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PubMed1998

Potentiation of treosulfan toxicity by the glutathione-depleting agent buthionine sulfoximine in human malignant glioma cells: the role of bcl-2.

Median survival of human malignant glioma patients is less than one year even with cytoreductive surgery and postoperative radiotherapy. Adjuvant chemotherapy has been rather ineffective. Here, we studied the potentiation by L-buthionine-[S,R]-sulfoximine (BSO), a glutathione-depleting agent, of anticancer drug actions on two human malignant glioma cell lines, LN-229 and T98G. LN-229 has wild-type p53 status, T98G is mutant for p53. Glutathione levels were depleted by BSO with similar kinetics in both cell lines. Only LN-229 cells were growth-inhibited by BSO. BSO had minor effects on the toxicity of doxorubicin, ACNU (1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosou rea, nimustine) and vincristine. BSO failed to alter teniposide or cytarabine toxicity. BSO induced prominent sensitization to the alkylating agent, treosulfan, in both cell lines, as assessed by viability assays, in situ DNA end labeling and quantitative DNA fragmentation. Treosulfan is thought to mediate toxicity via formation of reactive epoxides. In the absence of BSO, treosulfan had little acute cytotoxic and moderate antiproliferative effects. Synergistic glioma cell cytotoxicity induced by treosulfan and BSO was not associated with reactive oxygen species formation. Ectopic expression of bcl-2 did not alter basal glutathione levels but attenuated glutathione depletion induced by BSO. Bcl-2 provided only moderate protection from synergistic induction of glioma cell death by treosulfan and BSO. Glutathione depletion may play a role in BSO-mediated chemosensitization, but other mechanisms are probably involved as well. BSO may be a useful agent for glioma cell sensitization to specific chemotherapeutic drugs such as treosulfan.

Antineoplastic Agents, Alkylating↗
PubMed1997

Murine P-glycoprotein on stromal vessels mediates multidrug resistance in intracerebral human glioma xenografts.

Human glioma usually shows intrinsic multidrug resistance because of the blood-brain barrier (BBB), in which membrane-associated P-glycoprotein (P-gp), encoded by the human multidrug resistance gene MDR1, plays a role. We studied drug sensitivity to vincristine (VCR), doxorubicin (DOX) and nimustine (ACNU) in both intracerebrally and subcutaneously xenotransplanted human glioma. We examined the levels of MDR1 and murine mdr3 gene expression in the xenografts by reverse transcriptase polymerase chain reaction and the localization of P-gp by immunohistochemistry. Six of seven subcutaneously transplanted xenografts (scX) were sensitive to the above three drugs. In contrast, all three intracerebrally transplanted human glioma xenografts (icX) were resistant to P-gp-mediated drugs VCR and DOX, but were sensitive to the non-P-gp-mediated drug ACNU. Neither icX nor scX showed any MDR1 expression. Intracerebrally transplanted human glioma xenografts showed an increased level of murine mdr3 gene expression, whereas scX showed only faint expression. The localization of P-gp was limited to the stromal vessels in icX by immunohistochemistry, whereas scX expressed no P-gp. Our findings suggest that the P-gp expressed on the stromal vessels in icX is a major contributing factor to multidrug resistance in human glioma in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Total reconstruction of the upper lip after resection of a malignant melanoma.

The upper lip was totally reconstructed with a radial forearm sensory flap and vermilionplasty using medical tattooing after resection of a malignant melanoma. Three courses of chemotherapy (dacarbazine, nimustine, and vincristine) were given postoperatively. The reconstructed lip had good contour, colour, and sensory recovery.

Aged↗
PubMed1998

Enhancement of chemosensitivity toward anticancer drugs by high expression of caspase-1 in NIH 3T3 cells.

It has been well documented that caspase-1 (interleukin-1beta-converting enzyme, ICE) and its related cysteine proteinases such as caspase-3 (CPP32, apopain) and caspase-2 (ICH-1L) play important roles in apoptosis. In the present study, these genes were inserted into an inducible eukaryotic expression vector, pMSG, and transfected into NIH 3T3 mouse fibroblasts. The expression of caspases-1 and -3 was effectively induced by treatment with dexamethasone (Dex). The expression of caspase-2 was elevated in the transfected cells without treatment with Dex but was not further stimulated by Dex. High expression of these proteases alone induced neither apoptosis-like cell death nor any morphological change. However, the expression of caspase-1 but not of caspase-2 or -3 enhanced chemosensitivity toward cytotoxic anticancer drugs such as aclarubicin, epirubicin, adriamycin, nimustine and ifosfamide. It is thus concluded that caspase-1 mediates cytotoxic effects of these drugs.

