[Sunrabin for injection].
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Acute Disease↗
Biomedical subjects
S Tsukagoshi
Publications and source records attributed to S Tsukagoshi.
Characterization of metastatic clones derived from a metastatic variant of mouse colon adenocarcinoma 26.
A spontaneously metastatic variant (P-26-select) was selected from the murine colon adenocarcinoma 26 after repeated (26 times) cyclic in vivo passage of tumor cells from the lungs of mice bearing s.c. tumors. Clones were established from the cultured P-26-select cell line. These clones, the parent [P-no-select (culture cell line of colon 26 without in vivo selection)] and the metastatic variant (P-26-select) were then studied using three different assays to determine their metastatic potential. These assays included experimental metastasis, spontaneous metastasis from a nonresected s.c. growing tumor, and spontaneous metastasis following the resection of a primary footpad tumor. In general, there was an agreement among the results of these three assays of metastases, i.e., if a variant was spontaneously metastatic, it was also metastatic in the other assays of metastases. However, some experimentally metastatic clones did not necessarily show a high spontaneous metastatic potential to the lung. These results might indicate that the metastatic variant (P-26-select) is populated by spontaneously metastatic clones and also by clones which possess a propensity to metastasize experimentally. The morphology and growth properties of the clones were compared also.
Adenocarcinoma↗
Optimal treatment schedule and antitumor spectrum of 4-carbamoylimidazolium 5-olate (SM-108) in murine tumors.
By designing optimal administration schedules, it was found that 4-carbamoylimidazolium 5-olate (SM-108) showed an excellent antitumor potency against a number of murine tumors. The optimal administration schedule of SM-108 was an intermittent multiple administration, in which the drug was multiply administered to mice at definite intervals of less than 3 hr for about 1 day on Days 1, 5, and 9 following tumor implantation. Although usual daily administration of SM-108 exhibited poor efficacy, the intermittent multiple administration of SM-108 exhibited potent antitumor activity against a wide variety of tumors, such as Ehrlich carcinoma, P388, 6-mercaptopurine-sensitive and -resistant L1210, Lewis lung carcinoma, Colon 26 adenocarcinoma, and Sarcoma 180. Among them, Ehrlich carcinoma showed the most prominent susceptibility to SM-108. With the intermittent multiple administration of SM-108, complete suppression was obtained in both the ascitic and solid forms of this tumor over a wide dose range. The schedule dependency of the antitumor effect of SM-108 described above was reasonably explained by its in vitro growth-inhibitory effects and pharmacokinetics in the mice.
Animals↗
Vincristine-resistant P388 leukemia cells contain a large amount of calcium.
P388 leukemia cells resistant to vincristine contained more calcium in the cells than the parent sensitive line, especially in the form of EGTA-removable (surface-bound) calcium. Although the relationship, if any, between the high cellular calcium of resistant cells and drug-resistant phenotype is not clear, the possible implications of this result for the elucidation of the mechanisms of drug resistance are interesting.
Animals↗
Potentiation of vincristine and Adriamycin effects in human hemopoietic tumor cell lines by calcium antagonists and calmodulin inhibitors.
verapamil, a calcium-influx blocker, enhanced the cytotoxicity of vincristine (VCR) in vitro 6- to 12-fold in eight human hemopoietic tumor cell lines established from acute lymphatic leukemia, acute myelogenous leukemia, and Burkitt's lymphoma. Great enhancement of VCR cytotoxicity was obtained in a VCR-resistant subline of K562 myelogenous leukemia. A maximum of approximate 100-fold increase in VCR cytotoxicity occurred. Heterogeneity in VCR sensitivity (80-fold difference in sensitivity) was observed in vitro among these human tumor cells. BALL and Daudi cells of B-cell type were more susceptible to VCR. At 6.6 or 20 microM of verapamil, the values for the concentration of drug required for 50% inhibition of cell growth for each cell line fell into a rather narrow range, and heterogeneity in VCR sensitivity among cell lines was circumvented in vitro. Verapamil also enhanced the cytotoxicity of Adriamycin, although the extent of enhancement was considerably small. Enhancement of VCR cytotoxicity also occurred with other calcium antagonists and calmodulin inhibitors. At maximum effective concentration of these reagents, a 3- to 5-fold increase in VCR cytotoxicity occurred in K562 cells. In VCR-resistant K562 cells, a more prominent enhancement (20- to 45-fold) was observed with these reagents. VCR resistance was circumvented in vitro. The mechanism of enhancement of VCR cytotoxicity was explained by the enhanced accumulation of VCR in K562, especially in resistant cells.
