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PubMed1988

Vitamin A derivatives in the prevention and treatment of human cancer.

Vitamin A is essential for normal cellular growth and differentiation. A vast amount of laboratory data have clearly demonstrated the potent antiproliferative and differentiation-inducing effects of vitamin A and the synthetic analogues (retinoids). Recent in-vitro work has led to the exciting proposal that protein kinase-C may be centrally involved in many of retinoids' anticancer actions including the effects on ornithine decarboxylase induction, intracellular polyamine levels, and epidermal growth factor receptor number. Several intervention trials have clearly indicated that natural vitamin A at clinically tolerable doses has only limited activity against human neoplastic processes. Therefore, clinical work has focused on the synthetic derivatives with higher therapeutic indexes. In human cancer prevention, retinoids have been most effective for skin diseases, including actinic keratosis, keratoacanthoma, epidermodysplasia verruciformis, dysplastic nevus syndrome, and basal cell carcinoma. Several noncutaneous premaligancies, however, are currently receiving more attention in retinoid trials. Definite retinoid activity has been documented in oral leukoplakia, laryngeal papillomatosis, superficial bladder carcinoma, cervical dysplasia, bronchial metaplasia, and preleukemia. Significant therapeutic advances are also occurring with this class of drugs in some drug-resistant malignancies and several others that have become refractory, including advanced basal cell cancer, mycosis fungoides, melanoma, acute promyelocytic leukemia, and squamous cell carcinoma of the skin and of the head and neck. This report comprehensively presents the clinical data using retinoids as anticancer agents in human premalignant disorders and outlines the ongoing and planned studies with retinoids in combination and adjuvant therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

New prognostic factors and developing therapy of cutaneous melanoma.

The multiple molecular alterations underlying the neoplastic process and clinical characteristics of cutaneous melanoma are currently under intensive investigation. Recent studies have demonstrated that the levels of melanoma-associated proteins in tumor tissue or in patient serum can serve as new markers to predict disease outcome. Similarly, the expression of thousands of genes in melanoma tumors can be surveyed simultaneously using DNA arrays, allowing molecular profiling of individual tumors, which gives the possibility of classifying melanomas based on their biological diversity. Large clinical studies have also identified multiple prognostic factors, such as tumor ulceration, and led to development of a new, more precise melanoma staging system, which emphasizes the biological characteristics of the primary disease. These new findings may have an important role in earlier measurement of the clinical response and provide a basis for tailored melanoma therapy, the development of which will also be discussed in this review.

Antigens, Neoplasm↗
PubMedDate not supplied

Decreased insulin-like growth factor-I receptor sites on circulating mononuclear cells from children with acute leukemia.

Insulin-like growth factor-I (IGF-I) is a known mitogen for various cell types, including those of the hematopoietic cell system. To study the role of IGF-I in the neoplastic process of leukemia in children, the authors have determined the number of IGF-I binding sites on circulating mononuclear cells of children with acute leukemia as compared to normal children, using binding assays. The IGF-I binding sites per cell on peripheral mononuclear cells of children with leukemia decreased compared to those of the control group (411 +/- 73 and 1334 +/- 227, respectively, p < .001), while their affinity increased (Kd = 0.14 +/- 0.04 and 0.43 +/- 0.16, respectively, p = .05). Furthermore, in the patients, the number of the IGF-I binding sites was significantly lower in the subgroup of the peripheral mononuclear cells, which included lymphocytes and monocytes, as compared to their number in the peripheral blast cells (254 +/- 43.6 and 536 +/- 98.6, respectively, p = .02). A significant reduction was found in serum GHBP levels in the patients as compared to the controls (28.21 +/- 1.93 and 35.83 +/- 2.90, respectively, p = .02), while serum IGF-I and growth hormone levels were similar in patient and control groups. These results suggest a possible involvement of IGF-I in childhood acute leukemia, but further studies are needed to establish whether IGF-I plays a role in this disease.

Adolescent↗
PubMedDate not supplied

Serum carnitine levels of pediatric cancer patients.

