polycyclic hydrocarbons. The effective part of a planar contour in a carcinogenic hydrocarbon may be delimited by a right triangle, both its legs being 4.6 angstrom long. An example is 3,4-benzopyrene, containing the benzanthrone configuration (3, figure 1, I). Other types are those containing a 1,2_benzoanthracene configuration, II (3, figure l), or the 3,4_benzophenanthrene configuration, III (figure 1). The active part of I and II could fit into the outer half of the inter-step space of the right-handed helical up staircase, if the steric contours of the DNA are so regarded. The plane of the polycyclic hydrocarbon would be perpendicular to the purine or pyrimidine plate, the edge tending towards or under the desoxyribose and phosphate bond geometry (figure 2). Carcinogenicity is enhanced through the combination of the contours I and II as in the 3-methyl-cholanthrene (figures 1 and 2). The third type could clasp the bond sugar-base. Its carcinogenicity is enhanced when combined with I, as in 1,2,3,4_dibenzopyrene. The steric interaction of a carcinogenic molecule could cause deformations of bond lengths and anglesandloosenthehydrogen bonds of the base pairs. Other carcinogenic molecules may be sterically equivalent even after conjugation with glucuronic acid, or sulphuric acid, as are the aromatic amines, or after metabolism, yielding the alkylation agents.
ON THE INTERACTION OF OXYGEN WITH DNA The absorbance changes at 259 nm of native, or weakly denatured, or denatured DNA were studied; 2.66 x 10-6 M calf thymus DNA solution (Flukka) in 2 x 10m2 M hydrogen peroxide as well as 2.66 x 10-6 M aqueous DNA solution in distilled water were used. The DNA solutions and the blanks were exposed to temperatures of 25-lOOoC, and cooled suddenly, the test tubes being submerged into melting ice. The difference in absorption was maximal after twelve minutes exposure to 60°C (figure 3). The Tm in hydrogen peroxide (full line curve in figure 4) was found to be 76oC, being increased by 26OC compared to that in distilled water (dashed curve in figure 4). The aqueous DNA solution subjected to denaturation at 9OoC for twenty minutes, and left overnight at room temperature, and resubjected to the described procedure with H202, exhibited no difference in absorption as compared to that in water. The UV spectra were run on a Perkin-Elmer-Visible-NIR spectrophotometer with silica cells, a 10 mm path-length being employed. This phenomenon could be explained from the standpoint of molecular geometry assuming that the hydrogens of the guanine-cytosine base pairs are the sites of interaction. The electro-negative 02 set free from H 02 could bridge over the spacing between them, as a transition state igure 2). The spacing between Nl at guanine and Nl at cytosine is (T. The spacing between one H at N6 in cytosine, and one 2.86 angstrom(18). of the two H at N2 in guanine could be a little more than 1.32 + 2 x 0.3 angstrom, taking the bond angles into consideration. The bond length between the two 0 of 02 is 1.32 angstrom and the bond radius of 0 is 0.66 angstrom. The secondary valence forces may be interrupted due to a protracted temperature over 400C and 02 can be expelled, as is seen in figure 3. The presence of oxygen at that site may contribute to the 179
A \ Figure 2. A. Possible interaction of magnesium, oxygen, 3,4-benzopyrene, 3-methylcholanthrene and potassium with DNA. A fragment of DNA drawn according to Calbiochem sale pamphlet. B. Possible interaction of 3,4_benzophenanthrene type with DNA.
W
a ts ) 0.2 The time effect Figureupon 3. the difference in chromicity of the DNA solution exposed to 60°C, both in istilled water and in 2 x lo-P M hydrogen peroxide.
G t z 0
01
1
I
I
/'
& 0
0
0 .-/
/ r( T I s
\ 1
1 10
'1 'I \ 1 15
TIME, MINUTES
180
I
I /\
_
2 0
1
I 20
-f25
-
-
20
30
40
50
60
70
80
90 100 fEW$RATut?E PC)
Figure 4, The denaturation of the DNA both in water (dashed curve) and in hydrogen peroxide (full curve).
--1~~
. .