Calcium↗
Promotion by verapamil of vincristine responsiveness in tumor cell lines inherently resistant to the drug.
Cultured cell lines LL, B16, C26, and C38 established from mouse solid tumors of Lewis lung carcinoma, B16 melanoma, and colon adenocarcinomas 26 and 38, respectively, showed inherently different resistance to vincristine (VCR) in vitro. The inherent resistance to VCR of these cell lines was related to the ability of the cells to accumulate VCR. Verapamil, a calcium antagonist with coronary vasodilator activity, enhanced the cytotoxicity of VCR against these cell lines depending upon their susceptibility to VCR. C26 cells, the most resistant, became the most susceptible to VCR with a nontoxic dose of verapamil. A 12-fold increase in VCR cytotoxicity occurred. Only a 2.5-fold increase in VCR cytotoxicity was observed for B16 cells, the most sensitive cells. VCR cytotoxicity against each cell line reached almost the same level by verapamil (2.2 to 6.6 microM). Thus, the inherent resistance to VCR among the tumor lines was circumvented. Verapamil enhanced the cellular accumulation of VCR. A 3- to 4-fold increase in cellular VCR occurred in C26 cells, while approximately a 2-fold increase was observed for B16 and LL cells. A similar rate of enhancement was observed for both bound and free VCR, indicating that verapamil does not enhance the affinity of VCR to tubulin. Verapamil inhibited the outward transport of VCR from the cells. The most prominent inhibition was observed for C26 cells. Circumvention of inherent resistance of tumor cells to VCR by verapamil could be attained through an enhanced cellular accumulation of VCR in each of the tumor cells. The enhancement of VCR cytotoxicity and circumvention of inherent VCR resistance by verapamil could be explained by the cellular concentration of VCR, and also it might be related to the extent of VCR binding to tubulin in the cell. The chemotherapeutic effect of VCR is significantly enhanced by verapamil in colon adenocarcinoma 26-bearing mice.
Adenocarcinoma↗
Circumvention of vincristine and Adriamycin resistance in vitro and in vivo by calcium influx blockers.
Calcium influx blockers, diltiazem, nicardipine, nifedipine, niludipine, and nimodipine, which possess coronary vasodilator activity, greatly enhanced the cytotoxicity of vincristine (VCR) in tumor cells and especially in VCR-resistant sublines of P388 leukemia (P388/VCR) and human K562 myelogenous leukemia. The extent of enhancement was different among the drugs, and up to a 50- to 70-fold increase in VCR cytotoxicity occurred in P388/VCR cells with nontoxic or marginally toxic concentrations of diltiazem and nicardipine. A 50- to 100-fold enhancement occurred in VCR-resistant human K562 myelogenous leukemia cells with diltiazem, nicardipine, niludipine, and nimodipine. VCR resistance of these cell lines was circumvented completely by these blockers. Calcium influx blockers also enhanced the cytotoxicity of Adriamycin in P388 leukemia cells and especially in its Adriamycin-resistant subline. The extent of enhancement, however, was lower than that which occurred in VCR-resistant tumor lines with VCR. An approximately 10- to 30-fold increase in Adriamycin cytotoxicity occurred in P388 Adriamycin-resistant subline cells with diltiazem, nicardipine, niludipine, and nimodipine. Although VCR alone at 10 to 200 micrograms/kg did not confer a significant therapeutic effect in P388/VCR-bearing mice, calcium influx blockers in doses of 30 to 125 mg/kg administered daily for 10 days with VCR enhanced the chemotherapeutic effect of VCR in P388/VCR-bearing mice. A maximum of approximately a 40 to 50% increase in life span occurred with diltiazem, nicardipine, niludipine, and nimodipine. The calcium influx blockers also enhanced the therapeutic effect of Adriamycin in P388 Adriamycin-resistant subline-bearing mice, although the extent of enhancement was smaller than that observed with VCR in P388/VCR-bearing mice.
