Cancer cell metabolism: its relevance to cancer treatment.
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Antineoplastic Agents↗
Biomedical subjects
A Lupulescu
Publications and source records attributed to A Lupulescu.
Resolution enhancement in multiple-quantum MAS NMR spectroscopy.
Two techniques for resolution and sensitivity enhancement are introduced in multiple-quantum (MQ) MAS spectroscopy of rigid solids. The first makes use of ultrafast MAS with spinning frequencies of up to 35 kHz, while the second combines MAS at moderately fast spinning frequencies of about 13 kHz with multiple-pulse (MP) dipolar decoupling. For the latter approach, a semiwindowless WHH-4 sequence is applied during the MQ evolution period (MQ dimension) and/or detection period (single-quantum dimension). In the MQ dimension, the MP sequence has to be supplemented by two bracketing pulses in order to preserve the order and the intensities of the evolving MQ coherences. Double-quantum 1H NMR spectra of l-alanine recorded using both decoupling techniques are shown and compared to each other. Triple-quantum 1H NMR spectra under ultrafast MAS conditions are also presented.
Alanine↗
The role of hormones, growth factors and vitamins in carcinogenesis.
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Animals↗
Prostaglandins, their inhibitors and cancer.
Prostaglandins (PGs) and their analogs endoperoxides are a large series of compounds which mainly enhanced cancer development and progression, acting as cocarcinogens or tumor promoters, and having profound effects on carcinogenesis. Although PGs are ubiquitous tissue hormones exerting pleiotropic effects on cancer cells, their mechanism(s) of action at molecular and cellular levels are not yet elucidated. Autoradiographic, ultrastructural, antigenic, and cell surface studies revealed that PGs act namely by their specific receptors and by interfering with DNA, RNA and protein synthesis, cell membranes and cell communications. PGs also play a role in tumor immunology and transplantation, acting as immunomodulators. Prostaglandins exert their effects by autocrine and paracrine mechanisms similar to hormone-like substances, and hypophysectomy reduces some of their tumor-promoting effects. PGs may act synergistically with hormones, growth factors (GFs), and vitamins. Several drugs called PG-synthesis inhibitors or PG-antagonists are found to markedly inhibit the cyclooxygenase activity. Most of these PG-inhibitors (aspirin, ibuprofen, indomethacin, piroxicam, sulindac) or commonly called NSAIDs (nonsteroidal antiinflammatory drugs) also significantly inhibit cancer development and cancer progression, and are recently used in epidemiological studies for cancer prevention and treatment. Developing more active and less toxic NSAIDs, which can also more selectively inhibit PG synthesis, is a promising field in prostaglandin research.
Adjuvants, Immunologic↗
Estrogen use and cancer incidence: a review.
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Animals↗
The role of vitamins A, beta-carotene, E and C in cancer cell biology.
Vitamins A (retinol, retinoids), beta-carotene (provitamin A), E (alpha-tocopherol), and C (ascorbic acid) are used in experimental, clinical and epidemiological studies for cancer chemoprevention and treatment. The cellular and metabolic effects are depending on the dose used, duration of exposure, and cancer cell type. Despite recent advances, the anticarcinogenic mechanisms remain as yet unknown. Studies regarding the role of vitamins A, beta-carotene, E and C in cancer cell biology and metabolism are of critical importance for their use in cancer treatment. Autoradiographic, ultrastructural and cell surface studies demonstrated that vitamins A, E and C are strong regulator factors of cancer cell differentiation, cell regression, membrane biogenesis, DNA, RNA, protein, and collagen synthesis, as well as transformation of precancer cells into cancer cells. These vitamins exert cytotoxic and cytostatic effects, and may reverse the cancer cell to the normal phenotype. Interrelation of vitamins A, E and C with oncogenes and growth factors play an important role in cancer cell biology. The data presented in this review can provide new insights for the understanding of anticarcinogenic mechanisms, and a rationale for the use of vitamins A, E and C in cancer chemo-prevention and treatment.
Animals↗
Estrogen use and cancer risk: a review.
