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G D Luk

Publications and source records attributed to G D Luk.

At least 73 records · Page 4Linked to original sources
PubMed1988

Biochemical markers in colorectal cancer: diagnostic and therapeutic implications.

Markers that are now in use, including CEA and CA-19-9, are not specific or sensitive enough to detect early colorectal cancer. Newer tumor markers such as polyamines, ornithine decarboxylase, and altered blood group carbohydrate antigens may have a potential as future tumor markers. Additional studies of these markers as well as the development of new biochemical markers are warranted in the future to enhance the sensitivity and specificity of diagnosis of early colorectal cancer and those at risk for developing cancer. Finally, understanding events involved in abnormal cell proliferation (that is, elevated polyamines and ODC in colorectal cancer) may help direct future chemotherapy and possibly chemoprevention in high-risk groups such as adenomatous polyposis coli.

Antibodies, Monoclonal↗
PubMed1988

Strategies for the control of colorectal cancer.

An overview of this issue is presented, with a discussion of its application to control of colorectal cancer. A brief update on new findings in molecular and genetic aspects is also given. Finally, strategies for control of colorectal cancer are discussed.

Colorectal Neoplasms↗
PubMed1988

Colorectal cancer. Scope of the problem.

The extent of the problem of colorectal cancer is discussed. The need for early identification of the disease for cure is emphasized. The need for research into markers for early detection of disease as well as research into therapy for patients with established nonresectable cancer are also emphasized.

Colorectal Neoplasms↗
PubMed1987

Cytotoxic response of the relatively difluoromethylornithine-resistant human lung tumor cell line NCI H157 to the polyamine analogue N1,N8-bis(ethyl)spermidine.

Difluoromethylornithine (DFMO), an enzyme activated irreversible inhibitor of ornithine decarboxylase (ODC), depletes intracellular putrescine, and spermidine (Spd), but not spermine, and generally leads to an inhibition of cell proliferation, without cell death, in both normal and neoplastic cells. This is the case with a culture line of human large cell undifferentiated lung cancer, NCI H157, which will survive indefinitely in DFMO containing medium and ultimately actually grows through the DFMO block. We now provide evidence that a Spd analogue, N1,N8-bis(ethyl)spermidine (BES) also suppresses ODC activity in H157 cells but leads not only to complete depletion of putrescine and Spd but also reduces intracellular spermine to 20-30% of control levels. This depletion of polyamines is accompanied by a rapid decrease in cell proliferation and ultimately cell death. The cell death resulting from BES treatment is in direct contrast to results obtained with DFMO and occurs at concentrations of less than 10 microM, whereas 5 mM DFMO is required to maintain growth inhibition in NCI H157. The observed suppression of ODC activity by BES is consistent with mechanisms by which Spd itself regulates ODC activity. Our data suggest that although both agents, DFMO and BES, interfere with polyamine metabolism, the differential sensitivities to these agents indicate susceptibility to polyamine depletion may be agent and cell type specific. Such differences may be related to the different requirement of individual cell types for polyamines and different regulatory events in polyamine biosynthesis. These differences may be exploitable in the treatment of neoplastic disease with polyamine analogues or inhibitors of polyamine biosynthesis.

Carcinoma, Non-Small-Cell Lung↗
PubMed1987

Increased risk of cancer in the Peutz-Jeghers syndrome.

The Peutz-Jeghers syndrome is an autosomal dominant hereditary disease characterized by hamartomatous polyps of the gastrointestinal tract and by mucocutaneous melanin deposits. The frequency of cancer in this syndrome has not been studied extensively. Therefore, we investigated 31 patients with the Peutz-Jeghers syndrome who were followed from 1973 to 1985. All cases of cancer were verified by histopathological review. Cancer developed in 15 of the 31 patients (48 percent)--gastrointestinal carcinomas in 4, nongastrointestinal carcinomas in 10, and multiple myeloma in 1. In addition, adenomatous polyps of the stomach and colon occurred in three other patients. The cancers were diagnosed when the patients were relatively young, but after the Peutz-Jeghers syndrome had been diagnosed (interval between diagnoses, 25 +/- 20 years; range, 1 to 64). According to relative-risk analysis, the observed development of cancer in the patients with the syndrome was 18 times greater than expected in the general population (P less than 0.0001). Our results suggest that patients with the Peutz-Jeghers syndrome have an increased risk for the development of cancer at gastrointestinal and nongastrointestinal sites.

