Hormones, vitamins, and growth factors in cancer treatment and prevention. A critical appraisal.

BACKGROUND: Hormones, hormone agonists, hormone antagonists, vitamins and their synthetic analogues, and growth factors are currently the most widely used anticancer drugs. Although in many cases they provide dramatic results, in other cases their effects are conflicting. A critical appraisal of the effects of these drugs is needed. METHODS: To evaluate the potential therapeutic and preventive roles of these drugs as well as their areas of controversy, data published in the literature in the last two decades are reviewed in this article, and the author's personal findings are also reviewed. RESULTS: Hormones, hormone agonists, hormone antagonists, vitamins and their synthetic analogues, growth factors, and cytokines are replacing conventional cancer therapies (chemotherapy, surgical therapy, and radiation therapy) for many purposes, and recently became the "fourth arm" of cancer treatment. However, their mechanisms of action have not yet been elucidated. This article critically reviews the mechanisms of their action on cancer cells (specifically, DNA, RNA, oncogenes, and antioncogenes); their role in cancer cell division, cell cycle, apoptosis, and angiogenesis; and their relation to human cancers. Since hormones, vitamins, growth factors (GFs), and GF receptors play a cardinal role in multistage carcinogenesis, using monoclonal antibodies to develop novel hormone antagonists, vitamin synthetic analogues, and GF inhibitors will be of paramount significance for neoadjuvant systemic therapy and cancer prevention. CONCLUSIONS: It is hoped that the data presented in this review regarding the role of hormones, hormone agonists, hormone antagonists, vitamins, growth factors, and growth factor inhibitors will provide a rationale for designing effective new cancer chemoprevention strategies and clinical trials.

Control of precancer cell transformation into cancer cells: its relevance to cancer prevention.

It is well known that following the action of various carcinogens (chemical, physical, biological) on normal cells, a long period (latency) of several months to years (approximately 10 months approximately 30 years) in humans or one-half to two-thirds of the life span of laboratory animals occurs between development of precancer cells and their transformation into cancer cells. However, the molecular and biological events that take place within the precancer cells during this quiescent stage are not yet fully understood. The main purpose of this review is to evaluate the data from literature as well as my own findings regarding the preneoplastic cells and their progression into neoplastic cells. Recent studies reveal that preneoplastic cell development and transformation into cancer cells is determined initially by genetic (oncogenes, antioncogenes), with sequential multiple somatic mutations, and later by epigenetic or environmental cell factors such as hormones, growth factors (GFs), cytokines, vitamins, and prostaglandins (PGs). These factors can markedly change the evolution of preneoplastic cells by enhancing, retarding, or inhibiting their transformation into cancer cells, or even reversing them to a normal phenotype. These agents act on DNA, RNA, and protein synthesis, as well as on cell replication, cell cycles, cell surfaces, and intercellular communications. DNA, oncogenes, ultrastructural cell surface, and antigenic determination used as biomarkers are essential for early detection of preneoplastic cells and premalignant lesions. Further investigations regarding the precancer cell biology and metabolism will have a paramount significance for designing effective strategies for cancer prevention and treatment.

Effect of prolonged insulin treatment on carcinoma formation in mice.

Long-term insulin administration enhanced the incidence and development of chemically induced [3-methylcholanthrene (3-MCA)] squamous cell carcinomas in Swiss male mice. DNA radioactivity and light and electron microscopic autoradiography revealed that insulin administration significantly increased (2-fold) the [3H]thymidine incorporation and intracellular distribution in the neoplastic nuclei (38.50%) as compared to that of neoplastic nuclei treated with MCA alone (20%). Electron microscopic autoradiography showed a heavy [3H]thymidine distribution as developed grains over dense chromatin (heterochromatin) of neoplastic cell nuclei. Ultrastructural and cytological studies of insulin-treated carcinomas revealed the predominance of less differentiated squamous cell carcinomas with numerous vacuoles, polysomes, laminated concentric myelin figures, and phagolysosomes as compared to well differentiated squamous neoplastic cells treated with MCA only. Scanning electron microscopic observations revealed in the insulin + MCA-treated tumors the predominance of rounded cells covered with several elongated microvilli and blebs as compared to polygonal cells covered with sparse and thin microvilli, horny pearls with concentric keratinized layers after MCA treatment. An intense stromal tumor reaction can be also seen following insulin and MCA treatment. These findings demonstrate that insulin in pharmacological doses stimulates the carcinoma formation, increases DNA synthesis, and affects the squamous neoplastic cell differentiation.

Multiple vascular fibromas and myxoid fibromas of the fingers. A histologic and ultrastructural study.

A father and his son were seen because of multiple wartlike lesions on their fingers and palms. On histologic examination, these lesions showed changes compatible with vascular fibromas, myxoid fibromas, and, in a few instances, verruca vulgaris. We are not aware of reports of similar cases in the dermatologic literature.

Ultrastructural and cell surface changes of human psoriatic skin following Goeckerman therapy.