Secondary carnitine deficiency may occur in some diseases including malnutrition. The present study examined the serum carnitine levels of children with cancer and their relationship with nutritional status. Fifty-one (mean age: 104 +/- 23 months) patients with cancer were evaluated at diagnosis and 3 months after the initiation of the treatment. There were significant differences between the mean carnitine levels of patients before and during the treatment (p: .004). Although initial carnitine levels of patients were similar to those in control groups, there was a significant dif ference between the mean carnitine levels of patients and those of the control group at the third month (p: .02). The prevalence of malnutrition at the third month of the treatment (43%) was higher from the prevalence at diagnosis (33%) but this was not significant. No significant relationship was found between carnitine levels and nutritional status of patients either at diagnosis or during treatment. These results showed that inadequate intake of carnitine or its precursors could not be responsible for decrease in carnitine levels. Metabolic changes that result from therapy and/or from neoplastic process may be responsible for the decrease in carnitine levels. Detailed studies, including measurements of fractions of carnitine and urinary carnitine excretion according to individual drug, are necessary to determine real cause of this decrease.

Adolescent↗
PubMed1987

Paraneoplastic syndromes.

As the lengthy but nonetheless incomplete review suggests, paraneoplastic syndromes are protean in their manifestations and, for the most part, poorly understood. Indeed, some of the more common abnormalities in cancer patients that might be considered paraneoplastic--such as anorexia-cachexia syndrome or unexplained fever--have not been discussed because they are so poorly understood. Most of the syndromes reviewed are either clearly paraneoplastic or strongly associated with cancer. Their clinical importance does not lie in the number of patients affected; it is a small minority. Instead, the syndromes may occasionally be helpful in the diagnosis of cancer or in monitoring response to cancer therapy. They may also be confused with the effects of metastatic disease. In some patients, amelioration of the syndromes can reverse the patient's dominant symptoms and thus provide significant clinical palliation. In a more general context, studies of etiologic mechanisms in paraneoplastic syndromes may offer insights into a variety of unexplained abnormalities in cancer patients. The best-understood syndromes result from tumor production of biologically active substances or, to a lesser extent, from autoimmune phenomena. These would appear to be probable mechanisms in many recognized paraneoplastic syndromes of uncertain etiology and perhaps in some heretofore unrecognized paraneoplastic syndromes. Finally, paraneoplastic syndromes could also hold clues to the neoplastic process. Better understanding of the ways in which tumors regulate remote effects--such as release of TGFs--may ultimately enhance our knowledge of tumor growth itself.

Adrenocorticotropic Hormone↗
PubMed2001

Loss of heterozygocity at the thyroid peroxidase gene locus in solitary cold thyroid nodules.

Germline mutations in both alleles of the thyroid peroxidase (TPO) gene have been reported as a frequent cause of congenital hypothyroidism resulting from a total iodide organification defect (TIOD). Because TPO mutations have a prevalence of 1 in 66,000 newborns and is inherited in an autosomal recessive mode the frequency of a heterozygous germline mutation in the TPO gene should reach about 1 in 260 in the population. A somatic TPO mutation coinciding with a somatic loss of one of the TPO alleles or a TPO germline mutation could lead to somatic loss of TPO activity with impairment of thyroid hormone synthesis and decrease of growth control. The latter would lead to increased thyroid epithelial cell proliferation and the subsequent development of a scintigraphically cold thyroid nodule (CTN). To test this hypothesis we studied 40 CTN for the presence of mutations or loss of heterozygosity (LOH) in the TPO gene. For comparisons we also studied LOH in 17 autonomously functioning thyroid nodules (AFTN). Genomic DNA was extracted from nodular and surrounding tissue, polymerase chain reaction (PCR) amplified, sequenced, and analyzed for LOH. In 6 CTNs of 37 informative cases we detected LOH using the genomic markers sRA, D2S2268, and D2S319 within or near the TPO gene locus (2p24-25). In contrast, a genomic marker closer to the centromer (D2S144, 2p24-21) shows LOH in only 1 CTN. We did not detect LOH in AFTN. In none of the cases a germline or somatic mutation in the TPO gene was detectable in the TPO gene. LOH in 6 of 37 CTNs suggests that genetic defects at the TPO or the chromosomal locus 2p24-25 might play a role in the etiology of CTNs. However, we did not find the combination of LOH with a somatic mutation in the TPO gene. It is therefore likely that a gene defect near the TPO locus is part of the neoplastic process in a subgroup of CTNs.