3T3 Cells↗
PubMed1997

Prediction of drug cytotoxicity in 9L rat brain tumor by using flow cytometry with a deoxyribonucleic acid-binding dye.

OBJECTIVE: Flow cytometry (FCM) with a deoxyribonucleic acid (DNA)-binding dye, propidium iodide, provides a rapid and quantitative method to detect apoptotic cell death. This technique was used to examine the sensitivity of tumor cells to anticancer agents, as a novel test of chemosensitivity in vitro. METHODS: The in vitro chemosensitivity of 9L gliosarcoma cells to a panel of anticancer agents (cisplatin, nimustine, adriamycin, cyclophosphamide, vincristine, 5-fluorouracil, and methotrexate) was investigated by both FCM, yielding DNA histograms, and a microtiter tetrazolium test, measuring cellular metabolism. Clinically achievable concentrations of the agents were used for the analysis of DNA histograms and proliferation of 9L cells in vitro. Rats intracranially inoculated with 9L cells were treated with the agents, and tumor masses were visually monitored by using magnetic resonance imaging with gadolinium-diethylenetriaminepentaacetic acid enhancement. RESULTS: The cytotoxic effect of anticancer agents examined by the microtiter tetrazolium test correlated with a decreased G0/G1 peak in the DNA histograms. Serial FCM analysis showed that the decrease in the G0/G1 peak was subsequently accompanied by increased hypodiploid areas, suggesting DNA fragmentation induced by the agents. The in vitro chemosensitivity test and cell proliferation examination showed that all agents except cisplatin were effective. Growth retardation of inoculated brain tumors and prolonged survival of inoculated rats were observed with treatment with the anticancer agents, except cisplatin. CONCLUSION: The present study shows that FCM analysis with a DNA-binding dye can detect DNA damage induced by anticancer agents, and it suggests that this technique is a novel method to test chemosensitivity in vitro.

Animals↗
PubMed2005

A case of Werner syndrome with three primary lesions of malignant melanoma.

Three primary lesions of malignant melanoma developed in a 44-year-old Japanese woman with Werner syndrome. One lesion was on the right large pudental lip and the others in distinct locations on her left sole. After the wide local excision of these tumors, the wound of the large pudental lip was sutured, and the defects on the sole were covered with skin grafts. After one course of chemotherapy consisting of dacarbazine, nimustine, vincristine sulfate and local injection of Interferon beta were performed, severe myelosupression occurred and continued for two months. Defective production of WRN protein was confirmed by Western blotting, although the three representative mutations in Japanese patients, mutations 1, 4 and 6, which include over 90% of the Japanese patients, were not detected. We also reviewed 26 cases of malignant melanoma associated with Werner syndrome (WS), including ours.

Adult↗
PubMed2005

A case of epidermotropic metastatic malignant melanoma with multiple nodular lesions of the scalp.

Epidermotropic metastatic malignant melanoma (EMMM) is a form of metastatic malignant melanoma that has dermal cell nests with epidermotropism and specific histopathological features. We report a patient with eight nodular lesions of the scalp with histopathological findings compatible with EMMM. The tumors developed one year before consultation and increased in size simultaneously. The histopathological findings of all eight tumors were very similar. The tumor cells were located mainly in the dermis and partly in the basal layer of the epidermis. They contained melanin pigments and were positive for anti-HMB45 antibody. The tumors did not respond to combination chemotherapy with dacarbazine, nimustine, vincristine, and interferon-beta. Therefore, all the tumors were surgically removed. No local relapse, distant metastasis or re-elevation of plasma 5-S-cysteinyldopa was identified during nine months of follow-up. Histopathologically, all eight tumors lacked apparent vascular invasion, which may be related to a slow clinical course of the present case.

Aged↗
PubMed2007

Case of metastatic melanoma in an epitrochlear lymph node arising in a pregnant woman.