3paCcrllO
ml
2
,rc--------*
Figure 5. The increase in Cl' in the DNA solution bubbled with vinyl chloride; through denatured DNA (upper full curve), through DNA solution in distilled water (middle dashed curve), through potassium nitrate solution (partly dashed and partly dotted middle curve) and through hydrogen peroxide or magnesium nitrate (bottom dashed and dotted line).
181
protection of the DNA against thermal and other denaturation. Once denatured, the DNA is n&ot capable of any interaction with oxygen anymore, in contrast with Warburg's view (7). The preliminary suggestion (8) seems to be confirmed. In this manner, all agents which remove oxygen for a long time from tissue such as respiratory poisons, arsenic, anemia, pressure of foreign bodies and scars under the epithelium, may result in the cancer cell development.
MAGNESIUM Magnesium seems to be antagonistic to agents causing denaturation of the DNA and to be cancer prophylactic (9,10,11,12,13). When in the form of a polyvalent MgDNA salt, the DNA's helicity may be protested by the electrostatic forces of MgL+. On the other hand, the MgL+ bond radius cannot bind the two neighbouring phosphate groups in one polynucleotide chain once local bond deformation has occurred. The normal spacing between the two nearest phosphate groups of one polynucleotide chain is about 7 angstrom (18). The straight P-0-+Mgt-O-P bond length is about 7.88 angstrom, which fits into the DNA sturcture, when taking the One would expect that the denatured segments bond angles into account. of the DNA are unable to bind the divalent cations, but can still bind Magnesium content was found to be reduced in cancerous the univalent. tissues, and in addition the potassium content increased (15), both being the cations of the cell nucleus. Some cations like Co, or Cr, could influence adversely the helicity of the DNA (14).
THE ANTIALKYLATING
EFFECT OF OXYGEN AND MAGNESIUM
One can expect that the alkylation of guanine at Nl or N2, and of cytosine at N6 as well as of thymine at Nl will cause an irreparable local denaturation of the DNA macromolecule. Model experiments with vinyl chloride as a carcinogenic agent in vitro were carried out. Vinyl chloride was made to interact with DNA, when 8 ml of pure gas at 1 atm were bubbled and recycled for one hour through 15 ml of calf thymus (Flukka) n x 8 x 10-6 M aqueous DNA solution, where n=1,2,4,6; pH was about 5.8, at 37OC. The increase in Cl- was a measure of the alkylation according to the equation: RNH t ClHC=CH2
= RN-CH=CH2
t H+Cl-
The inorganic chlorine was determined nephelometrically. The results are shown in figure 5. The middle dashed curve belongs to the experiNo increase in Cl- was noticed as against the ments in pure water. gassed solution, when the distilled water was replaced by 1.94 x 10-l M hydrogen peroxide (bottom dashed and dotted line in figure 5). The increase in Cl- was highest when the denatured DNA solution without peroxide was gassed (upper full curve in figure 5). Vin 1 chloride was bubbled through 10-2 M magnesium 10-$ M potassium nitrate, under the same conditions
nitrate, and (21). The results are shown in figure 5. There was no increase in Cl- in magnesium nitrate (the bottom dashed and dotted line). The increase in Cl182
in potassium nitrate was similar to that in pure water (the middle partly dashed and partly dotted line). It is to be expected that the free NH groups will be more reactive with vinyl chloride than those forming the hydrogen bonds, which are interrup ted in a denatured DNA. Thus, a synergism of an alkylating agent and abnormal temperature may be suggested in vivo. Oxygen and magnesium could stabilize the bond lengths and angles of the DNA. Furthermore, oxygen may repulse the electronegative chlorine moiety of the alkylating molecule. The relative turbidities were measured with a Pulfrich nephelometer: 20 mm path length,green filter and comparing glass No 4 were employed. Cl- was determined according to the calibration curve carried out in presence of the calf thymus DNA. The concentrations 1 - 6 mg DNA/100 ml in standard solution influenced the turbidities to the same extent.
VIRAL AND VARIOUS OTHER CARCINOGENIC Segments of the DNA virus (6) or double be metastable. The (17) and in the DNA between viruses and
AGENTS
synthesized on the single strand RNA oncogenic stranded linear DNA adenovirus template (16) could internucleotide spacings in RNA are 3.0 angstrom double helix are 3.4 anstrom (18). Synergism chemical agents is also known.