Adolescent↗
PubMed1987

Prevalence and importance of pigmented ocular fundus lesions in Gardner's syndrome.

We examined 134 members of 16 families with Gardner's syndrome for pigmented ocular fundus lesions. Of 41 patients with documented Gardner's syndrome, 37 (90.2 percent) had such lesions. The lesions were bilateral in 32 of the patients (78.1 percent) and in 2 of 42 controls (4.8 percent). Twenty (46.5 percent) of 43 first-degree relatives at 50 percent risk for Gardner's syndrome had bilateral pigmented fundus lesions, indicating that they had probably inherited the abnormal gene. The presence of bilateral lesions, multiple lesions (more than four), or both appeared to be a specific (specificity, 0.952) and sensitive (sensitivity, 0.780) clinical marker for Gardner's syndrome. The lesions are probably congenital; they were observed in a three-month-old baby at risk. The multiplicity of the pigmented fundus lesions and their association with diffuse disturbances of the retinal pigment epithelium in the same eye suggest a widespread expression of the abnormal gene in the retinal pigment epithelial cells.

Female↗
PubMed1987

Biochemical markers in patients with familial colonic neoplasia.

Many potential markers, including biochemical markers, have been studied in an attempt to identify the presence of early colorectal neoplasia or risk of neoplasia, particularly in those families with hereditary colonic neoplasia syndromes. Unfortunately, most of these markers are useless in screening or diagnosis. Nevertheless, such markers as carcinoembryonic antigen (CEA) and CA 19-9 may have a role in pretherapeutic and posttherapeutic monitoring of disease or recurrence. The newer tumor markers, including the carbohydrate markers, ornithine decarboxylase (ODC) and the polyamines, are of great interest as potential tumor markers; ODC and the polyamines may also have a future potential as therapeutic targets. However, further studies are needed to determine their true sensitivity and specificity in hereditary colonic neoplasia syndromes, as well as in patients without genetic syndromes who are at risk for colorectal cancer.

Adenomatous Polyposis Coli↗
PubMed1987

Phase I trial and pharmacokinetic study of intravenous and oral alpha-difluoromethylornithine.

Eflornithine-HCl (alpha-difluoromethylornithine or DFMO), an irreversible inhibitor of ornithine decarboxylase, blocks polyamine synthesis and has demonstrated antitumor activity in cell culture and animal tumor models. This phase I study was designed to determine and compare toxicity and the maximally tolerated dose of a 4-day course of DFMO given to patients in oral, continuous intravenous infusion or pulse intravenous infusion forms. Twenty-four patients were entered into this study: 8 received intravenous pulse drug, 10 intravenous continuous infusion of drug, and 6 oral DFMO. The most frequent toxicity was nausea and vomiting which occurred in 9 courses of oral drug. Only two patients receiving intravenous DFMO had nausea and vomiting. Clinically significant thrombocytopenia and audiometric abnormalities were not encountered in contrast to previous experience with 28-day courses of oral DFMO. The maximally tolerated dose of a four-day course of oral DFMO was 3.75 gm/M2 every 6 hours. The maximally tolerated dose of intravenous pulse and continuous infusion DFMO was not attained. Pharmacokinetic studies demonstrated that the intravenous schedules achieved higher plasma levels of DFMO than those previously obtained with chronic oral dosing.

Administration, Oral↗
PubMed1987

Polyamines and the synthesis of estradiol-regulated growth factors in rat mammary cancer in culture.