Base Sequence↗
PubMed2003

Activin betaB expression in rat experimental goiter and human thyroid tumors.

Activins are dimeric proteins of the transforming growth factor beta superfamily, which exhibit multiple functions in gonadal and extragonadal tissues. Expression of activin A, composed of two betaA subunits, has been shown in the thyroid, whereas there has been no study regarding activin B (betaBbetaB) in this gland. In other tissues, such as the gonads, pancreas, and adrenal cortex, expression of both activin betaA and activin betaB has been described. In this study, we detected activin betaB mRNA and protein expression using reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry in rat experimental goiter and in human thyroid, including multinodular goiter, follicular adenoma, papillary carcinoma, and follicular carcinoma. Activin betaA mRNA and protein expression was also investigated in rat and human thyroid tissue. The expression of both activin betaB and activin betaA was highest in rat methimazole-induced goiter and in human follicular adenoma, and papillary and follicular carcinomas when compared with multinodular goiter and normal thyroid tissue. The increased expression of activin betaB as well as activin betaA, observed in this study, suggests that activin B and activin A may be involved in the proliferative and neoplastic processes of the thyroid.

Animals↗
PubMed2000

AIDS and Chagas' disease.

Chagas' disease can reactivate in patients with AIDS and present as a brain mass lesion or an acute diffuse meningoencephalitis indistinguishable from other opportunistic infections or neoplastic processes, such as toxoplasma encephalitis or central nervous system (CNS) primary lymphoma. The CNS tumor-like lesion is the most common manifestation of Chagas' disease reactivation in AIDS patients. The prognosis of untreated cases is grim and underscore the need for safe and effective therapeutic agents.

AIDS-Related Opportunistic Infections↗
PubMed1983

Systemic angioendotheliomatosis presenting with hemolytic anemia.

Two patients with systemic angioendotheliomatosis had prominent constitutional symptoms such as fever, loss of weight, and general weakness, and had multiple organ dysfunctions, including bizarre neurologic findings and dementia. Severe anemia that required frequent blood transfusions also was present. One patient developed severe hemolysis and hypersplenism that required splenectomy for relief; the other patient had intravascular hemolysis and autoimmune hemolytic anemia, which were treated unsuccessfully with conservative measures. In both cases, postmortem examination showed many large, noncohesive malignant cells within the lumen of the blood vessels in many of the organs. There was no infiltration or replacement of the normal tissues by the tumor cells. Histochemical studies showed that the tumor cells were pyroninophilic but did not have cytoplasmic immunoglobulins or activity of chloroacetate esterase and muramidase. The cells showed factor VIII antigen in their cytoplasm. Systemic angioendotheliomatosis may represent a true neoplastic process of the vascular endothelial cells.

Aged↗
PubMed1993

The triphenylethylene drug tamoxifen is a strong liver carcinogen in the rat.

Tamoxifen (TAM) is used in the treatment of breast cancer and is being given to healthy women to inhibit breast cancer. The present study examines the effects of TAM in female rats exposed for up to one year. Starting at 6 weeks of age, groups of 55-57 female Sprague-Dawley rats were given TAM by gavage daily at 2.8, 11.3 or 45.2 mg/kd body weight/day, for up to 1 year with two recovery segments, 4 weeks of recovery after 6 months of exposure, and 3 months of recovery after 12 months of exposure. Complete necropsies and histopathology were performed. Drug-related mortality was highest in the high TAM group. In the two high dose groups, hepatoproliferative lesions were present in time- and dose-related incidence, severity and multiplicity. In the high dose rats, at 6 months, hepatocellular adenomas and carcinomas were observed in 71 and 29% of rats respectively. With 1 month of recovery, at 7 months the adenomas and carcinomas were increased to 75%. At 12 months the adenomas were present in 50% and carcinomas in 75% of high dose rats. In the mid dose group, liver lesions were not found until 12 months; at this time 50% had adenomas and 10%, carcinomas. After a 3 month recovery period, 45% exhibited adenomas and 45%, carcinomas. Thus, TAM at 45.2 mg/kg/day elicited hepatocellular neoplasia sometime between 3 and 6 months of administration. At 11.3 mg/kg the neoplastic process was evident at 12 months. At 2.8 mg/kg, no hepatoproliferative changes were found. The strong hepatocarcinogenic effect of TAM in rats raises issues bearing on the prophylactic chronic administration to healthy women.