We describe a rare case of metastatic melanoma in an epitrochlear lymph node in a 29-year-old female patient. The patient had been aware of a brown macule on her right posterior forearm at puberty. Because the lesion had enlarged rapidly, she was referred to our hospital. Histological examination revealed a malignant melanoma. She underwent wide local excision with 3-cm margins and split thickness skin graft closure, but we were not able to perform sentinel node biopsy. She also received three cycles of systemic chemotherapy with dacarbazine, nimustine, vincristine and interferon-beta. However, an epitrochlear node (interval node) metastasis occurred during pregnancy (seventh week) 2 years after the operation. We emphasize that it is important for clinicians to pay attention to the possibility of epitrochlear node metastasis in patients with malignant melanoma in the upper extremity and that it is necessary to perform sentinel node biopsy to identify uncommon lymph node metastasis.

Adult↗
PubMed1989

A novel multidrug resistance in cultured leukemia and lymphoma cells detected by a monoclonal antibody to 85-kDa protein, MRK20.

A monoclonal antibody, MRK20, in F(ab')2 form [MRK20-F(ab')2], which reacts with 85-kDa membrane protein in a doxorubicin (ADM)-resistant subline (K562/ADM) of human myelogenous leukemia cell line, K562, was examined for reactivity with 41 cultured human leukemia and lymphoma cell lines. None of these cell lines had ever been exposed to any anticancer agent in vitro except K562/ADM. The relative resistance index to various drugs was calculated by dividing the 50% growth-inhibitory concentration (IC50) of the test cell line by IC50 of K562 (the negative control in the antibody experiment). MRK20-F(ab')2 reacted with seven cell lines, KYO-1 derived from chronic myelogenous leukemia in blastic crisis (CMLbc), CMK from acute megakaryoblastic leukemia, HEL from erythroleukemia, P31/FUJ from acute monocytic leukemia, KOPM-28 from CMLbc, PL-21 from acute promyelocytic leukemia and K562/ADM. MRK20-F(ab')2 did not react with 34 other cell lines. All seven MRK20-F(ab')2-positive cell lines had relative resistance index values of 2 or more to anthracyclines (ADM, pyrarubicin, daunorubicin), mitoxantrone, etoposide, bleomycin, and pepleomycin. There was no distinct correlation between the reactivity to MRK20-F(ab')2 and a higher relative resistance index than 2 to vinca alkaloids, actinomycin-D, cisplatin, 4-hydroperoxycyclophosphamide, nimustine hydrochloride, methotrexate or cytarabine. These results indicate that MRK20-F(ab')2 detects a novel multidrug resistance to anthracyclines, mitoxantrone, etoposide, bleomycin and pepleomycin in cultured human leukemia and lymphoma cells.

Antibiotics, Antineoplastic↗
PubMed1992

Effects of antitumor agents on subcutaneous implants and hepatic metastases of colon carcinoma 26 in mice.

We investigated the responses of experimentally produced hepatic metastases of colon carcinoma 26 tumor and subcutaneously (SC) implanted colon carcinoma 26 tumor in mice to 17 clinically-used and one under-development antitumor agents using same dose regimen. In intravenous administrations on days 7 and 14, there were no significant differences in their responses to most of the tested agents. However, there were big differences in the responses to some of the agents. Nimustine more effectively prolonged the lifespan of SC implanted tumor-bearing mice than of mice bearing hepatic metastases. Mitomycin C was, however, considerably more effective on hepatic metastases than on SC implanted tumor. ME2303, a new fluorinated anthracycline derivative, showed a similar effect to doxorubicin on both tumors. However, administrations of ME2303 on days 7, 11 and 15 showed more marked antitumor effect only on hepatic metastases than administrations on days 7 and 14. Doxorubicin was less active against both tumors for administrations on days 7, 11 and 15 than for those on days 7 and 14. These results suggest the importance of the site of tumor growth for the action of some drugs. ME2303 may be active against hepatic metastases if it is administered by multiple injections.

Alanine Transaminase↗
PubMed2002

O(6)-methylguanine-DNA methyltransferase (MGMT) as a determinant of resistance to camptothecin derivatives.

