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Biomedical subjects

S N Kim

Publications and source records attributed to S N Kim.

At least 55 records · Page 3Linked to original sources
PubMed1991

Role of induction chemotherapy in invasive cervical cancer.

The 386 cases of invasive cervical carcinoma treated with radiotherapy alone were statistically analyzed to delineate the high risk factors (HRFs) associated with a significantly high treatment failure rate; they were (1) stages III-IV, (2) lesion greater than or equal to 4.0 cm, (3) small cell carcinoma or adenocarcinoma, (4) stages I-II with lesion greater than or equal to 4.0 cm, and (5) lymphographic evidence of nodal metastasis. Then, chemoradiotherapy (induction chemotherapy plus subsequent radiotherapy) was instituted to 113 invasive cervical carcinoma patients with at least one such HRF. Each patient received two to three cycles of induction chemotherapy at about 3-week intervals. For squamous cell carcinoma, cisplatin, 100 mg/m2 iv, was followed immediately by 5-fluorouracil, 1000 mg/m2, as a 24-hr iv infusion x 5 days. For adenocarcinoma, cisplatin, 70 mg/m2 iv, on Day 1 was followed by cytoxan, 250 mg/m2, on Day 2, and adriamycin, 45 mg/m2, on Day 3. Five-year survival of these patients according to each HRF, in the above order, was 69.1, 67.2, 68.1, 78.3, and 79.5% after chemoradiotherapy, all significantly higher than 57.4, 53.0, 54.5, 48.0, and 48.8% by radiotherapy alone. Drug toxicities such as leukopenia, hepatotoxicity, nephrotoxicity, and hypomagnesemia were seen in 46.5, 53.2, 47.1, and 55.4% of all cycles, respectively. The toxicities altered drug schedule in 191 (61.2%) ongoing induction chemotherapy cycles. Our cisplatin-based induction chemotherapy is considered an effective preradiotherapy adjunct that can reduce treatment failure in HRF-associated invasive cervical carcinoma.

Adenocarcinoma↗
PubMed1991

Fertility and perinatal/postnatal studies in rats with the angiotensin-converting enzyme inhibitor, quinapril.

Quinapril, an inhibitor of angiotensin-converting enzyme (ACE) and an antihypertensive agent, was evaluated in rats for effects on fertility, reproduction, and perinatal and postnatal development. In a fertility study, male rats were treated by gavage for 60 days prior to and during mating and female rats were treated by gavage for 14 days prior to mating, during mating and gestation, and during lactation with doses of 0, 10, 50, or 100 mg quinapril/kg body wt. There were no significant effects on body weight, food consumption, fertility indices, fetal development, or neonatal growth, survival, development, behavior, or reproduction. In a perinatal/postnatal study, administration of quinapril to females at doses of 25, 75, or 150 mg/kg during late gestation and lactation had no effects on parturition, lactation, or postnatal development, but a significant decrease in neonatal body weight during the suckling period was observed at all doses. In a subsequent study, female rats were given 150 mg/kg during late gestation, lactation, or late gestation and lactation. No adverse effects were seen in the dams or the offspring, and no reduction in neonatal body weight was observed. Kidneys from pups whose mothers received quinapril during gestation and/or lactation had minimal juxtaglomerular cell hypertrophy, characteristic of treatment with ACE inhibitors. Low levels of quinaprilat (the major and pharmacologically active metabolite of quinapril) were detected in fetal blood and in neonatal blood, indicating offspring exposure to quinapril. Milk quinaprilat concentrations were 3-5% of the plasma concentrations 3-5 hr after dosing. These studies demonstrate no adverse effects of quinapril on fertility, reproduction, or perinatal and postnatal development.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Proliferative bone lesions in rats given anticancer compounds.