Animals↗
PubMed1995

A 50 Hz magnetic field blocks melatonin-induced enhancement of junctional transfer in normal C3H/10T1/2 cells.

There is strong evidence that pineal melatonin is involved in controlling neoplastic processes. We have reported that physiological, but not pharmacological or sub physiological, concentrations of melatonin enhance intercellular communication in normal C3H/10T/2 fibroblasts. Gap junctional intercellular communication intervenes in the control of cell proliferation and differentiation, and seems to play a crucial role in suppression of tumor promotion. A number of in vivo studies have shown that extremely low frequency (ELF) magnetic fields (MF) can act as cancer promoters or co-promoters. In vitro, 60 Hz MF have been reported to block melatonin-induced inhibition of cell proliferation in human breast cancer cells. The mechanisms responsible for the observed interactions of MF at the cellular level remain unknown. In the present study melatonin was added to confluent fibroblasts at a concentration of 10(-10) M. Twenty-seven hours later, a fluorescent dye was scrape-loaded into groups of cells and the transfer of the dye to adjacent cells through gap junctions was quantified. Under these conditions melatonin induced a significant increase of dye transfer; this increase was not observed when the cultures were exposed to the MF for 30 min before the previously reported results suggesting that the in vivo oncostatic action of melatonin could be exerted, in part, through modulation of the levels of gap junctional intercellular communication. Also, the data indicate that ELF-MF could counteract the melatonin-induced enhancement of junctional transfer.

Animals↗
PubMed1997

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine increases the numbers of tumors, cystic crypts and aberrant crypt foci in multiple intestinal neoplasia mice.

The multiple intestinal neoplasia (Min) mice have a mutation in the murine adenomatous polyposis coli (Apc) gene rendering them highly susceptible to spontaneous intestinal adenoma formation, similar to the familial adenomatous polyposis (FAP) syndrome in humans. We studied whether the most abundant mutagenic heterocyclic amine isolated from cooked food, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), could influence early intestinal neoplasia in C57BL/6J-Min/+ and C57BL/6J- +/+ (wild-type) mice of both sexes. PhIP was given in 4 weekly i.p. injections of 50 mg/kg. Ten weeks after the start of the experiment, PhIP had significantly increased the numbers of small tumors and cystic crypts in the proximal section of the small intestine in male Min/+ mice, and the numbers of aberrant crypt foci (ACF) in the large intestines of both males and females. The effects of PhIP were more pronounced in male than in female Min/+ mice. In +/+ mice, no tumors or cystic crypts in the small intestine, and no tumors and only a very few ACF in the large intestine, were induced by PhIP. These results show that a substance frequently present in the human diet is able to enhance the neoplastic process induced by a genetic lesion, which is also commonly found both in inherited and sporadic colon carcinomas in humans.

Animals↗
PubMed1998

Non-invasive detection of fecal protein kinase C betaII and zeta messenger RNA: putative biomarkers for colon cancer.