The role of estrogens as carcinogens, cocarcinogens or tumor promoters, as well as their mechanism(s) of action on cancer cells, are thoroughly reviewed. Although there is ample evidence that estrogens (natural and synthetic) can induce multiple benign and malignant tumors in animals, and most of these tumors are histologically similar to that in humans, there is no direct evidence that natural estrogens (estradiol-17 beta, estrone) are carcinogenic in humans. Recent evidence in cellular and molecular oncology revealed that estrogens act by genetic and epigenetic mechanisms on cancer cells, and a close relationship between estrogens, growth factors, and oncogenes is important for human cancer. Long-term exposure to estrogens should always be regarded as increased cancer risk. Estrogen replacement therapy (ERT) by unopposed estrogens in postmenopausal women with high familial cancer risk or existent premalignant lesions should be avoided, since estrogens may act as tumor promoters. Combination of estrogens with progesterone (or other progestins) cyclically or sequentially, significantly reduce and prevent the cancer risk.
Animals↗
Ultrastructure and cell surface studies of cancer cells following vitamin C administration.
Basal cell carcinomas in rats and squamous cell carcinomas in mice induced by a topical administration of a chemical carcinogen 3-methylcholanthrene (MCA) a single dose of 800 micrograms, were significantly reduced in number and size following a combined administration of vitamin C, a daily dose of 50 mg/kg b.wt. and MCA for 9 months. Ultrastructural studies of basal cancer cells and squamous cancer cells revealed an advanced cytolysis and disorganization of neoplastic cells, mitochondrial alterations, nuclear and nucleolar reduction, and increased phagolysosomes formation, following vitamin C and MCA administration compared to that of neoplastic cells following MCA alone. Scanning electron microscopic observations also revealed cytolysis, increased collagen synthesis, and cell disorganization with membrane disruption following vitamin C and MCA administration, as compared to round basal neoplastic or polyhedral squamous neoplastic cells following MCA treatment alone. These findings demonstrate that vitamin C exerts its antineoplastic effects by increasing cytolytic and autophagic activity, cell membrane disruption, and increased collagen synthesis, and thus, inhibits cancer cell metabolism and proliferation.
Animals↗
Vitamin C inhibits DNA, RNA and protein synthesis in epithelial neoplastic cells.
Radioactivity measurements and autoradiographic studies of DNA, RNA and protein synthesis using [3H]-thymidine, [3H]-uridine and [3H]-leucine revealed that Vitamin C administration significantly (by 50%) decreases the DNA, RNA and protein synthesis in the neoplastic cells of basal cell carcinomas and squamous cell carcinomas in mice and rats. Basal cell carcinomas and squamous cell carcinomas were induced by a topical application of a chemical carcinogen, 3-methylcholanthrene. The inhibition of DNA, RNA and protein synthesis is accompanied by advanced ultrastructural and cell surface changes. Since the concentrations of Vitamin C were significantly higher in the plasma of Vitamin C-treated as compared to that of non Vitamin C-treated animals, these findings demonstrate that Vitamin C inhibits DNA, RNA and protein synthesis in neoplastic epithelial cells, and thus exerts its antineoplastic effect.
Animals↗
Inhibition of DNA synthesis and neoplastic cell growth by vitamin A (retinol).
The inhibitory effect of vitamin A alcohol (retinol) on the DNA synthesis and neoplastic cell growth of chemically induced carcinomas (squamous cell carcinomas in Swiss male albino mice and basal cell carcinomas in inbred SD rats) by 3-methylcholanthrene [(MCA) CAS: 56-49-5] was studied. A marked inhibition of squamous cell carcinomas and basal cell carcinomas was observed following a combined administration of MCA and vitamin A (retinol) compared to the finding for animals treated with MCA alone (P less than .001). DNA radioactivity and autoradiographic studies with the use of [3H]thymidine showed a marked inhibition of DNA synthesis (twofold to threefold) in the neoplastic cell nuclei following a concomitant administration of vitamin A (retinol) and MCA (12%) as compared to the DNA synthesis following administration of MCA alone (31%) (P less than .001). Electron microscopic and cytologic observations revealed an advanced cytolysis and disorganization of neoplastic cells with reduction of polysomes, tonofilaments, and lysosome populations and mitochondrial alterations following vitamin A and MCA administration as compared to characteristic squamous neoplastic cells and basal neoplastic cells following MCA treatment alone. In addition, scanning electron microscopy revealed advanced changes of cell surfaces with reduction of microvilli and disorganization of cytoarchitecture. The present findings demonstrate that vitamin A exerts its anticarcinogenic effect by inhibiting DNA synthesis, disrupting cell surfaces, and possibly interfering with MCA metabolism in epidermal cells.
