Preclinical Efficacy of V⁴Q⁵dDAVP, a Second Generation Vasopressin Analog, on Metastatic Spread and Tumor-Associated Angiogenesis in Colorectal Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Control of metastatic spread of colorectal cancer (CRC) remains as a major therapeutic challenge. [V4 Q5 ]dDAVP is a vasopressin peptide analog with previously reported anticancer activity against carcinoma tumors. By acting as a selective agonist of arginine vasopressin type 2 membrane receptor (AVPR2) present in endothelial and tumor cells, [V⁴Q⁵]dDAVP is able to impair tumor aggressiveness and distant spread. Our aim was to evaluate the potential therapeutic benefits of [V⁴Q⁵]dDAVP on highly aggressive CRC disease using experimental models with translational relevance. MATERIALS AND METHODS: Murine CT-26 and human Colo-205 AVPR2-expressing CRC cell lines were used to test the preclinical efficacy of [V⁴Q⁵]dDAVP, both in vitro and in vivo. RESULTS: In syngeneic mice surgically implanted with CT-26 cells in the spleen, sustained intravenous treatment with [V⁴Q⁵]dDAVP (0.3 µg/kg) dramatically impaired metastatic progression to liver without overt signs of toxicity, and also reduced experimental lung colonization. The compound inhibited in vivo angiogenesis driven by Colo-205 cells in athymic mice, as well as in vitro endothelial cell migration and capillary tube formation. [V⁴Q⁵]dDAVP exerted AVPR2-dependent cytostatic activity in vitro (IC₅₀ 1.08 µM) and addition to 5-fluorouracil resulted in synergistic antiproliferative effects both in CT-26 and Colo-205 cells. CONCLUSION: The present preclinical study establishes for the first time the efficacy of [V⁴Q⁵]dDAVP on CRC. These encouraging results suggest that the novel second generation vasopressin analog could be used for the management of aggressive CRC as an adjuvant agent during surgery or to complement standard chemotherapy, limiting tumor angiogenesis and metastasis and thus protecting the patient from CRC recurrence.

Insights into the Transforming Growth Factor-beta Signaling Pathway in Cutaneous Melanoma

Transforming growth factor-beta (TGF-beta) is a pleiotropic growth factor with broad tissue distribution that plays critical roles during embryonic development, normal tissue homeostasis, and cancer. While its cytostatic activity on normal epithelial cells initially defined TGF-beta signaling as a tumor suppressor pathway, there is ample evidence indicating that TGF-beta is a potent pro-tumorigenic agent, acting via autocrine and paracrine mechanisms to promote peri-tumoral angiogenesis, together with tumor cell migration, immune escape, and dissemination to metastatic sites. This review summarizes the current knowledge on the implication of TGF-beta signaling in melanoma.

A Hydroxyurea-induced Leg Ulcer

Hydroxyurea is a cytostatic agent that has recently become the drug of choice in the treatment of various myeloproliferative diseases. The cutaneous side effects of hydroxyurea include xerosis, hyperpigmentation, nail discoloration, and scaling. Leg ulcers have only rarely been reported in association with hydroxyurea treatment. A 75-year-old woman presented with leg ulcers, nail discoloration, and xerosis. The leg ulcers were refractory to conventional treatment. She had been taking oral hydroxyurea since being diagnosed with essential thrombocytosis in 2002. Hence, we suspected hydroxyurea-induced leg ulcers and discontinued her hydroxyurea treatment; the ulcers gradually healed thereafter. We present a rare case of hydroxyurea-induced leg ulcers in Korea.