We have developed a non-invasive method utilizing feces, containing sloughed colonocytes, as a sensitive technique for detecting diagnostic colonic biomarkers. In this study, we used the rat colon carcinogenesis model to determine if changes in fecal protein kinase C (PKC) expression have predictive value in monitoring the neoplastic process. Weanling rats were injected with saline or azoxymethane (AOM) and 36 weeks later fecal samples and mucosa were collected, poly A+ RNA isolated, and quantitative RT-PCR performed using primers to PKC betaII and zeta. Fecal PKC betaII and zeta mRNA levels were altered by the presence of a tumor, with tumor-bearing animals having a 3-fold higher (P < 0.05) PKC betaII expression as compared with animals without tumors. In addition, AOM-injection increased mucosal PKC betaII mRNA expression compared with saline controls. No effect of tumor incidence on mucosal PKC betaII expression was observed. In contrast, fecal PKC zeta expression was 2.5-fold lower (P < 0.05) in animals injected with azoxymethane versus saline. Since tumor incidence exerts a reciprocal effect on fecal PKC betaII and zeta mRNA expression, data were also expressed as the ratio between PKC betaII and zeta. The isozyme ratio was strongly related to tumor incidence, i.e. ratio for animals with tumors was 2.18 +/- 1.25, animals without tumors was 0.50 +/- 0.16, P = 0.025. We demonstrate that the expression of fecal PKC betaII and zeta may serve as a noninvasive marker for development of colon tumors. A sensitive technique for the detection of colon cancer is of importance since early diagnosis can substantially reduce mortality.

Animals↗
PubMed1998

Differential induction of gamma-glutamyl transpeptidase in primary cultures of rat and mouse hepatocytes parallels induction during hepatocarcinogenesis.

In carcinogen-treated rats, gamma-glutamyl transpeptidase (GGT) is induced in preneoplastic liver lesions and liver tumors. However, in mice, GGT is rarely detected during hepatocarcinogenesis. Data in this study reveal that GGT is not induced in mouse hepatocytes when they are maintained in vitro under the same conditions that induce GGT activity in primary cultures of rat hepatocytes. GGT activity in rat hepatocytes increased 20-fold during the first 7 days in culture, but there was no induction of GGT in primary cultures of mouse hepatocytes. Comparison of intracellular glutathione levels in rat and mouse liver cells showed that the glutathione level was higher in the mouse liver cells than the rat. Blocking glutathione synthesis with buthionine sulfoximine reduced the intracellular glutathione concentration in mouse liver cells but did not trigger an induction of GGT. Analysis of the GGT mRNA in primary cultures of rat hepatocytes showed that only GGT mRNA(III) is induced. This is the same GGT mRNA species present in preneoplastic hepatic lesions and liver tumors in the rat (1-3). Therefore activation of promoter III in the GGT gene is responsible for induction of GGT in both hepatocytes in vitro and liver tumors in vivo. These data show that primary cultures of rat and mouse hepatocytes provide a model system with which to study interspecies differences in the regulation of this enzyme and to better understand the role of GGT in normal and neoplastic processes.

Animals↗
PubMed1981

Formation of urothelial and hepatic DNA adducts from carcinogen 2-naphthylamine.

The carcinogen, 2-naphthylamine (2-NA), induces tumor formation in the urinary bladder but not the liver of several species, including humans and dogs. Since its proximate carcinogenic metabolite, N-hydroxy-2-NA, was known to react directly with DNA in vitro to give specific carcinogen-base adducts, we investigated the in vivo formation and persistence of (2-NA)-DNA adducts in the bladder and liver and attempted to determine whether or not these lesions correlated with tissue susceptibility. Male beagle dogs were administered [3H]2-NA and sacrificed after 2 or 7 days. The DNA was isolated from the liver and urothelium and hydrolyzed enzymatically. The (2-NA)-deoxyribonucleoside adducts, which were quantitated by high pressure liquid chromatographic analysis, were the same as those found in vitro, namely 1-(deoxyguanosin-N2-yl)-2-NA, 1-(deoxyadenosin-N6-yl)-2-NA, and an imidazole ring-opened derivative of N-(deoxyguanosin-8-yl)-2-NA. The major difference detected between target and non-target tissues was in the total level of binding to DNA, which was 4-fold higher in the urothelium at 2 days and 8-fold higher at 7 days after 2-NA dosing. Analysis of specific adducts suggested that this difference may be due to the relative persistence of the C-8-guanine adduct in the urothelium as compared to the liver. Similar experiments with the non-carcinogen, 1-naphthylamine, failed to reveal binding in urothelial DNA and indicated a 20-fold lower binding level in hepatic DNA. Evidence for binding of 2-NA to glycogen is also presented and problems associated with measuring total radioactivity in glycogen-contaminated DNA fractions are discussed. The data obtained in this study, through from a necessarily limited number of animals, are consistent with the hypothesis that the formation and persistence of DNA-carcinogen adducts may be important in the initiation of the neoplastic process.