Analysis of Variance↗
Chemoprotective effect of progesterone on carcinoma formation in mice and rats.
The protective effect of progesterone on the development of chemically induced carcinomas (squamous cell carcinomas in mice and basal cell carcinomas in rats) by 3-methylcholanthrene [(MCA) CAS: 56-49-5] was studied. Progesterone administration decreased the average number, size, and weight of carcinomas by 45-50% as compared to those of tumors treated with MCA alone at any time interval. DNA radioactivity and autoradiographic studies with the use of [3H]thymidine showed an inhibition of DNA synthesis in the neoplastic cell nuclei following a concomitant administration of progesterone and MCA (18.4%) as compared to the DNA synthesis following administration of MCA alone (35.0%). Electron microscopic and cytologic observations revealed salient ultrastructural findings following progesterone administration, with advanced cytolysis, tumefied mitochondria, large populations of secondary lysosomes, and autophagic formations; also, cell differentiation tended to be of a glandular-adenomatoid type following progesterone and MCA administration as compared to the characteristic squamous cell and basal cell carcinomas after treatment with MCA alone. In addition, scanning electron microscopic observations revealed advanced cytolytic areas with several disintegrated neoplastic cells and cell debris intermingled with red blood cells, following progesterone and MCA administration. The present findings demonstrate that progesterone in pharmacologic doses exerts important chemoprotective effects on carcinoma formation, possibly by interfering with MCA metabolism and inhibiting DNA synthesis in the epidermal neoplastic cells, and thus plays an important role in tumorigenesis.
Animals↗
Enhancement of epidermal carcinoma formation by prolactin in mice.
Long-term administration of prolactin (PRL) markedly enhanced the induction of epidermal squamous cell carcinomas by a chemical carcinogen, 3-methylcholanthrene [(MCA) CAS: 56-49-5], in Swiss male albino mice. DNA radioactivity and quantitative estimation of autoradiographs with the use of [3H]thymidine revealed a significant increase in DNA content (twofold) and in the percentage of labeled neoplastic nuclei in mice treated with PRL plus MCA (48.50%) as compared to that in mice treated with MCA alone (23.50%). Ultrastructural and cytologic studies revealed the predominance of a trabecular-hepatoid type of epidermal carcinoma with advanced nuclear irregularities, glycogen granules, mirror-image cells, and phagolysosomes in PRL-MCA-treated carcinomas as compared to characteristic squamous neoplastic cells with enlarged nuclei, tonofilaments, and keratin formation in epidermal carcinomas following treatment with MCA alone. Scanning electron microscopy revealed the predominance of rounded cells covered by numerous thick microvilli and blebs with an intense stromal reaction following PRL-MCA administration as compared to characteristic polyhedral cells covered by small microvilli following treatment with MCA alone. These findings demonstrate that PRL is an important hormone in epidermal neoplastic cell growth and differentiation.
Animals↗
Tumorigenic potential of endoperoxide analogs.
The endoperoxide analogs known as U-46619 and U-44069 significantly enhanced the carcinoma formation and cellular atypicality initiated by a chemical carcinogen in mice. Studies of DNA radioactivity demonstrated that endoperoxides exerted their cocarcinogenic action by stimulating DNA synthesis. Thus, they play an important role in tumor cell proliferation.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Ultrastructural studies of xeroderma pigmentosum.
Electron microscopic observations of both sun-exposed and sun-protected skin from a black patient with xeroderma pigmentosum (XP) revealed abnormal ultrastructural changes in the melanin pigmentary system, tonofibrillar-desmosome complexes, endoplasmic reticulum, mitochondria, and nucleoli of all keratinocytes. The difference between the cellular changes in the sun-exposed skin and that protected from sunlight was quantitative rather than qualitative in character. The most salient changes were seen in sun-exposed specimens: melanosomes limited by a membrane showed a high degree of polymorphism with a tendency to form large complexes, and many fibroblast-like cells displayed an intense phagocytic activity for melanosomes, the latter finding not previously reported. The present study supports the conclusions of other investigators that XP is a heterogeneous disease. Clarification of the XP entities by continued research may identify the defective gene and lead to methods of correction by the molecular biologist.
