• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.8
• /
• pp.4739-4742
• /
• 2013

Carboplatin, a second generation platinum drug, is widely used to treat different types of cancers. However, myelosuppression remains a major consideration in its use. Genetic polymorphisms of enzymes involved in drug disposition can influence therapeutic outcome. The homozygous null deletion of phase II metabolic gene GSTT1 that abolishes its xenobiotic- detoxifying ability may be associated with carboplatin toxicity. Further, since carboplatin generates oxidative stress, polymorphisms of oxidative stress genes that regulate the cellular level of free radicals may have important roles in generating drug- related adverse effects. We here investigated the null polymorphism of GSTT1, and the -463G>A promoter polymorphism of oxidative stress gene myeloperoxidase (MPO) for carboplatin toxicity in a population of northern India. Cancer patients who were treated with carboplatin, and developed toxicity was considered. The study group comprised of 10 patients who developed therapy- related adverse effects. Peripheral blood was taken from patients for DNA isolation. GSTT1 null genotype was determined by conducting duplex PCR and MPO-463 G>A was determined by PCR followed by RFLP. Hematologic toxicity was experienced by 5 patients, 2 of them had grade 3 and 4 toxicity and 3 others had grade 2 toxicity. They also had gastrointestinal (GI) toxicity. Remaining 5 individuals developed GI toxicity but no hematological toxicity. While GG homozygous of MPO was present in majority of patients having hematologic toxicity (in 4 out of 5 individuals), one A allele (AG genotype) was present in 4 patients who did not have any hematological toxicity. Thus variant A allele of MPO -463G>A may be related to lower hematological toxicity. These preliminary data, however, are required to be confirmed in larger studies along with other relevant polymorphisms.

• Journal of Pharmaceutical Investigation
• /
• v.36 no.4
• /
• pp.263-269
• /
• 2006

Deficiencies in the early ADMET(absorption, distribution, metabolism, elimination and toxicity) information on drug candidate extract a significant economic penalty on pharmaceutical firms. Microscale cell culture analogue-microscale gastrointestinal(${\mu}CCA-{\mu}GI$) device using Caco 2, L2 and HEp G2/C3A cells, which mimic metabolic process after absorption occurring in humans was used to investigate the toxicity of the model chemical, acetaminophen(AAP). The toxicity of acetaminophen determined after induction of CYP 1A1/2 in Caco 2 cells was not significant. In a coculture system, although no significant reduction in viability of HEp G2/C3A and L2 cells was found, approximately 5 fold increase in the CYP 1A1/2 activity was observed. These results appear to be related to organ-organ interaction. The oral administration of a drug requires addition of the absorption process through small intestine to the current ${\mu}CCA$ device. Therefore, a perfusion coculture system was employed for the evaluation of the absolution across the small intestine and resulting toxicity in the liver and lung. This system give comprehensive and physiologic information on oral uptake and resulting toxicity as in the body. The current ${\mu}CCA$ device can be used to demonstrate the toxic effect due to organ to organ interaction after oral administration,

• Journal of Environmental Health Sciences
• /
• v.40 no.4
• /
• pp.294-303
• /
• 2014

Objectives: Excretion and tissue distribution of titanium oxide nanoparticles were evaluated in rats after oral administration. The relation between toxicity and systemic concentration of nanoparaticles was investigated. Methods: Rats were orally treated with titanium oxide nanoparticles (10, 100 mg/kg) for five consecutive days. General toxicity, blood chemistry, and serum biochemical analysis were analyzed. Titanium concentration in liver, kidney, lung, urine and feces were measured and histopathology was performed in these organs. Results: Induction of toxicological parameters was not observed and titanium nanoparticles were excreted via feces. Conclusion: Absorption of titanium oxide nanoparticles via the gastrointestinal tract after oral administration was very poor and systemic concentration of titanium oxide nanoparticles was not elevated. Titanium oxide nanoparticles did not cause toxicities in rats after oral administration.