The carcinogenicity of some forms of asbestos, synergistic with 3,4benzopyrene (19) could be explained as a partial thermal denaturation of the chromosomal DNA. A thermal isolation of the cell nucleus owing to these particles in the environmental plasm and intercellular space could be the result. A coagulation of the proteins surrounding the chromosomal DNA, due to strong tannic materials, could cause a mechanical steric compression and consequently local denaturation of the DNA macromolecule (20). The physical agents could bring about a local denaturation of the DNA directly through an abnormal temperature, or through the absorption of the radiant energy transformed to heat at certain wavelengths. The formation and incorporation of thymine dimer after ultraviolet irradiation ought to lead to a local denaturation of the DNA. The distance of the two plates in the thymine dimer is about 1.54 angstrom.
REFERENCES 1.
Ma19 E. Paper chromatography of tar polycyclic hydrocarbons. Nature 181: 698, 1958. An improved method for determination of Mikrocim. Acta, Wein, 1977; air-borne polycyclic hydrocarbons. I, 429.
2.
Maly E. Pozndmka ku genetickej rakovinnej inform&ii dizoxyribonukleovgch kyselin. A note on cancer genetic information of the DNA. Pracov. 1ekaPstvi 17: 121, 1965. 183
3.
Ma19 E. Kancerogeneze z hlediska molekularni geometrie. Set of abstracts of the second conference "Cemicka karcinogenita 1975". VQzk. iIstavorg. syntez Pardubice - Rybitvt, Czechoslovakia, 1975.
4.
Mellors RC, Keane JP, Jr, Papanicolaou GN. Nucleic acid content of the squamous cancer cell. Science 116: 265, 1952.
5.
Paulette-Vantrell J. DNA content and chromosome number in twentyfive human carcinomas. Oncology 24: 265, 1970.
6.
Temin H, Mizutani S. RNA-dependent DNA polymerase in virions of Rous sarcoma virus. Nature 226: 1211, 1970.
7.
Warburg 0.
8.
Ma19 E. 0 interakcii kysliku s kyselinou dezoxyribonukleovou. On the interaction of oxygen with DNA. Pracov. Lekai%tvS 22: 226, 1970. A preliminary report.
9.
Dubard.
On the origin
of cancer cells.
Magnesie et cancer.
Science 123: 309, 1956.
Bull Acad Med de Paris 79: 309, 1918.
10.
Delbet P. RQle du magnesium dans les phenom&nes biologiques. Monde medical 39: 969, 1929.
11.
Robinet L. Terrains magnesiens et cancer. Haut-Rhin, Bas-Rhin, Moselle Bull assoc franc. Etude can 19: 243, 1930.
12.
Estas P. Rapports du metabolisme avec le cancer du goudron. belge des sciences medicales 1: 189, 1929.
13.
Shear MJ. The role of sodium, potassium, calcium and magnesium in cancer. Amer J Cancer 18: 924-1024, 1933. A review.
14.
Eichhorn GL. Metal ions as stabilizers or destabilizers of the deoxyribonucleic acid structure. Nature 194: 74, 1962.
15.
Moravek V. Biochemie des Rous-Sarkoms der Huner. forsch 35: 626, 1932. Ibid, 36: 529, 1932.
16.
Graham FL, Van der Ebb AJ, Heijneker HL. Size and location of the transforming region in human adenovirus type 5 DNA. Nature 521: 687, 1974.
17.
Langridge R, Gomatos P.
18.
Wilkins NHP. Molecular configuration of nucleic acids. 140: 941, 1963.
19.
Salk R, Vasamae A. Induction of lung tumors in rats by intratracheal instillation of benzo/A/pyrene and chrysotile asbestos. Exper Oncology 2: 88, 1975.
20.
Issekutz B. 1951.
21.
Ma19 E.
The structure of RNA.
Zeitung Krebs-
Science 141: 694, 1963. Science
Gybgyszertan, meregtan es gydgyszren degles.
The unpublished paper.
184
Revue
Budapest