Animals↗
Enhancement of vincristine- and adriamycin-induced cytotoxicity by verapamil in P388 leukemia and its sublines resistant to vincristine and adriamycin.
A calcium antagonist, verapamil, enhanced the cellular uptake and cytotoxicity of vincristine (VCR) in adriamycin-resistant P388 leukemia (P388/ADM) cells and also enhanced the cellular uptake and cytotoxicity of adriamycin (ADM) in vincristine-resistant P388 leukemia (P388/VCR) and P388/ADM cells. The enhancement of cytotoxicity and cellular uptake of VCR in P388 and P388/VCR cells has been reported previously. [1]. VCR and ADM resistance was circumvented by verapamil. A common transport mechanism for VCR and ADM, which is responsive to verapamil, seems to exist in VCR- and ADM-resistant cells. However, the enhancement of ADM cytotoxicity and cellular uptake by verapamil was not evident in P388 cells.
Animals↗
New antitumor imidazole derivative, 5-carbamoyl-1H-imidazol-4-yl piperonylate, as an inhibitor of purine synthesis and its activation by adenine phosphoribosyltransferase.
The mechanism of action of 5-carbamoyl-1H-imidazol-4-yl piperonylate (SL-1250), which has a broad antitumor spectrum, was examined by in vitro cell culture and enzymatic studies. In the serum-containing culture medium, SL-1250 was rapidly deacylated to 4-carbamoylimidazolium 5-olate (SM-108). Thus, SL-1250 might be acting on the cells in the form of SM-108. The growth of L5178Y cells was completely inhibited by 10(-5) M SL-1250. It should be noted that this growth inhibition was significantly reversed in the presence of equimolar concentrations of guanine, guanosine, or guanosine 5'-monophosphate to those of SL-1250. However, hypoxanthine and xanthine were not effective. These effects of purine addition were observed to be quite similar in growth inhibition by SM-108. It was found that inosine 5'-monophosphate dehydrogenase (EC 1.2.1.14; IMP dehydrogenase), a key enzyme of de novo purine synthesis, from Ehrlich carcinoma cells was inhibited by SM-108 only when 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) and MgCl2 coexisted with SM-108. In contrast, a chemically synthetic ribonucleotide of SM-108 inhibited IMP dehydrogenase without PRPP and MgCl2, and the mode of inhibition was competitive with the Ki value of 2 x 10(-8) M. On the other hand, the inhibition of either growth of L5178Y cells or IMP dehydrogenase in the presence of PRPP and MgCl2 by these compounds was reversed by adenine. A nucleotide of SM-108 was chromatographically identified when [14C]SM-108 was incubated in the enzyme solution with PRPP and MgCl2. This conversion by enzyme was also inhibited by adenine. Viewed together, these results strongly suggest that SL-1250 is, after being converted to SM-108, activated to its nucleotide form by adenine phosphoribosyltransferase (EC 2.4.2.7) and that this SM-108 nucleotide blocks de novo synthesis of guanosine 5'-monophosphate by inhibiting IMP dehydrogenase.
Adenine Phosphoribosyltransferase↗
Different susceptibilities of cultured mouse cell lines to mouse interferon.