Proliferative endosteal lesions were observed in metaphysis and diaphysis of femur and sternebra of Wistar (CRL:[WI]BR) rats administered 3 chemically-distinct anticancer compounds with dissimilar mechanisms of action: trimetrexate glucuronate, an antifolate; pentostatin, an adenosine deaminase inhibitor; and CI-980, a mitotic inhibitor. Islands of woven bone, often circumscribed by conspicuous myelostromal proliferation, were seen on Days 8-28 in rats given trimetrexate glucuronate daily by gavage, and on Day 4 but not Day 29 in rats given a single intravenous dose of pentostatin. Intravenous administration of CI-980 for 1 or 5 days resulted in marrow necrosis, marked centripetal new bone formation, and myelostromal proliferation on Days 4 and 8, respectively. These lesions were not present at the termination of these latter studies (Days 29 and 35, respectively). In conclusion, anticancer compounds induced local bone marrow injury and the release of local inflammatory mediators which may have provided the stimulus for bone formation and myelostromal proliferation.

Animals↗
PubMed1990

Pharmacokinetic and toxicity scaling of the antitumor agents amsacrine and CI-921, a new analogue, in mice, rats, rabbits, dogs, and humans.

The aim was to investigate interspecies relationships between body weight (W) (kg) and various pharmacokinetic parameters for the anti-tumor agents amsacrine and its 4-methyl-5-(N-methylcarboxamide) analogue, CI-921, and examine which pharmacokinetic parameter, if any, might be used to predict the toxicity of these agents. Pharmacokinetic, plasma protein binding, and toxicity data were available for CI-921 in mice, rats, rabbits, dogs, and humans. For amsacrine, similar interspecies pharmacokinetic data were available but toxicity and protein-binding data were available for only 3 species. Significant linear relationships were obtained for CI-921 between log W and log Vss (liters) (r = 0.971, P = 0.006), and log W and log Cl (liters/h) (r = 0.911, P = 0.031) resulting in the allometric equations Vss = 1.22W0.68 and Cl = 0.91W0.51. For amsacrine these corresponding equations were Vss = 3.37W0.81 (r = 0.996, P less than 0.001), and Cl = 2.28W0.46 (r = 0.952, P = 0.012). When interspecies differences in plasma protein binding were taken into account, the allometric relationships improved and the exponents of the power equations increased. For CI-921 the allometric equations for the kinetic parameters calculated from plasma "free" concentrations were: Vssfu (liters) = 247W0.93 (r = 0.984, P = 0.002) and Clu (liters/h) = 186W0.76 (r = 0.961, P = 0.009). The dog was a noticeable outlier in the relationship between the log maximum tolerated dose (MTD) (mg/kg) of CI-921 and log W. Omission of the latter resulted in a highly significant allometric relationship, MTD = 23.6W-0.14 (r = -0.988, P = 0.012). For amsacrine there was no significant allometric relationship between MTD and W. CI-921s prolonged t1/2 in the dog and the dog's increased susceptibility to CI-921 toxicity suggested a relationship between MTD and t1/2 (h). A significant linear relationship was observed between in MTD and t1/2 (r = -0.994, P less than 0.001), from which the following equation was developed MTD = 47.5e-0.51t1/2 Combining the amsacrine toxicity data in the latter relationship yielded a similar equation MTD = 44.7e-0.51t1/2 (r = -0.933, P less than 0.0001). It was concluded that allometric equations may be developed for CI-921 and amsacrine from animal pharmacokinetic data which allow a reasonable prediction of Cl and Vss in patients, despite these agents being eliminated mainly by biotransformation. However, similar relationships between toxicity and body weight were susceptible to variation between individual species. Species differences in the toxicity of these agents were predictable from the t1/2. This study emphasized the importance of pharmacokinetic data in preclinical toxicity and efficacy testing of antitumor agents.

Amsacrine↗
PubMed1990

Involvement of vitamin D3 with cardiovascular function. III. Effects on physical and morphological properties.