Hand-Foot syndrome induced by sorafenib, a multitargeted tyrosine kinase inhibitor, in a patient with advanced renal cell carcinoma / 소아과

Renal cell carcinoma (RCC) arising from epithelial cells of the renal tubules is a highly aggressive and malignant tumor in all ages; however, it rarely occurs in children. the standard treatment for RCC is radical nephrectomy with lymph node dissection when the tumor is localized and can be completely resected. Adjuvant chemotherapy, radiotherapy, and immunotherapy are used for pediatric patients with advanced RCC involving lymph nodes or metastatic lesions. Sorafenib is an oral, multikinase inhibitor that has recently been approved for use in metastatic RCC. Common toxicities that have been reported include dermatologic changes such as rash or desquamation and hand-foot skin reaction, diarrhea, fatigue, alopecia, and hypertension. In particular, hand-foot syndrome (HFS) an erythematous skin lesion of the palms and solesis most often caused by cytostatic chemotherapeutic agents. In this report, we have studied a 14-year-old female patient with hand-foot syndrome that occurred in association with sorafenib for the treatment of metastatic RCC. Furthermore, this case demonstrates that reversal of complications can be achieved by discontinuing the drug and intervention with topical steroids, vitamin E, and high-dose pyridoxine.

Effects of BCG or CP-2 on the DNA Synthesis in the Epithelial Cells of the Mouse Appendix / 대한해부학회지

This experiment was performed to evaluate the morphological responses of the appendicular mucosa of the mouse, inoculated with Ehrlich carcinoma cells in the inguinal area, following administration of BCG or CP-2 (Coptis chinensis-Croton tiglium extracts). Healthy adult ICR mice weighing 25 gm each were divided into normal and experimental groups (experimental control, BCG or CP-2 treated group). Each experimental group mouse was inoculated with 1 x 10(7) Ehrlich carcinoma cells subcutaneously in the inguinal area. From the next day after inoculations, 0.2 mL of saline, BCG (0.5 mL/25 g B.W.: 0.03 x 10(8) ~ 0.32 x 10(8) CFU) or CP-2 (30 mg/kg) were injected subcutaneously to the animals every other day, respectively. The day following the 7 th injection of BCG or CP-2, each mouse was injected with a single dose of 0.7 microCi/gm of methyl-3H-thymidine (25 Ci/mmol, Amersham Lab., England) through tail vein. Seventy minutes after the tritiated thymidine injection, animals were sacrificed. The number of the labeled epithelial cells of the appendicular mucosae were observed and evaluated. On histological studies of the experimental control, BCG or CP-2 treated mice, general morphologies of the appendicular mucosae were similar. On autoradiographic study, number of the labeled cells of normal control, experimental control, BCG treated or CP-2 treated groups were 362.2+/-56.12, 350.7+/-42.65, 265.8+/-27.08 and 241.3+/-53.29, respectively. Above results show that BCG and CP-2 suppress the DNA synthetic activity of the epithelial cells of the appendix, but did not show any remarkable morphological alterations on the mucosae. These results suggest that BCG and CP-2 are ones of effective anticancer drugs for the cytostatic therapy.

Effects of Acriflavine-Guanosine Composition (AG60) on the DNA Synthesis and Ultrastructure of Epithelial Cells of the Appendix of Mice Inoculated with Ehrlich Carcinoma Cells / 대한해부학회지