The precise mechanisms of resistance to camptothecin (CPT)-derived DNA topoisomerase (topo I) inhibitors and the determinants remain unclear. We found that a DNA repair protein, O(6)-methylguanine-DNA methyltransferase (MGMT), participated in resistance to irinotecan hydrochloride (CPT-11), its active metabolite SN-38, and a novel CPT derivative, DX-8951f. In 17 human cancer cell lines, MGMT gene expression level closely correlated with sensitivity to the CPT derivatives, and inhibition of MGMT activity by nontoxic 5 microM O(6)-benzylguanine augmented the drug activity in relation to the MGMT expression levels in 8 cell lines examined. Transfection of pCR / MGMT-sense into U-251MG and pCR / MGMT-antisense into T98G and HEC-46 cells revealed that increased MGMT expression decreased the sensitivity to CPT-11, SN-38, and DX-8951f, whereas repressed MGMT expression sensitized cells to the drugs. Western analysis revealed that treatment of MGMT-expressing T98G cells with the drugs caused a decrease of both MGMT and topo I in a dose-dependent manner. Although, in the transfectants, MGMT expression did not so closely correlate with the sensitivity to drugs as to nimustine hydrochloride (ACNU), MGMT is probably an important resistance determinant to CPT derivatives, and may play some role in the topo I-mediated DNA damage and / or the repair process.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Dependence of chemotherapy response on p53 mutation status in a panel of human cancer lines maintained in nude mice.

In contrast to findings in vitro, the clinical response to anticancer chemotherapy is not simply associated with the p53 mutation status. To analyze the relationship between the actual response of solid tumors with p53 mutation and other biological characteristics, we used a human cancer-nude mouse panel of 21 lines derived from stomach, colorectal, breast, lung, and liver cancers for experimental chemotherapy. We examined the tumor growth rates of the cancer lines and the effects of nine drugs in clinical use, namely, mitomycin C (MMC), cisplatin (CDDP), nimustine hydrochloride (ACNU), irinotecan (CPT-11), cyclophosphamide (CPA), 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207), a 4:1 mixture of uracil and FT-207 (UFT), 5'-deoxy-5-fluorouridine (5'-DFUR), and adriamycin (ADM), on these tumors. The chemotherapy response was expressed as the tumor growth inhibition rate (IR). The genomic DNA sequences of the p53 gene in exons 5 through 8 were analyzed in these cancer tissues, and p53 mutations were detected in 10 of the 21 cancer lines (48%). Resistance to MMC was observed in p53 mutant tumors with smaller IRs than those for wild-type tumors (57.7% vs. 79.9%, P < 0.03). No significant differences were noted with the other eight drugs. To explore the role of the p53 function in the chemotherapy response, we calculated the correlation coefficients between chemosensitivity and tumor growth rate separately in p53 mutant and wild-type groups. In the p53 wild-type group, we found a positive correlation for the following drugs: ADM (P < 0.02), ACNU (P < 0.007), CPA (P < 0.011), UFT (P < 0.012), and FT-207 (P < 0.02). In the p53 mutant group, only CPA (P < 0.003) showed a positive correlation. The kinetics suggests that in the wild-type tumors, DNA damage caused by anticancer drugs occurs proportionally to the rate of DNA synthesis, and p53-mediated apoptosis is subsequently induced. The low frequency of positive correlation in the p53 mutant tumors is compatible with the loss of function or malfunction of mutant p53. The present results provide kinetic evidence that p53 function affects the response to anticancer drugs. Preserved p53 function tended to confer good chemosensitivity on rapidly growing tumors. However, the p53 mutation status did not seem to be suitable for use as an exclusive indicator to predict the chemotherapy response of human cancer xenografts.

Animals↗
PubMedDate not supplied

Assessment of micronucleus induction in murine SCCVII cells treated with various anticancer agents.

The possibility of using the cytokinesis-block micronucleus (MN) assay as a rapid test of chemosensitivity was investigated. SCCVII murine carcinoma cells growing exponentially in vitro were treated for 1 h under aerobic conditions with various concentrations of 11 anticancer agents: mitomycin C, doxorubicin, epirubicin, cisplatin, carboplatin, etoposide, vincristine, 5-fluorouracil, methotrexate, nimustine and dacarbazine. After removing the drugs, cytochalasin B (1.5 micrograms/ml) was added to block cytoplasmic but not nuclear division. At various times during culture, the proportions of binucleate cells (BNC) and multinucleate cells in the total cell population, and the mean number of micronuclei per single BNC were determined. Cell survival was also determined using the standard colony formation assay and was compared with the MN frequency. Maximal percentage of BNC was usually reached at 24-30 h of culture, except for cells treated with doxorubicin and epirubicin, in which it was reached at 30-72 h. All drugs induced formation of micronuclei and dose-response curves for MN frequency were obtained using the data at peak percentage of BNC times. For all drugs, MN frequency increased with concentration, but at the highest concentrations used (which are considered to be overly toxic) the MN frequency was rather lower. This decrease in MN frequency was largely attributable to the decrease in percent BNC. When the data at the highest concentrations of all drugs were excluded, a correlation was found between MN frequency and surviving fraction (r = 0.85). Therefore, it was concluded that the cytokinesis-block MN assay can be used to assess sensitivity of at least some tumor cells to appropriate concentrations of various chemotherapeutic agents.