We have recently provided evidence to suggest that the polyamine pathway plays an essential role in the expression of the growth-promoting effect of estradiol (E2) regulated growth factors in the N-nitrosomethylurea (NMU) induced rat mammary tumor cultured in vitro in the soft agar clonogenic assay. To further explore the interaction between the polyamine pathway and autocrine control of tumor growth by E2, we tested whether, in our system, polyamines play a role in the synthesis of E2-regulated growth factors. Conditioned medium (CM) obtained from tumors treated with E2 and the polyamine biosynthesis inhibitor alpha-difluoromethyl-ornithine (DFMO) (1 mM) no longer exhibited the colony-stimulating effect which was consistently observed with E2-CM. Such growth promoting activity was restored in a dose-dependent fashion with CM obtained from tumors treated with E2, DFMO, and increasing concentrations of spermidine (from 1 to 100 microM). Conditioned medium obtained from tumors treated with DFMO with and without spermidine in the absence of E2 had no discernible effects on colony formation. The colony stimulating effect of the CM employed could not be accounted for by the contaminating presence in the media of E2, DFMO, or polyamines. These results indicate that, in our system, the polyamine pathway plays an important role in the synthesis of E2-regulated growth factors.

Animals↗
PubMed1987

Polyamines in normal and cancer cells.

Based on available evidence, it appears that polyamines are critical for proliferation of both normal and transformed cells. Although the requirement of polyamines for DNA replication and cell proliferation is established, the molecular events in which the polyamines are essential are yet unknown. Furthermore, transformed and cancer cells, possibly because of their higher proliferative rate, appear to be more dependent on polyamine metabolism than their normal counterparts. This has been shown by the in vivo response of tumor models and human tumor xenografts in nude mice to polyamine depletion by DFMO. Although there has been associated toxicity to the host, the inhibition of cell proliferation has been higher in the implanted tumors than in the host. DFMO, a specific irreversible inhibitor of ODC, has been used extensively in studies which have shed light on the role of polyamines in cell proliferation and differentiation. DFMO has shown interesting anti-tumor effect in a number of experimental tumor models. Currently, DFMO clinical trials are being completed, and it will be of interest to see whether this polyamine inhibitor, or other newer polyamine analogs and inhibitors, will find a place in the treatment of neoplastic disorders.

Animals↗
PubMed1987

Polyamines in intestinal and pancreatic adaptation.

The intestinal mucosa is a rapidly proliferative tissue, with a highly dynamic cell population. Its total cellular mass is well controlled and can adapt, with hypo- or hyperplasia, to a wide variety of stimuli. Luminal nutrients, hormonal factors, and pancreatic and biliary secretions have all been implicated in the regulation of intestinal mucosal adaptation. Similarly, the same factors appear essential for the maintenance of exocrine pancreatic structure and function. The polyamines (putrescine, spermidine, and spermine) and the key enzyme controlling their synthesis (ornithine decarboxylase, ODC) are important for many cell growth processes, and may play important roles in intestinal and pancreatic adaptation. During intestinal adaptation in response to jejunectomy, lactation and pancreatico-biliary diversion (PBD), intestinal contents of ODC and polyamines are increased, paralleling increases in mucosal proliferative indices and DNA synthesis. With administration of the specific inhibitor of ODC (difluoromethylornithine, DFMO) the increases in ODC and polyamines are suppressed, and intestinal adaptation is abrogated. In pancreatic hyperplasia induced by caerulein, pancreatic polyamines are increased. With DFMO administration, caerulein-induced increases in pancreatic DNA synthesis were inhibited and pancreatic hypertrophy was partially suppressed. PBD-induced pancreatic hypertrophy, however, was not affected by DFMO. Thus, the role of polyamines in the adaptation of the pancreas, with a relatively quiescent proliferative status, is as yet undefined. It seems clear, however, that the induction of ODC and the resultant increase in polyamine biosynthesis are critical for the normal growth and especially for adaptive hyperplasia of the intestinal mucosa.

Adaptation, Physiological↗
PubMed1986

mRNA from human colon tumor and mucosa related to the pol gene of an endogenous A-type retrovirus.