This experiment was performed to evaluate the morphological responses of the mucosa of the mouse appendix, inoculated with Ehrlich carcinoma cells in the inguinal area, following administration of Acriflavine-Guanosine Composition (AG60). Healthy adult ICR mice weighing 25 gm each were divided into normal, experimental control and AG60 treated group. Experimental control and AG60 treated groups, mice were subcutaneously inoculated with 1 x 10(7) Ehrlich carcinoma cells in the inguinal area. From next day after the carcinoma cell inoculations, 0.2 mL of saline or AG60 (5 mg/kg/0.2 mL) were injected subcutaneously to the animals every other day, respectively. The day following the 7 th injection of saline or AG60, each mouse was injected with a single dose of 0.7 microCi/gm of methyl-3H-thymidine (25 Ci/mmol, Amersham Lab., England) through tail vein. Seventy minutes after the 3H-thymidine injection, animals were sacrificed, and appendix tissues were fixed in 10% formalin solution for light microscopy. The number of the labeled mucosal epithelial cells of the appendix were observed and evaluated. For the electron microscopic study, the tissues were fixed in 2.5% glutaraldehyde-1.5% paraformaldehyde solution, followed by post-fixation with 1% osmium tetroxide solution. Ultrathin sections were counter stained with uranyl acetate-lead citrate solutions, and observed. On light microscopic observation of experimental control and AG60 treated mice, did not show any remarkable morphological alterations on the mucosae. On autoradiographic study, number of the labeled cells within 3.5 mm width mucosae of normal control, experimental control, AG60 treated mice were 362.2+/-56.12, 350.7+/-42.65 and 90.7+/-33.48, respectively. On ultrastructural observation of the experimental control and AG60 treated mice, general morphologies of the epithelial cells of appendix were similar. But intranuclear filamentous structures, intramitochondrial dense granules, and myelin figures were occasionally observed in the absorptive cells of AG60 treated mice than control ones. Above results show that AG60 suppress the DNA synthetic activity of the mucosal epithelial cells of mouse appendix, but did show slight ultrastructural alterations in the absortive cells. These results suggest that AG60 is one of effective anticancer drug for the cytostatic therapy.

Antitumor Activity of Oxaliplatin, 5-FU and Paclitaxel Given Alone or in Combination with ZD1839 in Human Gastric Carcinoma Cells in vitro / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Oxaliplatin (LOHP), 5-FU, and paclitaxel (PTX) are considered highly active against advanced gastric carcinomas, and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, ZD1839 is considered as a good candidate for the treatment of gastric cancers when given alone or in combination with cytotoxic agents. The present study evaluated the antitumor effects of these agents in SNU-1 human gastric cancer cells either alone or when given as a doublet (i.e., as a cytotoxic-cytostatic combination). MATERIALS AND METHODS: We selected SNU-1 cells that showed DNA mismatch repair (MMR) deficiency and EGFR overexpression. Growth inhibition was measured by MTT and by direct cell counting and cell cycle distribution by flow cytometry. The combination index (CI) was used to describe synergistic interaction. RESULTS: The four drugs showed IC50s ranging from 1.81 nM to 13.2microM. MTT assay appeared to underestimate the cytotoxicity of PTX, which was attributed to a significant resistant fraction (32%). LOHP and PTX induced G2/M arrest, 5-FU increased in S phase, and ZD1839 in-creased in G1 in a concentration dependent manner. PTX ZD1839 showed the greatest synergism and LOHP ZD1839 showed a similar result. The cell cycle effect of PTX was potentiated by the coadministration of ZD1839. A previously developed cytostatic TPi model was used to assess the contribution of cell cycle arrest to overall growth inhibition, and 64% and 80% of the overall growth inhibition was attributed to cell cycle arrest for LOHP and PTX, when exposed to 7.55microM and 10 nM for 72 hr, respectively. CONCLUSION: This study demonstrates the antitumor activity and significant cell cycle arrest effect of ZD1839 against human gastric carcinoma cells and its synergistic interaction with LOHP and PTX. These results provide a preclinical rationale for the clinical development of ZD1839 and its use in combination with LOHP or PTX against human gastric cancers that express EGFR.

Expression of Cyclin D1, Cyclin E, p21Cip1 and p27Kip1 in Chemically Induced Rat Mammary Tumor Treated with Tamoxifen and Transforming Growth Factor-1