Ultrastructural and cell surface studies of skin in psoriatic patients prior to and after Goeckerman therapy (crude coal tar and UVB-light) have demonstrated significant cellular changes following this treatment: hyperactivity of melanocytes with melanosome polymorphism, increase of desmosomes, tonofilaments, keratohyaline granules, a decrease in mitochondria, keratinosomes, polysomes, dark cells and a reduction in size of nuclei and nucleoli. The enlargement of intercellular spaces and the redundancy of basement membrane were also reduced. Langerhans cells were moderately decreased and exhibited a normal ultrastructural pattern. No significant changes in cutaneous nerve distribution or morphology were observed in these cases. Scanning electron microscopy following treatment revealed a regular surface and orientation of corneocytes, with flattened surfaces; and a reduction of their ridges on the surfaces, as well as of the intercellular spaces and red blood cells. These findings indicate that Goeckerman therapy restored the ultrastructural and cell surface pattern in the psoriatic skin by inducing orthokeratinogenesis, development of the tonofibrillar-desmosome system, and decrease in mitochondria, nuclei and nucleoli.

Cytologic and metabolic effects of prostaglandins on rat skin.

The cellular and metabolic effects of exogenous prostaglandins E1, E2, and F2alpha (PGE1, PGE2, and PGF2alpha) were studied in the skin of rats by using scintillation counting, autoradiography, electron microscopy, and scanning electron microscopy. Radioactivity measurements demonstrated that prostaglandins of the E series induced a marked increase in the incorporation of [3H]leucine, [3H]thymidine, [3H]uridine, and [3H]proline in the rat skin, mostly at 1 hr, whereas PGF2alpha inhibited this phenomenon. Light microscopic autoradiography revealed an increased incorporation of [3H]leucine in the cytoplasm of hyperplastic epidermis of PGE-treated rats; also, the incorporation of [3H]thymidine, [3H]uridine, and [3H]proline was significantly increased over the epidermal nuclei, nucleoli, and the collagen fibers of PGE-treated rats. Electron microscopy revealed ultrastructural changes of the epidermal cells and fibroblasts following PGE administration, including an increase in polyribosomes, endoplasmic reticulum, keratohyaline granules, and enlarged intercellular spaces; PGF2alpha induced advanced cytolysis and cell disintegration, with increased lysosome formation. Scanning electron microscopy showed hypertrophied collagen fibers in PGE-treated rats; however, a disruption and disintegration of collagen fibers occurred in PGF2alpha-treated rats. The level of PGE1 in the skin of treated rats was markedly elevated as compared to those of controls. These findings demonstrate that prostaglandins are potent regulators for the epidermal cell ultrastructure and metabolism as well as for collagen synthesis.

Straight-hair nevus syndrome: a case report with scanning electron microscopic findings of hair morphology.

Straight-hair nevus of the scalp is a distinct clinical entity. A case is reported and 2 other cases from the literature are reviewed. In our patient, specific morphology of the hair shown by scanning electron microscopy suggested a disorder in keratogenesis from loss of cuticular cells. Straight-hair nevus is probably a form of localized trichodysplasia.

Effect of protective agent against lipid-solvent-induced damages. Ultrastructural and scanning electron microscopical study of human epidermis.

The ultrastructural and relief (cyto-architectural) changes of human epidermis following exposure to a protective gel and acetone or kerosene were studied in healthy volunteers. Topical applications of acetone and kerosene on unprotected skin produced cell damage and a disorganized pattern in the upper layers of epidermis. The ultrastructural changes following acetone consisted of large paranuclear vacuoles, swollen mitochondria, and clumped tonofilaments. Severe disorganization with intense cytolysis and enlarged intercellular spaces occurred after exposure to kerosene. Scanning electron microscopy revealed edematous connified cells (corneocytes) following acetone exposure, whereas kerosene induced the occurrence of large lacunae in the swollen corneocytes. The application of a protective agent prior to solvent exposure substantially reduced the ultrastructural and relief changes of epidermal cells.

Effect of lipid solvents on protein, DNA, and collagen synthesis in human skin: an electron microscopic autoradiographic study.

The effect of acetone and kerosene on the synthesis of protein, DNA, and collagen was studied by electron microscopic autoradiography using [3H]leucine, [3H]thymidine, and [3H]proline as tracers in human skin. Quantitative analyses following concomitant administration of tritiated leucine and acetone or kerosene demonstrated, at 90 min, a marked decrease in silver grains as compared to control or nonexposed areas. Incorporation of tritiated thymidine is moderately stimulated only by acetone, whereas radioactive proline distribution is not significantly affected. Electron microscopic autoradiograms revealed that tritiated leucine is distributed over all epidermal cells, mostly in the stratum spinosum of control epidermis; a marked decrease of silver grains from [3H]leucine followed both lipid solvent exposures. The autoradiographic reaction is specifically located over cytoplasmic organelles, such as polysomes, endoplasmic reticulum, and especially tonofilaments. Tritiated thymidine resulted in silver grains mostly over nuclear chromatin and these were moderatly increased after acetone application, whereas the incorporation of radioactive proline in the fibroblasts and collagen fibrils were not significantly influenced. These investigations indicate a dissociated effect of lipid solvents on protein, DNA, and collagen synthesis in human skin.