• Journal of Gastric Cancer
• /
• v.23 no.4
• /
• pp.609-621
• /
• 2023

Purpose: Determination of optimal treatment strategies for HER2-positive advanced gastric cancer (AGC) in randomized trials is necessary despite difficulties in direct comparison between trastuzumab deruxtecan (T-DXd) and nivolumab as third or later-line treatments. Materials and Methods: This single-institution, retrospective study aimed to describe the real-world efficacy and safety of T-DXd and nivolumab as ≥ third line treatments for HER2-positive AGC between March 2016 and May 2022. Overall, 58 patients (median age, 64 years; 69% male) were eligible for the study (T-DXd group, n=20; nivolumab group, n=38). Results: Most patients exhibited a HER2 3+ status (72%) and presented metastatic disease at diagnosis (66%). The response rates of 41 patients with measurable lesions in the T-DXd and nivolumab groups were 50% and 15%, respectively. The T-DXd and nivolumab groups had a median progression-free survival of 4.8 months (95% confidence interval [CI], 3.3, 7.0) and 2.3 months (95% CI, 1.5, 3.5), median overall survival (OS) of 10.8 months (95% CI, 6.9, 23.8) and 11.7 months (95% CI, 7.6, 17.1), and grade 3 or greater adverse event rates of 50% and 2%, respectively. Overall, 64% patients received subsequent treatment. Among 23 patients who received both regimens, the T-DXd-nivolumab and nivolumab-T-DXd groups had a median OS of 14.0 months (95% CI, 5.0, not reached) and 19.3 months (95% CI, 9.5, 25.1), respectively. Conclusions: T-DXd and nivolumab showed distinct efficacy and toxicity profiles as ≥ third line treatments for HER2-positive AGC. Considering the distinct features of each regimen, they may help clinicians personalize optimal treatment approaches for these patients.

• Journal of Gastric Cancer
• /
• v.15 no.2
• /
• pp.113-120
• /
• 2015

Purpose: Although several clinical trials have proven the efficacy of adjuvant S-1 treatment in gastric cancers, it is still unclear which patients receive the most benefit. In this study, we prospectively recruited patients with locally advanced gastric cancer who had undergone curative resection followed by adjuvant S-1 administration to investigate which factors affect the outcomes. Materials and Methods: Between July 2010 and October 2011, we enrolled 49 patients who underwent curative resection for stage II or III gastric cancer and who subsequently received adjuvant S-1 treatment for 1 year. Results: Twenty-nine patients (59.2%) continued S-1 treatment for 1 year, and 12 patients (24.5%) experienced recurrent disease during the follow-up period. Patients with continuation of S-1 for 1 year had significantly increased rates of disease-free survival (P<0.001) and overall survival (P=0.001) relative to the patients who discontinued S-1 during year 1. Multivariate analysis indicated poor outcomes for patients with stage III disease and those who discontinued S-1 treatment. Excluding patients who discontinued S-1 due to cancer progression (n=7), adjuvant treatment with S-1 still demonstrated a significant difference in the disease-free survival rate between the patients who continued treatment and those who discontinued it (P=0.020). Conclusions: S-1 is tolerated as adjuvant treatment in gastric cancer patients. However, discontinuing S-1 treatment may be an unfavorable factor in the prevention of recurrence. S-1 adjuvant treatment should be continued for 1 year if possible through the proper management of toxicities.

• The Journal of Korean Medicine
• /
• v.32 no.3
• /
• pp.18-24
• /
• 2011

Objective: Leejung-tang (Rechu-to in Japanese) is a traditional Korean herbal formula used for treatment of gastrointestinal disorders such as vomiting, stomach pain, chronic gastritis and gastrointestinal ulceration. The present study was carried out to investigate the potential acute toxicity of Leejung-tang water extract (LJT) by a single oral dose in Crl:CD (SD) rats in compliance with current guidelines. Methods: In the preliminary study, there were no adverse effects such as death, clinical signs, and body weight changes at dose levels of 500, 1000, and 2000 mg/kg/day body weight. Based on the results, a dose of 2000 mg/kg was selected as the toxicological limited dose. LJT was administered once by gavage to male and female rats at dose levels of 0 and 2000 mg/kg bodyweight. During the study period, mortalities, clinical findings, and body weight changes were observed for 14 days following the administration. On day 14 after the treatment, the animals were sacrificed by carbon dioxide overdose and complete gross postmortem examinations were performed. Results: In present study, no treatment-related deaths were observed. There were no adverse effects on clinical signs and body weight changes. In addition, there were no observed gross findings in all groups except for a kidney cyst in the 2000 mg/kg/day female group. Conclusion: The results indicated that LJT did not induce toxic effects at a dose level up to 2000 mg/kg in rats and its median lethal dose ($LD_{50}$) was considered to be over 2000 mg/kg/day body weight for both genders.

• Development and Reproduction
• /
• v.19 no.4
• /
• pp.167-180
• /
• 2015

Arsenic is a toxic metalloid that exists ubiquitously in the environment, and affects global health problems due to its carcinogenicity. In most populations, the main source of arsenic exposure is the drinking water. In drinking water, chronic exposure to arsenic is associated with increased risks of various cancers including those of skin, lung, bladder, and liver, as well as numerous other non-cancer diseases including gastrointestinal and cardiovascular diseases, diabetes, and neurologic and cognitive problems. Recent emerging evidences suggest that arsenic exposure affects the reproductive and developmental toxicity. Prenatal exposure to inorganic arsenic causes adverse pregnancy outcomes and children's health problems. Some epidemiological studies have reported that arsenic exposure induces premature delivery, spontaneous abortion, and stillbirth. In animal studies, inorganic arsenic also causes fetal malformation, growth retardation, and fetal death. These toxic effects depend on dose, route and gestation periods of arsenic exposure. In males, inorganic arsenic causes reproductive dysfunctions including reductions of the testis weights, accessory sex organs weights, and epididymal sperm counts. In addition, inorganic arsenic exposure also induces alterations of spermatogenesis, reductions of testosterone and gonadotrophins, and disruptions of steroidogenesis. However, the reproductive and developmental problems following arsenic exposure are poorly understood, and the molecular mechanism of arsenic-induced reproductive toxicity remains unclear. Thus, we further investigated several possible mechanisms underlying arsenic-induced reproductive toxicity.