BACKGROUND: Tamoxifen (TAM) inhibits the action of estrogen by binding to estrogen receptors, and also has non-estrogen receptor mediated cytostatic activities. Transforming growth factor-1 (TGF-1) inhibits the proliferation of many other cell types, such as epithelial, hematopoietic and endothelial cells. METHODS: We investigated the effects of tamoxifen on the growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors and the expression of cyclin D1, cyclin E, p21Cip1, and p27Kip1 by performing immunohistochemistry and Western blot analysis, and studied whether TGF-1 injection amplified the effects of TAM. When tumor size reached between 10-15 mm in the largest dimension, the rats were divided into 3 groups: DMBA-control group (n=12), DMBA-TAM group (n=14) and DMBA-TAM plus TGF-1 group (n=5). RESULTS: The consecutive administration of TAM markedly decreased the tumor development compared with the DMBA-control group. The DMBA-TAM and DMBA-TAM plus TGF-1 groups showed decreased expression of bromodexoyuridine, cyclin D1, cyclin E, and p21Cip1 when compared with those of the DMBA-control group. On the other hand, the labeling index of p27Kip1 was higher in the DMBA-TAM plus TGF-1 group than in the DMBA-control group. CONCLUSION: TAM suppresses tumor development, which may be associated with down-expression of cyclin D1 and cyclin E, and overexpression of p27Kip1, and addition of TGF-1 does not influence tumor development treated by TAM.

Anticancer Effect of AG60 (Acriflavine-Guanosine Compound) on the Ehrlich Cancer Cells Light Microscopic, Autoradiographic and Electron Microscopic Study / 대한해부학회지

To evaluate the effect and working mechanism of a newly developed anti-cancer drug, AG60 (acriflavine-guanosine compound, Taerim Pharm. Co. Seoul, Korea), histotologic, autoradiographic and electron microscopic studies were carried out. For the histologic study, each Ehrlich carcinoma cells (10(7) cells)-inoculated mouse was subcutaneously injected with saline (0.2 ml), 10 mg/kg of AG60, or 30 mg/kg of AG60, every other day, respectively. Animals were sacrified on the 14th day from the first injection, and tumor masses were fixed in 10% formalin solution. Tissue sections of the tumor were stained with hematoxylin and eosin. For the electron microscopic study, Ehrlich carcinoma (10(7) cells)-inoculated mice were subcutaneously injected every other day with saline (0.2 ml) or 30 mg/kg of AG60, respectively. The day after 7th injection (14th day), animals were sacrified, small piece of tumor masses were fixed in 2.5% glutaraldehyde-1.5% paraformaldehyde solution followed by fixation in 2% osmium tetroxide solution. Ultrathin sections were counter stained with uranyl acetate-lead citrate solutions, and observed with JEM 100CX electron microscope. For the autoradiographic study, each Ehrlich carcinoma (10(7) cells)-inoculated mouse was injected every day with 0.2 ml of saline, 5 mg/kg of AG60, or 30 mg/kg of AG60, respectively. The day following the last injection, each animal was given a single dose of 0.7 micricurie/g of methyl-3H-thymidine (Amersham Lab., England) through the tail vein. Seventy minutes after the thymidine injection, animals were sacrified, tumor masses were collected and fixed in 10% neutral formalin. Tissue blocks were washed, dehydrated, embedded and cut in 6 micrometer-thick sections. Deparaffinzied sections were dipped in the autradiographic emulsion E1 (Amersham Lab., England) and dried and stocked in the dark room. Filmed sections were exposured five weeks in the dark room, and were developed in the developer. Labeled indices (mean number of labeled cells per 100 cancer cells) and labeled grain indices (mean number of labeled silver grains per one cancer cell, and total granule numbers per every 100 cancer cell) were observed and calculated. The results were as follows : 1. On histological study, massive apoptosis were occured following the injection of AG60. Only small number of live cancer cells were observed. 2. On electron microscopic study, massive apoptotic figures including fragmentation of nuclei and cytoplasms, multiple nucleoli, condensation of nucleus and cytoplasm, deep invaginations and microcleft formations of nuclei, margination of heterochromatin along the inner nuclear membrane and microcleft , etc. were noticed. Giant cells represent the "tumor cell-tumor cell emperipolesis", and many of them seem to be in process of "cytolytic emperipolesis". 3. On autoradiographic study, labeled grains of 3H-thymidine were suppressed to only 11%~5% of control cancer cells following AG60 administrations. Discussed on the above experiments, it is suggested that severe suppression of DNA, RNA and protein syntheses by AG60 induce massive apoptosis of cancer cells. AG60 is expected as one of most effective anticancer drugs for the cytostatic therapy, the disease stabilization, the improved quality of life, the prolongation of life, and possibly the chemoprevention.

