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Biomedical subjects

L B Hendry

Publications and source records attributed to L B Hendry.

At least 37 records · Page 2Linked to original sources
PubMed1992

Stereochemical complementarity of progesterone, RU486 and cavities between base pairs in partially unwound double stranded DNA assessed by computer modelling and energy calculations.

Computer modeling was used to examine the relative fit of progesterone and RU486 in cavities constructed between base pairs in double stranded DNA. Progesterone was capable of forming two stereospecific hydrogen bonds between the carbonyl groups and protonated phosphate groups on adjacent strands. Favorable van der Waals and electrostatic energies were exhibited upon insertion of progesterone into DNA indicating an excellent fit. While RU486 could be accommodated between the base pairs and formed hydrogen bonds, there was a high van der Waals energy in the resulting complex. When the complexes were subjected to energy minimization, the conformation of the DNA was significantly altered in the RU486-DNA complex but not in the progesterone-DNA complex. No mechanistic interpretation of these results is proffered; however, such information may have evolutionary significance and could prove useful in designing new progesterone agonists and antagonists.

Base Composition↗
PubMed1991

Stereochemical complementarity of progesterone and cavities between base pairs in partially unwound double stranded DNA using computer modeling and energy calculations to determine degree of fit.

Computer modeling was applied for the first time to investigate previously reported complementarity of progesterone and cavities formed between base pairs in partially unwound double stranded DNA. Computer graphics enabled a more objective assessment of complementarity; energy calculations provided a rigorous method to evaluate degree of fit. Graphics confirmed that the complementarity was virtually "lock and key", i.e. close contacts were formed between van der Waals surfaces in the progesterone/DNA complexes and hydrogen bonds were formed between the two carbonyl groups on opposite ends of the steroid and phosphate groups on adjacent strands of DNA. Molecular mechanics calculations revealed that insertion of the steroid resulted in a relatively stable complex i.e. both van der Waals and electrostatic energies were lowered due to favorable steric interactions and stereospecific hydrogen bonds, respectively. Three published X-ray crystal structures of progesterone exhibited similar complementarity. Ent-progesterone which does not occur naturally possessed very poor complementarity. These findings confirm that the structure of progesterone is directly reflected in the stereochemistry of DNA. While no mechanistic explanation for these results is proffered, we hypothesize that such complementarity must have played a decisive role in the evolution of steroid hormone structure and function.

Base Composition↗
PubMed1991

3-phenylacetylamino-2,6-piperidinedione inhibition of rat Nb2 lymphoma cell mitogenesis.

3-Phenylacetylamino-2,6-piperidinedione (A10), an amino acid analog, has been reported to possess antineoplastic activity against certain neoplastic tissues. The antimitogenic properties of A10 were studied by determining its effect on prolactin (PRL)- and interleukin 2 (IL-2)-stimulated mitogenic responses in the rat Nb2 lymphoma cell line. The addition of A10 (1-12 mM) to PRL (0.4 ng/ml)-stimulated cells inhibited growth in a dose-dependent manner. DNA synthesis patterns studied by thymidine incorporation demonstrated that A10 was significantly inhibitory (25% at 20 hr; 50% at 40 hr, P less than 0.01). IL-2 stimulation of mitogenesis was also sensitive to A10 inhibition. The inhibition of PRL stimulated mitogenesis was reversible when A10 was removed after 24 hr of culture and A10 showed no toxicity in a chromium release assay. These data suggest that A10 effects may be cytostatic, rather than cytotoxic.

Animals↗
PubMed1988

Stereochemical complementary of DNA and steroid agonists and antagonists.

Modelling studies in our laboratories over the past decade have demonstrated that a variety of natural products exhibit stereochemical complementarity with nucleic acids. In the case of steroid hormones, the basic cyclopentanophenanthrene skeleton fits between base pairs in partially unwound double stranded DNA; heteroatoms on the steroids form stereospecific donor/acceptor linkages to hydrogen bonding heteroatoms on the DNA. Each of the hormones appears to fit best in the site, i.e. 5'-dTdG-3'.5'dCdA-3'; the pattern of donor/acceptor linkages is unique for each type of hormonal activity. Steroid hormone agonists fit into the same site as the parent hormone; degree of fit correlates with degree of hormonal activity. Steroid hormone antagonists (e.g. RU 486; tamoxifen; anandron) fit into the same site as the agonists but possess different donor/acceptor linkages than the parent hormone; these linkages occur within the site between the base pairs or along the outside surface of the DNA helix in the major or minor grooves. A chronological review of the underlying concepts and observations leading to these discoveries is presented. Work in progress and some potential implications of the emerging technology are also discussed.

DNA↗
PubMed1988

Actions of an endogenous antitumorigenic agent on mammary tumor development and modeling analysis of its capacity for interacting with DNA.