Animals↗
PubMed1995

The antitumor effect of MX2, a new morpholino anthracycline, against malignant glioma cell lines and its subcellular distribution.

The chemotherapeutic effect of MX2 (3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin), a new lipophilic morpholino anthracycline, against rat C6 and human T98G glioma cells, was examined in vitro and in vivo. The subcellular distribution of MX2 was also studied. The drug concentrations of MX2 required for the 50% inhibition of cell growth (IC50) for C6 and T98G cells were 25.5 +/- 1.3 ng/ml and 70.6 +/- 6.8 ng/ml, respectively, which were much lower than the IC50 values for nimustine (ACNU). A C6 subline resistant to ACNU, C6/ACNU, was established by continuous exposure to graded concentrations of ACNU. The IC50 of MX2 for C6/ACNU was 28.3 +/- 2.2 ng/ml, indicating no cross-resistance to MX2. In the rats bearing the intracerebral C6 tumors, the life span was increased by about 40 to 100% after intravenous administration of MX2 at doses ranging from 1 to 3 mg/kg of body weight. Confocal laser scanning microscopy demonstrated visually the good accumulation of MX2 in the implanted intracerebral C6 tumors, as well as its predominant distribution in the cytoplasm over the nucleus in both cell lines in vitro. Ultrastructural studies also demonstrated the cytotoxic effects of MX2 against glioma cells. Our results suggest that MX2 may be a useful chemotherapeutic agent in the treatment of malignant gliomas and that confocal laser scanning microscopy is useful for the study of the cellular pharmacokinetics of anthracycline derivatives, such as MX2.

Animals↗
PubMed1987

Comparative studies of pulse and continuous exposure in human tumor clonogenic assay.

To assess the influence of different schedules of drug exposure in human tumor clonogenic assay on in vitro cytotoxicity of antitumor drugs, the in vitro sensitivities of a human carcinoma cell line, PC-9, to various antitumor drugs were measured by using two different procedures: exposure was either by pulse for 1 h prior to plating or continuous throughout the period of growth in agar. Marked differences between the two procedures in testing actinomycin D, etoposide, 5-fluorouracil, vinblastine and vindesine but not in adriamycin, daunomycin, melphalan, nimustine and ranomustine were observed. The former and the latter were classified as schedule dependent drugs and a schedule independent drugs, respectively. In this study, the schedule dependency of in vitro drug response appears to be related mainly to time-dependency and partially to other factors, such as stability during culture in medium.

Adenocarcinoma↗
PubMed1991

Toxicity of anticancer agents, growth and chemosensitivity of human tumour xenografts in a segregating stock of AF nude mice.

An investigation of the usefulness of a segregating stock of nude mice [AF nude mice (AF-nu)] for screening anticancer agents was undertaken. The toxicity of anticancer agents, takes and growth rates of human tumour xenografts and chemosensitivities of xenografts in AF-nu were studied and compared with those in BALB/cA nude mice (BALB/cA-nu). The results showed differences in the pattern of mortalities of AF-nu and BALB/cA-nu administered a range of anticancer agents. Body weight changes in the two nude mouse strains differed in the case of 5-fluorouracil, but not for nimustine, adriamycin and vincristine. All tumours transplanted in AF-nu grew as in BALB/cA-nu. Growth rates of 2 xenografts (gastric cancer and glioblastoma) were not significantly different between the 2 nude mouse strains, but those of 2 lung tumour xenografts were significantly greater in AF-nu than those in BALB/cA-nu. There were no significant differences in chemosensitivities of human tumours in AF-nu and BALB/cA-nu (consistency rate as evaluated by our criteria was 88%). From these results, it is suggested that AF-nu are more suitable for anticancer agent screening and experimental chemotherapy of human tumour xenografts than BALB/cA-nu because of lower costs and high reproductive rate. Although they are genetically heterogeneous, sets of experimental animals sharing the same gene pool can be produced routinely.

Animals↗
PubMed1999

Dose-related increases in cerebrospinal fluid concentrations of methotrexate in a postoperative patient with glioblastoma.