1-Naphthylamine↗
PubMed1999

4-(hydroxyphenyl)retinamide selectively inhibits the development and progression of ductal hyperplastic lesions and carcinoma in situ in mammary gland.

In most previous chemoprevention studies on inhibition of mammary carcinogenesis, the formation of palpable tumors has been used as an end-point. Little is known about whether chemopreventive agents may similarly or selectively suppress hyperplastic and premalignant stages of the neoplastic process. In this study, we evaluated the effect of 4-(hydroxyphenyl)retinamide (4-HPR) on the development and progression of hyperplastic lesions and carcinoma in situ (CIS) in the N-methyl-N-nitrosourea (MNU) mammary carcinogenesis model in rats. 4-HPR was used as the chemopreventive agent because of its proven inhibitory effect on both the early and late phases of mammary carcinogenesis. Treatment with 4-HPR (2.0 mM/kg diet), beginning 2 days after MNU administration and administered continuously for 10 weeks, suppressed all mammary gland lesions (hyperplasia, CIS and invasive carcinoma) in 35% of animals. In the remaining 65%, 4-HPR allowed the development of hyperplastic lesions, alone or combined with CIS, and/or invasive carcinomas (CA). 4-HPR also increased by 2-fold the ratio between CIS and CA (0.75 per animal in control versus 1.5 in 4-HPR-treated animals), suggesting that it may also suppress the transition of CIS into CA. 4-HPR, when administered beginning 4 weeks after MNU administration [when hyperplastic and premalignant (CIS) lesions are present in the mammary gland], inhibited the frequency of terminal end bud hyperplasia (TEBH) and CA but did not significantly suppress ductal hyperplasia, ductal alveolar hyperplasia, alveolar hyperplasia and CIS. In these animals, 4-HPR induced partial disintegration of mostly peripheral areas of lesions, including carcinomas. Taken together, our data indicate that 4-HPR selectively suppresses the development and progression of hyperplastic lesions and CIS in TEBs. Furthermore, it appears that, in addition to mammary carcinomas, TEBH and CIS could also be used as end-point biomarkers in breast cancer chemoprevention studies.

Animals↗
PubMed1984

Dietary vanadyl(IV) sulfate inhibits chemically-induced mammary carcinogenesis.

The induction of murine mammary carcinogenesis by 1-methyl-1-nitrosourea was blocked by the feeding of a purified diet formulation supplemented with 25 p.p.m. vanadium as vanadyl(IV) sulfate during the post initiation stages of the neoplastic process. Treatment with vanadyl(IV) sulfate reduced both cancer incidence and the average number of cancers per rat and prolonged the median cancer-free time without inhibiting the overall growth of the animals. Vanadyl(IV) sulfate appears to be an effective non-toxic agent for the chemoprevention of experimental breast cancer in the rat.

Animals↗
PubMed1984

Effect of lead acetate on N-(4'-fluoro-4-biphenyl)acetamide-induced renal carcinogenesis in the rat.

This study assessed the effect of lead acetate (Pb) on N-(4'-fluoro-4-biphenyl)acetamide (FBPA)-induced renal carcinogenesis. A quantitative investigation was performed to determine the effects of Pb on the numerical density (Nv) and percent volume (%V) of FBPA-induced renal tubular hyperplasia and microscopic nodules. A secondary goal was to evaluate, on a quantitative basis, the role of these putative premalignant lesions in the development of renal carcinoma. Additionally, by quantifying the number per unit area of karyomegalic cells, their relationship to the neoplastic process was examined. Generally, Pb was found to accelerate the onset and development of all renal lesions. Karyocytomegaly did not serve as an indicator of the degree of carcinogenicity of any of the treatment regimens.

Adenocarcinoma↗