The expression of endogenous retroviral genes in mammals may be etiologically related to genetic diseases including cancer. Recently, A-type human endogenous retroviral genomes have been cloned using the reverse transcriptase (pol) genes of rodent intracisternal A-particles (IAP). In this report, RNA from human colon adenocarcinoma and surrounding mucosa was hybridized to mouse IAP pol and gag genes to examine the expression of human endogenous A-type retroviruses. Abundant, heterogeneous size, polyadenylated transcripts homologous to the mouse IAP pol gene were detected in both tissues. Transcripts homologous to the mouse IAP gag region were not found.

Adenocarcinoma↗
PubMed1986

Human lung tumor sensitivity to difluoromethylornithine as related to ornithine decarboxylase messenger RNA levels.

The differential response to polyamine depletion has been studied in two types of human lung tumor cells. Small cell lung carcinoma cells die following polyamine depletion by difluoromethylornithine treatment while non-small cell lines demonstrate a typical cytostatic response. We now report that a small cell line, NCI H82, has a lower apparent capacity for polyamine biosynthesis than does a representative non-small cell, NCI H157. In subconfluent cultures, the ornithine decarboxylase activity is 25 times lower in the small cell than the non-small cell and by comparison, the polyamines in the small cell line are markedly reduced. Most significantly, levels of mRNA coding for ornithine decarboxylase are approximately 100-fold lower in the small cell than the non-small cell line, and this difference does not appear to be a result of gene rearrangement. These results suggest that differential sensitivity to polyamine depletion is related to different steady-state levels of ornithine decarboxylase mRNA.

Carcinoma↗
PubMed1986

Essential role of polyamine metabolism in hepatic regeneration. Inhibition of deoxyribonucleic acid and protein synthesis and tissue regeneration by difluoromethylornithine in the rat.

We studied liver regeneration after partial hepatectomy and the effects of inhibition of ornithine decarboxylase (ODC) and putrescine administration. The specific ODC inhibitor, alpha-difluoromethylornithine was given as a 3% oral solution (5.4 g/kg X day intake) to hepatectomized rats as well as sham-operated controls. alpha-Difluoromethylornithine had no effect other than inhibition of the low basal levels of ODC in sham-operated rats, but it markedly inhibited increases in ODC by 85% in hepatectomized rats. alpha-Difluoromethylornithine reduced hepatic deoxyribonucleic acid synthesis by 61%, protein synthesis by 46%, and liver weight increased by 83%, showing that alpha-difluoromethylornithine inhibition of ODC inhibits liver regeneration. Putrescine (2 mmol/kg X day) was then given intraperitoneally to hepatectomized rats and controls. Putrescine had no effect in rats not given alpha-difluoromethylornithine. In rats given alpha-difluoromethylornithine, putrescine markedly reversed the inhibitory effect of alpha-difluoromethylornithine on ODC (83%), deoxyribonucleic acid synthesis (94%), protein synthesis (95%), and liver regeneration (85%). These results document that the increases in ODC are important in hepatic regeneration and that polyamine metabolism plays an important role in the increased deoxyribonucleic acid and protein synthesis in this hepatic proliferative response.

Animals↗
PubMed1986

Anchorage dependency effects on difluoromethylornithine cytotoxicity in human lung carcinoma cells.

Difluoromethylornithine (DFMO), a specific, irreversible, enzyme-activated inhibitor of ornithine decarboxylase activity, the first and rate-limiting step in polyamine biosynthesis, has been shown to inhibit neoplastic cell proliferation in culture. In most cases, such inhibition is not accompanied by cell loss, with the exception of multiple cell lines of human small cell lung carcinoma (SCC), a human leukemia cell line (HL-60), and possibly the B16 melanoma cell line. The first two cell types grow as anchorage-independent suspension cultures, the HL-60 as single cells and the SCC as multicellular spheroid aggregates. Moreover, in the spectrum of human lung carcinoma cells in culture, the SCC cells respond in a cytotoxic manner to DFMO, whereas the non-small cell lung carcinoma (non-SCC) cells, which are anchorage dependent, show only growth inhibition, without actual cell loss. In the present study, we have investigated relationships between anchorage-dependent and -independent growth patterns of cells in culture and their response to DFMO treatment. Two non-SCC lung cancer cell lines, which normally grow as anchorage-dependent monolayers, show growth inhibition but no cell loss with the addition of DFMO. When these anchorage-dependent cells were forced to grow as multicellular aggregates, by coating the culture flask with Teflon, the cells developed an increased sensitivity to DFMO. They showed not only inhibition of cell proliferation but also cell death. Two SCC cell lines, which normally grow as anchorage-independent spheroids, developed adherence to the culture dishes coated with fibronectin. These cells, which show a cytotoxic response to DFMO during normal anchorage-independent growth, developed a decreased sensitivity to DFMO, showing only cell growth inhibition, but no cell death when treated during anchorage-dependent growth. Our data thus suggest that the state of anchorage dependence of lung cancer cells in culture is a critical factor in determining their response to polyamine depletion during treatment with DFMO.