Cultured mouse cells were treated with 3.3 approximately 10,000 units of mouse interferononon for 3 days and further cultivated in fresh medium for 2 days (recovery incubation). The IC50 (concentration of drug required for 50% inhibition) of interferon was not changed much after the recovery incubation. The most susceptible cell line to interferon was B16 melanoma; the IC50 was 10.5 units per ml of medium on day 3 after the start of treatment. P388 leukemic cells, Lewis lung carcinoma cells, and colon adenocarcinoma 38 cells were moderately susceptible to interferon and the IC50s of these cell lines were 200, 80, and 180 units per ml medium, respectively, on day 3. The cells least susceptible to interferon were those of colon adenocarcinoma 26; IC50 was greater than 10,000 units per ml. In the recovery incubation, the growth of B16 melanoma cells, P388 leukemic cells, Lewis lung carcinoma cells and colon adenocarcinoma 38 cells was considerably inhibited when these cells were treated with more than 100 approximately, 1,000 units of interferon per ml medium. The rate of multiplication was usually more than 1 for these cell lines, except for Lewis lung carcinoma cells where the rate of multiplication was less than 1. This indicates that interferon is not cytocidal towards B16 melanoma cells, P388 leukemic cells, or colon adenocarcinoma 38 cells, but mouse interfer is cytocidal towards Lewis lung carcinoma cells when the cells are treated with a relatively high concentration of interferon and then cultured in the medium without interferon.
Adenocarcinoma↗
Collateral sensitivity of 6-mercaptopurine-resistant sublines of P388 and L1210 leukemia to the new purine antagonists, 5-carbamoyl-1H-imidazol-4-yl piperonylate and 4-carbamoylimidazolium 5-olate.
Two new purine antagonists, 5-carbamoyl-1H-imidazol-4-yl piperonylate (SL-1250) and 4-carbamoylimidazolium 5-olate (SM-108), were investigated for their antitumor activities against 6-mercaptopurine (6-MP)-resistant sublines of P388 and L1210 leukemia. It was found that both resistant sublines exhibited collateral sensitivity instead of cross-resistance to these new antipurine drugs. Since more potent cytotoxic activities of these drugs against 6-MP-resistant cells were observed even in vivo cell culture systems, this collateral sensitivity was proved on a cellular basis. Biochemical studies revealed that 6-MP-resistant sublines of both P388 and L1210 leukemia are deficient in hypoxanthine-guanine phosphoribosyltransferase activity. In these cells, not only the activation of 6-MP to its nucleotide but also the synthesis of guanosine 5'-monophosphate via the salvage pathway seems to be severely restricted. However, SL-1250 and SM-108 can be activated to their nucleotide even in these 6-MP-resistant cells because the activation of these compounds is proceeded by adenine phosphoribosyltransferase. In conclusion, suppression of de novo purine synthesis with SL-1250 and SM-108 seems to be a very efficient means of killing these 6-MP-resistant cells, which lack a salvage pathway for guanosine 5'-monophosphate.
Animals↗
[Immunohistological study of the localization of hepatitis B virus associated antigens in human pancreatic tissue (author's transl)].
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Adolescent↗
4'-O-tetrahydropyranyladriamycin as a potential new antitumor agent.
Chemotherapy with 4'-O-tetrahydropyranyladriamycin (THP-ADM), a new derivative of Adriamycin, was equally or more effective against several experimental mouse tumors than it was with Adriamycin (ADM). When mice with P388 leukemia were given i.p. injections of THP-ADM or ADM daily for 9 consecutive days, the maximum increases in life span (ILSs) of the mice were 190 and 175%, respectively. Eight of 24 mice treated with THP-ADM were free of tumor, while one of 24 mice treated with ADM was free of tumor. A single i.p. injection of either drug was also effective; maximum ILS was 170% for mice treated with THP-ADM and 240% for those treated with ADM. Nine of 12 mice were found to be free of tumor. THP-ADM was equally or slightly more effective against P388 leukemia than was ADM when either drug was given i.v. The maximum ILS was 106% with THP-ADM and 77% with ADM when the drug was given for 9 consecutive days. Single i.v. injections of THP-ADM or ADM were almost equally (ILS, 100%) effective. Chemotherapy with THP-ADM was also very effective against L1210 leukemia. THP-ADM administered i.p. five times, every other day starting from Day 1, was more effective than ADM was against Lewis lung carcinoma, B16 melanoma, and colon adenocarcinoma 38 inoculated s.c. In the study with Lewis lung carcinoma, metastasis to the lungs was well suppressed by THP-ADM. ADM was more effective than was THP-ADM against colon adenocarcinoma 26. Because THP-ADM was more cytotoxic than or almost equally as cytotoxic as ADM against the established cell lines from the above mouse tumors, we suggest that THP-ADM is more efficiently transported into cultured cells.