Effects of New Nultidrug - Resistance Reversing Agent, KR-30035, on Tumoral Uptake of Tc-99m MIBI In-vitro and In-vivo / 대한암학회지

PURPOSE: Verapamil is one of the most extensively characterized modulators of P-glyco- protein (P-gp) mediated multi-drug resistance (MDR), but its plasma concentration required to reverse MDR can cause cardiovascular toxicity. KR-30035 is a newly synthesized verapamil analogue with more potent cytostatic effects, but has lower cardiovascular effects than verapamil. We have assessed the MDR reversing effects of KR-30035 by measuring Tc-99m MIBI uptake in cultured tumor cells and in nude mice bearing human tumor xenografts. MATERIALS AND METHODS: In-vitro uptake of Tc-99m MIBI was measured in murine leukemia cells (L-1210) and those MDR-positive variants after incubation with different concentrations of KR-30035. Results were compared to those with verapamil. Organ and tumoral uptake of Tc-99m MIBI was compared between P-gp (+) human colon cancer (HCT15 cells) and P-gp (-) lung cancer (A549 cells) in nude mice, treated with either KR-30035 or verapamil. RESULTS: There was no significant difference in in-vitro uptake of Tc-99m MIBI between verapamil and KR-30035 group at any concentrations. MIBI uptake in P-gp (+) cells continuously increased either with verapamil or KR-30035 in a dose-dependent manner. Tc-99m MIBI uptake ratios of the tumor [P-gp (+' tumor uptake divided by P-gp (-) uptake] were significantly higher with KR-30035 than with verapamil in tumor bearing nude mice. Washout rate of Tc-99m MIBI from P-gp (+) HCT15 cells was lower in verapamil or KR-30035 groups than in the control group, which was 0.19, 0.19 and 0.27 respectively. CONCLUSION: These studies revealed that KR-30035 can potentially be used as an active modulator of MDR, with its significantly lesser cardiovascular toxicity than verapamil. Our results warrants further evaluation of this novel agent.

Effects of REtinoic Acid and Radiation on the Growth of Cell Lines of Human Head and Neck Squamous Cell Carcinoma / 대한암학회지

PURPOSE: Mammalian tumor cells differ in their response to ionizing radiation to a degree that some patients are readily curable with conventional doses of radiation, while others are rarely controlled. In experimental systems, it is possible to demonstrate differences between cell lines both in intrinsic radiosensitivity and in the apparent capacity to repair damage. Retinoic acid is a substance that has previously been reported to increase radiosensitivity, but at concentrations likely to have cytostatic effects or induce cellular differentiation. We chose several head and neck cancer cell lines to investigate radiation sensitivity and synergism in combination with retinoic acid. Material and Methods: Seventeen head and neck cancer cell lines (MDA886, P1, P13, A-431, PCI-50, UMSCC-10A, UMSCC-10B, UMSCC-11A, UMSCC-11B, UMSCC-17A, UMSCC-17B, UMSCC-19, UMSCC-22B, UMSCC-30, UMSCC-38, 1YA, 1YB) are irradiated with variable dose of radiation (1 Gy, 5 Gy, 9 Gy) for determination of radiosensitivity of each cell lines. The less radiosensitive cell lines are treated with retinoic acid for evaluation of the effects of retinoic acid on cellular X-ray sensitivity and recovery from X ray-induced potentially lethal damage. RESULTS: Lowest growth inhibition rates are seen UMSCC-11A and 1YA cell lines in 1 Gy, so that we treated with retinoic acid such cell lines. We obtained the following RESULTS: 1) two cell lines appear not inhibitory effect on recovery from X-ray induced potentially lethal damage but growth inhibition synergism when irradiated with retinoic acid in 1 Gy of radiation dose. 2) two cell lines were little effect on radiosensitivity and inhibitory effect on recovery from X-ray damage in 0.5 Gy radiation dose. CONCLUSION: We found that direct radiosensitizing effects of retinoic acid on 1 Gy of radiation dose may act synergistically for cell growth inhibition in vitro study(three cell lines: UMSCC-11A, 1YA, UMSCC-11B). Further in vitro and in vivo experiments are now necessary to evaluate retinoic acid as radiosensitizer for head and neck cancer radiation therapy.