OBJECTIVE: To investigate the postoperative pharmacokinetics of methotrexate in the plasma and cerebrospinal fluid (CSF) in the space created by tumor removal of a patient with glioblastoma during hyperosmotic disruption of the blood-brain barrier (BBB) and intraarterial chemotherapy with a stepwise increase in the methotrexate dosage. CASE SUMMARY: A 30-year-old Japanese woman with glioblastoma received four courses of hyperosmotic disruption of the BBB and intraarterial chemotherapy with a combination of peplomycin, vindesine, nimustine, pirarubicin, and methotrexate. The patient was initially administered mannitol; anticancer drugs were then infused into the left internal carotid artery. Following the first, second, third, and fourth courses of treatment, methotrexate 350, 700, 1000, and 1500 mg, respectively, were administered for 30 minutes. Samples of blood and CSF from the space created by tumor removal were obtained. Methotrexate concentrations were measured by fluorescence polarization immunoassay and the pharmacokinetic parameters of methotrexate in plasma and CSF were estimated. RESULTS: The plasma concentration of methotrexate peaked at the end of drug infusion, then decreased in a biexponential decay manner during the remainder of the treatment period. The CSF concentration of methotrexate in the space created by tumor removal peaked two hours after drug administration, then monoexponentially decreased. Although the maximal CSF concentration of methotrexate in the space created by tumor removal was lower than that in the plasma, the CSF concentration of methotrexate in the space created by tumor removal exceeded that in the plasma six hours after drug infusion. The half-life of methotrexate in the CSF exceeded that in the plasma. The AUC for the plasma and CSF methotrexate concentration increased parallel with the methotrexate dosage. The mean CSF AUC of methotrexate was 59.4% of that found in plasma. CONCLUSIONS: The CSF AUC of methotrexate in the space created by tumor removal increased parallel with the methotrexate dosage during hyperosmotic disruption of the BBB and intraarterial chemotherapy.

Adult↗
PubMed1995

[Different effects of anticancer drugs on two human thyroid cell lines with different stages of differentiation].

We established two human thyroid tumor cell lines. One cell line (hPTC) was established from the tissue of a papillary thyroid carcinoma surgically excised from a 27-year-old female patient. The other cell line (hAG) was established from the tissue of an adenomatous goiter excised from a 59-year old female patient. Synthesis of cAMP by hPTC and hAG increased when they were stimulated by TSH. hPTC and hAG continued to divide as a monolayer in a tissue culture for three years and two years, respectively. We assessed the efficacy of anticancer drugs (doxorubicin:ADR, cisplatin:CDDP, nimustine:ACNU, bleomycin:BLM, cyclophosphamide:CPA, aclarubicin:ACR) with resard to hPTC. The hPTC cells were cultured in 24-well plates in the presence of the anticancer drugs for 48 hours, and the cellular DNA of the live cells was measured with diaminobenzoic acid. ADR had the lowest ED50 (0.029 mu g/ml) and the clinical blood concentration was 13.8 times that of the ED50. The clinical blood concentration divided by ED50 for the other anticancer drugs are, in order of higher values, 2.3 for CPA, 1.7 for BLM, 1.2 for CDDP, 0.5 for ACR, and less than 0.1 for ACNU. ADR showed time-independent effects since a 2-hour exposure of ADR to the hPTC cells resulted in the significant reduction of the cellular DNA content of the live cells even after 48 hours. The effects of the other anticancer drugs were time-dependent. We then studied the difference of the effects of ADR on hPTC and hAG. ED50 for hPTC was significantly low (0.035 mu g/ml) compared to that for hAG (0.460 mu g/ml). Since free radical formation is one of the major anticancer mechanisms of ADR the effects of free radicals on ED50's for hPTC and hAG were measured by adding glutathione (GSH), N-acetylcystein (NAC), buthionine sulfoximine (BSO), and alpha-tocopherol (alpha-toco) into the culture media. GSH catches up with free radicals in the extracellular fluid. NAC promotes production of GSH in the cytoplasm, but BSO interferes with the production of GSH in the cytoplasm. alpha-toco catches up with free radicals on the plasma membrane. GSH and alpha-toco did not effect ED50 for hPTC and hAG. However, NAC increased ED50 for hPTC and hAG, and BSO reduced ED50 for hPTC and hAG. The effects of NAC and BSO on ED50 for hPTC were greater than those for hAG.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenoma↗