Adenocarcinoma↗
Enzyme catalyzation of the deacylation of N4-acyl derivatives of 1-beta-D-arabinofuranosylcytosine in the mouse liver microsome.
Enzymatic hydrolysis of acylamide of N4-acyl-1-beta-D-arabinofuranosylcytosine was studied. The highest enzyme activity among various homogenates from mouse tissues, as expressed by specific activity, was found in liver homogenate. More than 50% of the activity in the liver was found in the microsomal fraction. The hydrolysis products of N4-palmitoyl-1-beta-D-arabinofuranosylcytosine by microsomal enzyme were identified stoichiometrically as 1-beta-D-arabinofuranosylcytosine and palmitic acid. The microsomal enzyme showed an optimum pH at 9.0 in Tris-HCl buffer. Michaelis constant for N4-palmitoyl-1-beta-D-arabinofuranosylcytosine was 2.5 X 10(-5) M. The enzyme did not require divalent cations for the reaction. Mn2+ and Co2+ at 1 mM strongly inhibited the reaction. The relative rates of hydrolysis of N4-palmitoyl-, N4-stearoyl-, N4-lauroyl-, N4-butyryl-, and N4-behenoyl-1-beta-D-arabinofuranosylcytosine were 100, 47.6, 31.3, 15.9, and 9.1, respectively. The enzyme might play an important role in the formation of 1-beta-D-arabinofuranosylcytosine from N4-acyl derivatives of 1-beta-D-arabinofuranosylcytosine.
Amidohydrolases↗
Increased accumulation of vincristine and adriamycin in drug-resistant P388 tumor cells following incubation with calcium antagonists and calmodulin inhibitors.
Some calcium antagonists and calmodulin inhibitors enhance the intracellular levels of vincristine and Adriamycin in vincristine- and Adriamycin-resistant P388 leukemia cells by inhibiting their outward transport. The high intracellular drug accumulation was directly related to the enhancement of the cytotoxicity of the antitumor agents, and the vincristine and Adriamycin resistance in these cells was circumvented.
Animals↗
Restored in vitro sensitivity of adriamycin- and vincristine-resistant P388 leukemia with reserpine.
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Animals↗
Prevention of vinblastine-induced cytotoxicity by ruthenium red.
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Calcium-Transporting ATPases↗
Enhancement of vinblastine-induced cytotoxicity by lysolecithin and phosphatidylinositol.
Vinblastine inhibited the growth of cultured KB cells 3 days after drug treatment by 55% and 67% at 2.7 ng/ml and 3.5 ng/ml of the medium, respectively. Lysolecithin and phosphatidylinositol showed only a marginal inhibitory effect on the growth of KB cells at respective concentrations of 35-125 microgram/ml and 50-150 microgram/ml of the medium. Lysolecithin, however, enhanced the cytotoxicity of vinblastine. Depending upon the concentrations of lysolecithin (35-125 microgram/ml), the growth of KB cells was inhibited by 60-91% and 86-98% at respective vinblastine concentrations of 2.7 ng/ml and 3.5 ng/ml. Enhancement of vinblastine-induced cytotoxicity also occurred similarly for phosphatidylinositol. The mechanism could be explained partly by an elevated amount of intracellular vinblastine. Other possible mechanisms can only be speculated.
Cells, Cultured↗