Anti-tumor Effects of Growth Factor Inhibitors and Anti-metastatic Agents in Human Gastric Cancer Cell Lines / 대한암학회지

PURPOSE: For tumor growth, invasion and metastasis, a cascade of linked sequential biological events is essential; overproduction of growth factors, activation of proteolytic enzymes, induction of tumor angiogenesis, and enhanced tumor cell motility and attachment. We tried to test whether the biological therapy against the biological targets can modulate the specific biological characteristics, and furthermore increased anti-tumor effects can be induced when the biological therapy and cytotoxic chemotherapy were combined. MATERIALS AND METHODS: YCC-1, 2, 3, 7, and AGS human gastric cancer cell lines were used in these studies. Pentosan polysulfate (PPS) as a heparin-binding growth factor (HBGF) inhibitor, Tranexamic acid as a plasmin inhibitor, Adriamycin as a chemotherapeutic agent, were selected. The methods were Northern blot analysis for the detection of Midkine (MK) expression, soft agar assay for autocrine tumorigenicity. The expression of uPA, PAI-1 was determined by ELISA, while the MMPs activities were evaluated by zymography. The effects of each drug on tumorigenicity and tumor cell proliferation were evaluated by soft agar assay and cell proliferation assay, respectively. RESULTS: YCC-3, 7, AGS cell lines expressed MK mRNA, whereas YCC-1, 2 did not. YCC-2 cell line showed increased expression of uPA and MMP activities. Only MK expressing YCC-3 and 7 cell lines showed the tumorigenicity. PPS suppressed the colony forming activities as much as Adriamycin did (PPS; 8~24%, Adriamycin; 12~40%), but it showed only cytostatic effects in cell proliferation assay (PPS; 60~103%, Adriamycin; 22~97%). When PPS was combined with Adriamycin on the Adriamycin resistant, MK expressing YCC-7 cell line, the growth inhibition rate increased up to 84%, while that of PPS or Adriamycin single treatment was 40%, 22%, respectively (p=0.001). CONCLUSION: The modulation of specific biological targets can induce the anti-tumor effects. This suggests the possible clinical application of biological therapy in gastric cancer.

Experimental study on the effect of surmin on penile squamous carcinoma cell line(CUPE-1) / 대한비뇨기과학회지

Experimental study was done to investigate the effect of suramin on the in vitro and in vivo proliferation and metastasis of penile squamous carcinoma cell line(CUPE-1), morphological changes of CUPE-1 cells induced by suramin and mechanism of action of suramin. Suramin inhibited in vitro proliferation of CUPE-1 significantly with 1C50 of 100 microgram/ml media. In vitro antiproliferative effect of suramin on CUPE-1 was reversible after stopping administration of the drug. Weekly intraperitoneal administration of 200 mg/kg of suramin to nude mouse inhibited the proliferation and metastasis of intraperitoneally implanted CUPE-1 cells significantly. but did not show significant effect on the proliferation of subcutaneously implanted CUPE-1 cells. Suramin induced senile changes on ultrastructure of CUPE-1 cells. Suramin of 300 microgram/ml inhibited the prolireration-stimulating effect of EGF significantly, whereas, suramin of 100 microgram/ml did not inhibit the effect of EGF significantly. Suramin did not show significant cytotoxicity on 3H-thymidine release assay. These results suggest that suramin is a promising drug for the treatment of advanced penile squamous cell carcinoma and blood level of suramin in clinical trial should be continuously maintained in about 300 microgram/ml, and that the main machanism of suramin against CUPE-1 is cytostatic. by antagonizing the action of EGF and inducing growth arrest and senile change.