Biopsy↗
Glucagon control of carcinogenesis.
Long term administration of glucagon markedly enhanced carcinoma formation in mice simultaneously treated with a chemical carcinogen, 3-methylcholanthrene (3-MCA). The number and size of squamous cell carcinomas were 3-fold greater compared to those in mice treated with MCA alone. DNA labeling and the percentage of [3H]thymidine-labeled cells were also 2- to 3-fold higher in glucagon- and MCA-treated mice than in those treated with MCA only or 5- to 6-fold higher than those in control mice. Ultrastructural studies of glucagon- and MCA-treated tumors revealed the predominance of acinar-cystoid and secretory types of tumors, with the occurrence of large and dense secretory granules (Zymogen-like granules), markedly dilated endoplasmic reticulum cisternae, and lysosomes compared to only typical squamous neoplastic cells observed in MCA-treated mice. Scanning electron microscopic observations also indicated that neoplastic cells of MCA and glucagon-treated tumors exhibited characteristic secretory features on their cell surfaces (a marked increase in blebs and microvilli). These findings demonstrate that glucagon in pharmacological doses significantly enhanced the carcinogenic process and changed the cytodifferentiation of neoplastic cells and, thus, plays an important role in controlling tumor cell biology and neoplastic transformation.
Animals↗
Reserpine and carcinogenesis: inhibition of carcinoma formation in mice.
Long-term administration of reserpine, an alkaloid, significantly retarded the induction of squamous cell carcinomas by a chemical carcinogen, 3-methylcholanthrene (MCA) in Swiss male albino mice. The incidence and development of carcinomas in mice simultaneously treated with reserpine and MCA was notably lowered as compared to those occurring in mice treated with MCA alone at any time interval. DNA synthesis and the percentage of labeled cells with [3H]thymidine was also significantly decreased in the nuclei of tumor cells following reserpine and MCA administration as compared to the findings for cells treated with MCA alone (18.50 and 39.00%, respectively). Electron microscopic and cytologic observations of tumors revealed the predominance of large areas of cytolysis and disintegration with an increase of lysosomes, myelin figures, and a decrease of mitochondria and polyribosome populations in tumor cells treated with reserpine and MCA, as compared to those results after treatment with MCA only. These findings demonstrate that reserpine significantly inhibited the carcinoma induction by a chemical carcinogen (MCA) in mice, possibly by inducing an advanced cytolysis and decreasing DNA synthesis in mouse tumor cells.
Animals↗
Hormonal regulation of epidermal tumor development.
The effects of hormones and hormone-like substances such as thyroxine, estradiol, hydrocortisone, calcitonin, prostaglandins (F2a, A2) or hormone deficiency (hypophysectomy, gonadectomy) on the development of carcinomas in mice and rats induced by 3-methylcholanthrene were investigated. Thyroxine, PGF2a, calcitonin, and estradiol markedly enhanced the development of squamous cell carcinomas and basal cell carcinomas; an inhibition occurred following hydrocortisone, hypophysectomy, and gonadectomy. DNA labeling using [3H]-thymidine and radioautography revealed that DNA synthesis in neoplastic cells is also markedly influenced by the same hormones. Tumor histology and ultrastructure are profoundly affected and an increase of epithelial pearls, hyperchromatic basophilic cells, tonofilaments, polyribosomes, and lysosomes is observed following thyroxine and PGF2a. An increase of keratinization and intramitochondrial granules occurred with estradiol and increased sclerosis followed calcitonin. A marked reduction of cell organelles occurred after hydrocortisone, hypophysectomy, and gonadectomy. Scanning electron microscopy shows salient changes in tumor cytoarchitecture and cell surfaces (blebs, ruffles). These findings demonstrate that hormones can change the development of carcinomas, DNA synthesis as well as their cellular differentiation and consequently may be important modulators of epidermal carcinogenesis.
Animals↗
Heavy incorporation of 3H-prostaglandin F2 alpha in the neoplastic cells as revealed by autoradiographic studies.
A marked uptake (9-fold) of the 3H-PGF2 alpha was found specifically over heterochromatin in the nuclei of neoplastic cells. Lower but significant uptakes of 3H-PGF2 alpha were also found in the nuclei of control epidermal cells, which indicate the presence of nuclear receptors in the epidermal neoplastic cells.
Animals↗