Antineoplaston A10 (3-phenylacetylamino-2,6-piperidinedione) is an agent derived from human urine which is remarkable for its antineoplastic activity and lack of toxicity. This study deals with the discovery of a hormonal component to the action of A10 on rodent tumor formation and approaches to the delineation of its mechanism of action. Oral administration of A10 dramatically delays onset of spontaneous mammary tumor incidence in female and orchidectomized male C3H+ mice. The action in the male qualitatively mimics that of androgens. In the rat, A10 ingestion is very effective in preventing carcinogen-induced mammary tumors, but does not cause regression of pre-established tumors. It selectively blocks the occurrence of the estrogen-sensitive subpopulation of tumors, acting in a fashion completely analogous to that of tamoxifen; in contrast to tamoxifen, however, A10 has no measurable affinity for the estrogen receptor. Modeling studies demonstrate a stereoselective capacity for interaction between A10 and specific deoxyribonucleotide base pair sequences. The potential affinity is lower than that for classical intercalating antitumor agents, and the stereospecificity differs from that which we have previously established for estrogens. We offer an interpretation of the data in terms of direct effect of A10 at the genomic level to alter the cellular responsiveness to steroid hormones.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Initial studies of a phytoestrogen-deoxyribonucleic acid interaction.

Molecular modeling studies show that estrogens such as estradiol complement the topography of spaces between base pairs in unwound DNA and simultaneously hydrogen bond phosphate moieties on opposite strands. We demonstrate here that the phytoestrogen coumestrol has this capability, in addition to its documented properties of UV absorbance at lambda greater than 300 nm and fluorescence. The latter properties enable spectroscopic examination of interactions with DNA by methods not possible with estrogenic steroids. On exposure to calf thymus DNA, the UV spectrum of coumestrol displays a bathochromic shift and simultaneous hypochromic effect with an isosbestic point at 370 nm, suggesting a shift between coexisting free and bound states. Similar results are observed with the intercalating agents adriamycin, ethidium bromide, and acridine. The fluorescence spectrum of coumestrol is quenched on exposure to DNA as are those of adriamycin and acridine. Coumestrol differs from the intercalators in that denatured DNA does not affect its UV spectrum or alter its relative fluorescence yield. Unlike classical intercalators, coumestrol has no influence on the thermal stability of calf thymus DNA. Preliminary electrophoretic analysis of DNA plasmid conformers indicates that coumestrol is incapable of significantly altering DNA superhelical density, in contrast to ethidium bromide. These initial physicochemical data provide evidence for the DNA base-estrogen electronic and/or hydrophobic interactions suggested by modeling studies, yet tend to rule out classical intercalation as an explanation for these phenomena.

Animals↗
PubMed1987

Stereochemical modelling studies of the interaction of antineoplaston A10 with DNA.

Antineoplaston A10 (3-phenylacetylamino-2,6-piperidinedione), a peptide analogue originally isolated from human urine, has been demonstrated to fit between base pairs in DNA. Examination of the fit of A10 into the 10 possible sites in unwound DNA using published criteria revealed a preference, but not absolute specificity, for the sequence 5'-dTdT-3' X 5'-dAdA-3'. Good fits were also observed for the sequences 5'-dTdC-3' X 5'-dGdA-3' and 5'-dCdT-3' X 5'-dAdG-3'. In each case at least one stereospecific hydrogen bond was possible between the imino proton of the piperidinedione ring stacked between the two pyrimidines and a neighbouring phosphate oxygen of the DNA backbone. These findings support the prediction that A10 may interact reversibly with DNA and thereby compete with carcinogens that form covalent linkages with DNA (e.g., arene oxides). It follows that such interactions should prevent the growth of tumours induced by various carcinogens.

Antineoplastic Agents↗
PubMed1987

Inhibition of spontaneous mouse mammary tumour development by antineoplaston A10.

Antineoplaston A10, a human urinary product of minimal toxicity and demonstrable antineoplastic activity, was examined as a modulator of spontaneous mammary tumour development in C3H+ mice. These animals normally express the viral response with appearance of tumours in greater than 95% of the mice by 9-10 months of age. Inclusion of A10 as a 1% dietary supplement from the age of 3 months dramatically increased the disease-free interval. At 10-11 months of age, none of the animals had developed tumours, and the incidence reached 95% only at 21 months of age. In spite of this effect, the survival interval following tumour detection could not be prolonged by treatment with A10. Male C3H+ mice, normally fully protected against spontaneous mammary tumour by their testicular androgens, can be made susceptible to such tumorigenesis by castration. The age at which castration is performed influences the age of onset of the disease: castration at one month leads to initial appearance at 5 months of age; castration at 2 months to appearance at 7-8 months. When such animals are maintained on A10-containing diets following castration, the onset of tumour appearance is delayed until 7 months and 10 months for the 1- and 2-month castrated animals respectively. The results indicate a clear inhibitory action of A10 on MMTV-induced spontaneous mammary tumour occurrence in a manner similar to the protective effect of androgens.

Animals↗
PubMed1986

The stereochemical complementarity of DNA and reproductive steroid hormones correlates with biological activity.