We have previously shown that depletion of vitamin D3 in rats results in a large increase in the contractile function of isolated hearts (R. E. Weishaar, J. Clin. Invest. 79: 1706-1712, 1987). To characterize the mechanism responsible for this increase, the effect of vitamin D3 depletion on key physical and morphological properties of cardiac muscle was examined. Depletion of vitamin D3 increased the heart weight/body weight ratio. This increase could neither be blocked by limiting hypocalcemia nor reversed by restoring increasing serum calcium levels. The cardiomegaly observed 9 wk after vitamin D3 depletion was not accompanied by an increase in myocardial water content or leakage of myocardial creatine phosphokinase and was not caused by myocardial cell hypertrophy. Histological examination of ventricular muscle from vitamin D3-deficient rats revealed a significant decrease in myofibrillar area and a significant increase in extracellular space. The increase in extracellular space was accompanied by a significant increase in myocardial collagen. Prevention of hypocalcemia in the vitamin D3-deficient rats did not prevent the increase in myocardial collagen. Such alterations in the physical and morphological properties of myocardial tissue might represent the basis for the change in myocardial contractile function that accompanies lengthy periods of vitamin D3 deficiency.

Animals↗
PubMed1989

Cell-mediated immunity in patients with invasive carcinoma of the cervix.

Multiple in vitro immune parameters were investigated in thirty-four untreated patients with invasive carcinoma of the cervix and in twenty-five controls. The parameters measured were percentages and absolute counts of T and B cells, percentage of T cell subsets, lymphocyte response to phytohemagglutinin (PHA) and concanavalin A (Con A), natural killer (NK) activity, antibody-dependent cellular cytotoxicity (ADCC), and interleukin 2 (IL-2) activity. Patients with invasive cervical carcinoma, as compared with controls, showed a decrease in the percentage and count of T cells, a decrease in the percentage of helper-inducer (CD4+) T cells, decreased CD4+/CD8+ ratio, depressed lymphocyte response to PHA and Con A, and depressed NK and ADCC activities. There were no significant differences in these immune parameters between early and advanced tumor stages. The levels of total lymphocytes, monocytes, suppressor-effector (CD8+) T cells, and B cells were similar to those of the controls. IL-2 productivity in patients was lower than that in controls. In patients with invasive cervical carcinoma, a decrease in the percentage of CD4+ cells was associated with depressed PHA response and decreased IL-2 productivity was correlated with the reduced percentage of CD4+ cells and decreased NK activity. This study shows a significant defect in an important immune surveillance mechanism in patients with invasive carcinoma of the cervix and suggests that impaired IL-2 activity production may be related to quantitative and qualitative alterations in lymphocyte subpopulations which play a major role in immune surveillance against cervical cancer.

Female↗
PubMed1987

The pathogenesis of trimethyltin chloride-induced nephrotoxicity.

In exploratory studies aimed at elucidating CNS effects due to heavy metal toxicity, signs of compromised renal function were seen in rats. The studies reported here describe the sequential steps of the development of nephrotoxicity by trimethyltin chloride (TMT) in rats. Single doses of 12.25 mg/kg TMT administered orally to 150- to 175-g Long-Evans rats elicited overt signs of toxicity including behavioral abnormalities and marked weight loss. Concurrent with the development of these signs, nephrotoxicity was manifested as functional kidney compromise and associated histopathologic evidence of tubular damage. Pathological changes in the kidneys from treated rats were hyaline droplet inclusions, attenuated brush border, basolateral vacuolization, and eosinophilic granular casts in the proximal tubule cells. These lesions were detected as early as 2 days post-treatment and progressed with time in an orderly and sequential fashion. Renal lesions between 5 and 8 days were mild to severe cortical tubular dilatation, hydropic degeneration, and diffuse hyaline droplet deposition in the lower nephron tubules. Medullary edema and exfoliation of degenerated tubular epithelial cells with cast formation followed from 8 to 11 days. The morphological changes were accompanied by marked elevation of blood urea nitrogen, parallel with polyuria at Day 2 and oliguria by Day 14. Behavioral abnormalities as well as weight loss correlated well with the time course and severity of renal dysfunction and progression of morphological changes. A second experiment compared the effects of TMT in rats of different weights. Heavier rats were more sensitive than lighter rats to the nephrotoxic effects of TMT. These effects were independent of recognizable neurotoxic effects of TMT in the hippocampus.