A comparative study of cytostatic intravesical instillation for superficial bladder tumor / 대한비뇨기과학회지

A total or 56 patients who underwent TUR-BT for superficial (stages O and A) bladder tumors received various chemoprophylactic treatment to prevent recurrence. 16 patients underwent resection only (Group I). Of the 56 patients treated with chemoprophylactic agents 18 patients were given thio-tepa at weekly interval for 8 weeks (Group 2). 20 patients were given adriamycin. weekly one time for 6 weeks (Group 3). 16 patients were given mitomycin C, weekly one time for 8 weeks (Group 4). All chemoprophylactic groups were followed by monthly one time for 1 year and the dosages of the used agents (thio-tepa, adriamycin and mitomycin C) were 60 mg/l dosage, 50 mg/l dosage and 30 ml/l dosage, respectively. During follow-up period (mean duration; 19.8-25. 2 months), 1umor recurred 56.2 % of group 1 patients, 27.7 % of group 2 patients, 25.0% of group 3 patients, 18.9 % of group 4 patients and 22.2% of total patients. Therefore three drugs were effective to decrease the recurrence rate of superficial bladder tumor and no significant differences in recurrence rate were noticed among drugs. Toxicity of the three agents were negligibly minimal except 2 patients who developed severe gross hematuria after adriamycin instillation.

Anti-tumor activity of tumor necrosis factor alone and combination with VP-16 on renal cell carcinoma in a nude mice xenograft model / 대한비뇨기과학회지

Investigations of the anti-tumor activity of recombinant mouse TNF and etoposide(VP-16) in a nude mouse subcutaneous implantation xenograft model utilizing the CURC-1 human renal cell carcinoma cell line were performed. Recombinant mouse tumor necrosis factor-alpha(rTNF-alpha) and VP-16. both well known cytotoxic and cytostatic anticancer agents were evaluated singly and in combination against subcutaneously growing CURC-1. The results were as follows : 1. In the absence of treatment(Group I). subcutaneously growing CURC-1 tumor nodules demonstrated continued rapid growth. 2. Administration of rTNF(Group II) induced significant tumor regression in the subcutaneous nodules. 3. Administration of rTNF and Etoposide(Group III) demonstrated significant tumor growth inhibition. On histopathological findings, Group I (control) shows rare leukocyte infiltration and no tumor necrosis. In contrast, Group II shows tumor necrosis and more leukocyte infiltration than Group I . Group III demonstrates tumor necrosis. tumor cell degeneration and more leukocyte infiltration than Group II. These results suggest that TNF have antineoplastic effect against subcutaneous human renal cell carcinoma nodule but the synergistic effect of TNF with VP-l6 is uncertain.

Radioprotective Effect of Mesna on Mouse Testis / 대한치료방사선과학회지

Mesna has been used with ifosfamide to prevent urotoxicity in the treatment of testicular cancers. This drug also protected the toxicities of adriamycin without compromising cytostatic activity. With n idea of radioprotective role of sulfhydryl group of radioprotectors and of mesna decreasing the toxic effect of adriamycin which produces free radicals, mesna and radiation were administered to mice to study the protective effect of this drug and to identify the difference in regenerative capacity of the germ cells in the testis between radiation-treated and both mesna- and radiation-treated groups. The shape and numbers of spermatogenic cells in the seminiferous tubules were examined every week after irradiation. In both groups, initial reduction and later recovery in germ seel numbers and shape was observed. The lowest germ cell number was found around three weeks after irradiation. Mean germ cell number of the mesna-treated group was significantly higher than radiation-treated group at all observed periods (p<0.05). More competent regeneration was present in mesna-treated group. These results suggest that mesna protect the testis from radiation injury. Further study will be necessary to identify whether mesna protects other tissues from radiation and it does not hamper tumor control.