• Journal of The Korean Society of Clinical Toxicology
• /
• v.4 no.1
• /
• pp.58-60
• /
• 2006

The venom gland of Toad contains large quantities of cardiac glycosides, and toad venom poisoning is similar to digitalis toxicity and carries a high mortality. Sometimes after ingestion of aphrodisiac pills which contain dried toad, a patient develops gastrointestinal symptoms and bradycardia, psychoneurologic symptoms. We have experienced 2 cases of toad venom intoxication, who ingested asian toads. Patients were presented to our ED with nausea, vomiting, and abdominal pain. The patients were peformed monitoring and conservative treatment and were fully recovered. Toad venom intoxication should be considered in patients with clinical manifestation of gastrointestinal irritation, cardiac arrhythmias, hyperkalemia, and detectable serum digoxin level without current medication of digoxin.

• Korean Journal of Clinical Pharmacy
• /
• v.14 no.2
• /
• pp.61-70
• /
• 2004

Heptaplatin is a new platinum derivative with antitumor activity against gastric cancer. Preclinical studies showed that it is less toxic than other platinum analogues. The purpose of this study is to evaluate the efficacy and toxicity of the combination therapy of heptaplatin and 5-fluorouracil in Korean advanced gastric cancer patients. This study was investigated retrospectively. The patients group consisted of 65 advanced gastric cancer patients with no prior radiotherapy. All patients received heptaplatin $400\;mg/m^2$ by 2-3 hour infusion on Day 1 and 5-FU $1000\;mg/m^2by 12-24 hour continuous infusion for 5 days. After the first cycle, subsequent doses were adjusted according to the toxicity. Courses were repeated every 28 days. As results, objective response occurred in 16 patients $(24.6\%)$. Two were complete and 14 were partial response. Median progression free survival was 32 weeks with $29\%$ of patients progression free at 1 year. The most common hematologic toxicity was anemia. Grade 3 or 4 anemia was seen at $2.7\%$ of treatment cycles. Grade 3 or higher leucopenia was seen at $1.2\%$ of cycles. Grade 3 or 4 neutropenia and thrombocytopenia occurred at $6.1\%\;and\;1.5\%$ of cycles, respectively. The most common nonhematologic toxicity was proteinuria. Though no patients experienced grade 3 or 4 proteinuria, proteinuria was a considerable factor for this chemotherapy. Grade 3 or higher gastrointestinal toxicities were nausea and vomiting ($4.6\%$ of patients) and diarrhea ($1.5\%$ of patients). Grade 2 renal toxicity with elevation of serum creatinine was seen in $0.3\%$ of cycles, which is less than that of other platinum analogues. This study showed that combination therapy of heptaplatin and 5-FU have modest antitumor activity against advanced gastric cancer without severe renal toxicity.

• Asian Pacific Journal of Cancer Prevention
• /
• v.13 no.4
• /
• pp.1553-1556
• /
• 2012

Introduction: Antimetabolites may cause severe toxicity and even toxic death in cancer patients. Our aim was to evaluate the relationship between antimetabolite toxicity and pharmacogenetics in patients with severe clinical toxicity or alanine transaminase (ALT) elevation after fluorouracil (5FU), capecitabine or methotrexate administration. Patients and Methods: Cancer patients with severe antimetabolite toxicity were evaluated for methylenetetrahydrofolate reductase (MTHFR) gene C667T, thymidilate synthase (TS) gene 5´UTR variable number of tandem repeats (VNTR), dihydroprymidine dehydrogenase (DPYD) gene IVS14+1G/A, Xeroderma pigmentosum (XPD) gene Lys751Gln and X-ray repair cross-complementing group 1 (XRCC1) gene Arg399Gln polymorphisms. Results: Eighteen patients were enrolled, with a male/female ratio of 0.8. They had osteosarcoma in methotrexate group (n=7), gastrointestinal malignancies in 5FU group (n=9) and breast cancer in the capecitabine group (n=2). Mucositis and dermatitis occurred in all groups, together with ALT elevation in the methotrexate group and 2 toxic deaths were encountered. DPYD, TS, MTHFR, XPD and XRCC1 gene polymorphism rare allele frequencies were observed to be higher than in the general population. Conclusion: Pharmacogenetics might contribute to tailored therapy.