Animals↗
PubMed1986

Preclinical toxicity of the new antineoplastic agent, ametantrone acetate, in mice and dogs.

Ametantrone acetate (anthracenedione diacetate, NSC 287513) is an experimental antineoplastic agent with activity against a comprehensive panel of solid transplantable tumors in mice and dogs were carried out to establish tolerable levels. In mice, LD10, LD50 and LD90 values were respectively, 26, 35 and 47 mg kg-1 28 days following single intravenous injection and 22, 67 and 206 mg kg-1 14 days after single intraperitoneal injection. Hemorrhage and necrosis of the small intestine occurred in intercurrent deaths. A 5-day, consecutive intraperitoneal dosing study yielded 28 day, LD10, LD50 and LD90 values of 18, 21 and 26 mg kg-1, respectively, in mice. Bone marrow hypoplasia, lymphoid depletion and focal cardiac changes were observed in animals which died during the 28-day postdose observation period. In dogs, single intravenous injections repeated twice at intervals of 3-8 weeks resulted in leukopenia and thrombocytopenia at a dose of 2.71 mg kg-1 and decreased myeloid: erythroid ratios at a dose of 0.68 mg kg-1. Five consecutive daily intravenous injections in dogs of 0.7 mg kg-1 induced significant clinical and laboratory signs of toxicity but 0.35 mg kg-1 day-1 was tolerated. In dogs, bone marrow, lymphoid tissue and gastro-intestinal tract in both sexes and gonads in the males were target organs for toxicity. Clinical signs and clinical laboratory abnormalities abated in surviving mice and dogs. The spectrum of tissue changes induced by ametantrone was qualitatively similar to that elicited with other intercalating agents.

Animals↗
PubMed1986

Teratology studies of ametantrone acetate in rats and rabbits.

Ametantrone acetate is an antineoplastic drug chemically described as 1,4-bis [[2-[(2-hydroxyethyl)-amino] ethyl]amino] -9,10-anthracenedione diacetate salt. The drug has activity against leukemia and solid tumors in animal models. The purpose of this study was to investigate the teratogenic potential in pregnant rats and rabbits when administered during the critical period of organogenesis. Daily doses of 1.5, 3.0, and 6.0 mk/kg were administered IP to pregnant rats on days 6 through 15 of gestation, and 0.2, 0.4, and 0.8 mg/kg to rabbits on days 6 through 18. Dose-related weight loss occurred in both species during treatment as well as in the entire gestation period. Maternal and fetal parameters were evaluated upon uterotomies in rats on gestation day 20 and rabbits on day 28. In both species, there was dose-related blue discoloration of abdominal viscerae and of skin at injection sites. In rats, fetal malformations and developmental variations were comparable between treated and control fetuses. However, the incidence of fetal malformations was increased in rabbits given 0.4 and 0.8 mg/kg but not at 0.2 mg/kg. Based on these data, ametantrone was considered teratogenic at dose levels of 0.4 mg/kg and above in rabbits.

Abnormalities, Drug-Induced↗
PubMed1985

Cardiotoxicity study of amsacrine in rats.

The cardiac functional and tissue changes produced by the antineoplastic agent, amsacrine, were evaluated in CD male rats. Amsacrine was administered intraperitoneally to groups of 12 male rats in single weekly doses of 12, 6, and 3 mg/m2 for 13 weeks. The drug elicited target organ toxicity in the bone marrow, lymphoid tissue, and gonads. There were blood biochemical alterations with transient elevations of total serum creatine phosphokinase, creatine phosphokinase-MB fraction, aspartate aminotransferase, and lactate dehydrogenase levels at 12 mg/m2, suggesting myocardial damage; however, there was no associated pathologic evidence of cardiotoxicity. This study indicates that amsacrine has negligible cardiotoxicity in rats when administered weekly for 13 weeks even at the lethal dose levels.

Aminoacridines↗
PubMed1985

Spermatocytic seminoma in the rat.