Carcinoma, Small Cell↗
PubMed1986

Long-term maintenance therapy of established human small cell variant lung carcinoma implants in athymic mice with a cyclic regimen of difluoromethylornithine.

We report that cyclic p.o. administration of alpha-difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, is an effective long-term (1-year) maintenance therapy for established implants of cultured human small cell lung carcinoma in athymic (nude) mice. Human small cell lung carcinoma cells, from a line which exhibited cell death in culture in the presence of DFMO, were inoculated into athymic mice and permitted to grow to palpable tumors (3-5-mm nodules with mean volume of 0.04 cm3). The animals were then randomized into untreated, continuous treatment and cyclic (3 weeks of 4 beginning 1 week after 8 weeks continuous) treatment groups. Treatment consisted of 3% DFMO in the drinking water (5.1 g/kg/day). The tumors in the untreated group grew to 27 cm3 by 8 weeks and the animals had a median survival of 7.6 weeks. Tumor growth was inhibited by 99% (0.3 cm3) in the continuous treatment group in comparison to untreated controls. Survival was prolonged with 93% survival at 10 weeks and a 101% increase in median survival to 15.3 weeks (P less than 0.05). The cyclic DFMO group had a 98.3% inhibition in tumor growth for longer than 1 year (0.56 cm3; P less than 0.05). Survival was also markedly prolonged compared to the untreated group with 100% survival up to 24 weeks and a median survival of 54.3 weeks (P less than 0.05). No significant toxicities were observed in the first 10 weeks of DFMO treatment even though antitumor effects were observed. With continuous DFMO treatment, the animals eventually became debilitated and developed marked weight loss and thrombocytopenia; by 20 weeks, mortality was 79%. With cyclic therapy, the animals resumed weight gain, recovered from thrombocytopenia and, at 20 weeks, had 0% mortality. By 55 weeks, mortality was 50% which, however, was not significantly different (P approximately 0.50) from mortality of a control group of nontumorous, athymic mice that had weekly body weight and skin fold measurements concurrently with the experimental, tumor-bearing animals. Thus, the observed mortality is ascribable to continuous encroachment on the normally sterile environment. These data suggest a role for DFMO in long-term therapy of sensitive human tumors such as small cell lung carcinoma, especially in patients with a low tumor burden. Furthermore, a cyclic regimen might be an important tool in maintaining clinical remissions induced by conventional combination chemotherapy.

Animals↗
PubMed1986

Phase II trials of alpha-difluoromethylornithine, an inhibitor of polyamine synthesis, in advanced small cell lung cancer and colon cancer.

alpha-Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, blocks polyamine synthesis and has demonstrated antitumor activity against small cell lung cancer and colon cancer in cell culture and animal tumor models. To evaluate clinical efficacy and further define toxic effects of this new agent, phase II trials of DFMO were performed in previously treated patients with advanced small cell lung cancer and previously untreated patients with metastatic colon cancer. Oral DFMO was administered at a dose of 2.25 g/m2/day every 6 hours continuously to patients with small cell lung cancer. The same dose was given to patients with colon cancer but on a schedule of "3 weeks on, 1 week off" to avoid hearing loss. Evaluation of toxicity indicated that thrombocytopenia was seen only in patients receiving continuous DFMO who had received prior chemotherapy, while reversible hearing loss and gastrointestinal side effects occurred on both intermittent and continuous schedules in previously treated and untreated patients.

Aged↗