Modeling studies revealed that progesterone, testosterone, and estradiol are stereochemically complementary to the cavity formed between base pairs in the DNA sequence, 5'-dTdG-3' X 5'-dCdA-3'. Each steroid aligned precisely with the topography of the cavity and formed 2 stereospecific hydrogen bonds linking phosphate oxygens on adjacent DNA strands. Hydrogen bonding donor-acceptor relationships were different for each hormone. The remarkable stereochemical specificity of the hormone-DNA complexes was demonstrated by the lack of complementarity of steroid enantiomers and steroid analogs having alternate ring systems and/or changes in the position of functional groups. Fit of molecules into DNA in the manner of the parent hormone correlated with biological activity. Antagonists also fit into the cavity but differed from agonists in their hydrogen bonding linkages to DNA and/or extended out of the cavity beyond the helix. Unlike flat intercalating agents which form stable complexes with DNA, wedge shaped steroids may thus be capable of forming reversible sequence-specific complexes with DNA. We conclude that the stereochemistry of DNA can be used to predict hormonal activity.

Animals↗
PubMed1986

Psycho-social aspects of youth unemployment: an interpretative theoretical model.

By utilizing representative samples of short-term (n = 33), long term (n = 14) unemployed adolescents and YTS trainees (n = 49) in North-East Scotland, the present study attempted to identify psycho-social variables involved in the individual adolescent's ability to cope with unemployment. The research was built around a series of semi-structured interviews with all subjects. Results suggested a variety of apparent contradictions--family support vs. parental pressure; informal community-based education as helpful vs. school education as irrelevant; high aspirations as reinforcing or frustrating; peer groups as supportive or socially constraining; time structure as welcome or monotonous and restrictive; self-esteem being sapped or maintained aggressively and defensively high. From the data a theoretical model is offered which attempts to resolve the paradoxes by interpreting the experience of unemployment for young people in terms of positive and negative "trade-offs".

Adolescent↗
PubMed1986

3-Phenylacetylamino-2,6-piperidinedione, a naturally-occurring peptide analogue with apparent antineoplastic activity, may bind to DNA.

Antineoplaston A10 (3-phenylacetylamino-2,6-piperidinedione), a peptide analogue originally isolated from human urine and serum, appears to have antineoplastic activity. In view of the close resemblance of the structure of A10 to that of DNA intercalative anticancer drugs, spectroscopic studies were performed to determine whether its mode of action could similarly involve binding to DNA. DNA thermal denaturation studies demonstrated that A10 was capable of interacting with DNA in a specific manner; of the synthetic polynucleotides employed in this study, A10 had the greatest effect on poly(dA-dG).poly(dC-dT), suggesting some sequence preference. However, ultraviolet and fluorescence spectroscopic studies demonstrated that interactions of A10 with DNA were weak in comparison to those of classical intercalating agents. Mass spectroscopic studies suggested that A10 did not react covalently with DNA. The weak yet apparently specific interaction of A10 with DNA indicates that the mode of action of A10 may involve binding to chromatin, facilitated by nuclear protein receptors analogous to steroid and thyroid hormones.

Antineoplastic Agents↗
PubMed1985

Apparent stereochemical complementarity of estrogens and helical cavities between DNA base pairs: implications for the mechanism of action of steroids.

The shape of the space occupied by a model of the estrogenic steroid hormone estradiol-17 beta conforms closely to a helical cavity between neighboring base pairs in partially coiled B-DNA. The orientation of estradiol-17 beta when fitted into DNA allows stereochemically complementary hydrogen bonding of both the 3- and 17 beta-hydroxyl groups to phosphate oxygens of the deoxyribose-phosphate backbone on adjacent strands. Changes in the chirality (handedness) of the steroid skeleton or in the absolute stereochemistry of hydrogen bonding groups prevent formation of complementary fits in the DNA. Synthetic estrogens can also adopt conformations which are stereochemically complementary to the cavities between base pairs. The complementary relationships between active estrogens and nucleic acids may be related to constraints on the evolution of the structure and the biological function of steroids.

Base Composition↗
PubMed1981

Are there structural analogies between amino acids and nucleic acids?

Space-filling molecular models have been used to examine structural analogies between amino acids and nucleic acids. The three-dimensional structures of amino acid R groups appear to be stereochemically related to cavities formed by removal of single bases in double helical nucleic acids. The common L amino acids may thus be complementary to their codons.

Adenine↗
PubMed1981

First approximation of a stereochemical rationale for the genetic code based on the topography and physicochemical properties of "cavities" constructed from models of DNA.

To examine the question of whether or not the genetic code has a stereochemical basis, we used artificial constructs of the topography and physicochemical features of unique "cavities" formed by removal of the second codon base in B-DNA. The effects of base changes on the stereochemistry of the cavities are consistent with the pattern of the genetic code. Fits into the cavities of the side chains of the 20 L amino acids involved in protein synthesis can be demonstrated by using conventional physicochemical principles of hydrogen bonding and steric constraints. The specificity of the fits is remarkably consistent with the genetic code.

Amino Acids↗