During the necropsy of a 2-yr-old untreated control rat from a carcinogenicity study, a tan brown nodular mass was observed within the tunica albuginea of one testis. Both testes were processed for light and transmission electron microscopy. Histologically, the testicular mass was composed of round to polyhedral cells with distinct cell boundaries, amphophilic cytoplasm, fine nuclear chromatin, and a delicate fibrovascular supporting stroma. Ultrastructurally, the tumor cells displayed features associated with spermatocytic differentiation. Based on the light microscopic and the ultrastructural features, the tumor was considered a spermatocytic seminoma of the testis, a rare tumor in the rat.

Aging↗
PubMed1984

Bacterial and mammalian cell mutagenesis, sister-chromatid exchange, and mouse lung adenoma bioassay with the antineoplastic acridine derivative amsacrine.

Amsacrine is a DNA intercalating agent with antineoplastic properties in lymphoproliferative disorders. This report describes a group of short-term tests with multiple endpoints to characterize the mutagenic and carcinogenic properties of this drug. In vitro studies included bacterial and mammalian cell mutagenesis, and sister-chromatid exchange and chromosome aberrations in mammalian cells. In vivo, mice were given amsacrine for 7 wk at 2, 5, and 10 mg/kg and were observed for an additional 17 wk. The standard bacterial assay revealed cytotoxicity at 2000 and 5000 micrograms/plate in the preincubation assay. No significant increase in revertants occurred in Salmonella strains, except for TA1537 in the activation phase. Amsacrine at 4.0 micrograms/ml was cytotoxic to V-79 cells in the cell mutation assay, and at lower dose levels was a direct-acting mutagen for the HGPRT locus. Sister-chromatid exchange rate of Chinese hamster ovary cells was increased more than twofold at 2 micrograms/ml without metabolic activation. Cell anomalies included changes in metaphase cell kinetics and chromosome damage. Mice in the lung adenoma bioassay failed to show increased numbers of tumors, while indicating lack of tolerance and survival beyond 5 mg/kg. The results indicate clear genotoxicity to mammalian cell systems with a spectrum of changes from point mutation and SCE induction to cell-cycle alterations, irrespective of exogenous metabolic activation. These results corroborate previous findings in animal and human cell systems in vitro. The reduction of genotoxicity in bacterial assays after exogenous metabolic activation may suggest some detoxification, and the magnitude of effects observed in mammalian cells indicates that exogenous metabolic activation is not required to manifest amsacrine's activity. The lack of tumor-inducing potential in mice may be attributed to strong cytotoxic effects in this species, or to an insensitivity of the target organ, or to assay systems that may mask the carcinogenic potential.

Adenoma↗
PubMed1982

Increase in the serum macrophage migration inhibitory activity and lysozyme in dogs affected with cyclic hematopoiesis.

Cyclic neutropenia (CN) is an inherited disease known to occur in both humans and Gray Collie dogs. In dogs, the disease is characterized by a profound and cyclic decrease in circulating granulocytes at 12-day intervals. Other formed elements of the blood also show cyclic changes and thus the disease is also called cyclic hematopoiesis (CH). In this study, daily serum levels of lysozyme and a factor with macrophage migration inhibitory (MIF) activity were assayed. Both MIF activity and lysozyme levels were elevated more than 2-fold and fluctuated cyclically in CH dogs during the 12-day cycle: CH dogs CH 490 and CH 491, had 32.7 +/- 16.8% and 35.9 +/- 18.3% migration inhibitory activity, respectively, as compared to 15.1 +/- 1.4% in normal dog N 492; CH 490 and CH 491 had 78.7 +/- 43.7 units and 86.9 +/- 58.7 units of lysozyme, respectively, as compared to 33.4 +/- 1.7 units in N 492. The change of MIF activity tended to precede that of lysozyme activity in CH dogs. Furthermore, MIF levels and monocyte counts correlated significantly during the 12-day neutropenia cycle (CH 490, r = 0.677, P less than 0.001; CH 491, r = 0.583, P less than 0.01).

Agranulocytosis↗