Relationship between antitumor effect and metabolites of 5-fluorouracil in combination treatment with 5-fluorouracil and guanosine in ascites sarcoma 180 tumor system.

The antitumor activity of 5-fluorouracil (FUra) against ascites Sarcoma 180 was significantly enhanced by coadministration of guanosine, and slightly by adenosine, but not by cytidine or uridine. In advanced ascites Sarcoma 180, guanosine also enhanced the action of FUra, but adenosine, uridine, and cytidine did not. The potentiation of antitumor activity by guanosine was reversed by addition of cytidine.

Potentiation of the chemotherapeutic effect of 5-fluorouracil by combination with guanosine 5'-monophosphate.

The chemotherapeutic effect of the 5-fluorouracil (5-FU)-guanosine 5'-monophosphate (GMP) combination in various mouse tumor systems was compared with that of 5-FU monotherapy. Antitumor activity of 5-FU against L-1210 leukemia was potentiated without increasing its toxicity to the host when GMP at 30-100 mg/kg/day was injected simultaneously with 5-FU. Any time interval between the administrations of 5-FU and GMP diminished the increase in survival.

Effect of pyrimidines, purines and their nucleosides on antitumor activity of 5-fluorouracil against L-1210 leukemia.

The chemotherapeutic action of 5-fluorouracil (5-FU) monotherapy on L-1210 leukemia in mice was compared with combinations of pyrimidines (uracil, uridine, deoxyuridine, cytosine, cytidine, deoxycytidine, thymine and thymidine) or purines (adenine, adenosine, deoxyadenosine, guanine, guanosine, deoxyguanosine and inosine) with 5-FU. The antitumor activity of 5-FU was enhanced by coadministration of uracil, thymine or guanosine, but the toxicity of the first two compounds was also enhanced. Only when 5-FU was administered with guanosine, was not only the antitumor activity but also the therapeutic ratio potentiated without increasing its toxicity.

Antitumor activity of 1-acyloxymethyl derivatives of 5-fluorouracil against L1210 leukemia.

Antitumor activity of 15 1-acyloxymethyl derivatives of 5-fluorouracil was examined by both intraperitoneal injection and oral administration in L1210 leukemia system. Therapeutic ratio for dodecanoyloxymethyl derivative by intraperitoneal injection was 23 which was greater than that for 5-fluorouracil (11). On the other hand, undecanoyloxymethyl derivative of 5-fluorouracil showed the highest therapeutic ratio (5.

Murine lymphoma L5178Y cells resistant to purine antagonists: differences in cross-resistance to thioguanine-platinum(II) and selenoguanine-platinum(II).

To determine whether the antitumor activities of thioguanine-platinum(II) [TG-Pt(II)] and selenoguanine-platinum(II) [SeG-Pt(II)] are due to direct actions of these compounds or to the actions of their hydrolysis products, studies were made on a purine antagonist-resistant, murine lymphoma L5178Y/MP subline that lacked the anabolic enzyme hypoxanthine-guanine phosphoribosyltransferase necessary for tumor inhibition. The L5178Y/MP subline proved to be highly resistant to both TG-Pt(II) and thioguanine; the resistance ratios to the two compounds were almost identical. The subline showed high resistance to selenoguanine, but the cross-resistance to SeG-Pt(II) was negligible.

Antitumor activity of alkyldisulfide derivatives of 6 mercaptopurines against L-1210 leukemia.

Antitumor activity of twenty seven 6-alkyl disulfide derivatives of 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) were examined in the system of murine L-1210 leukemia. When given by intraperitoneal administration, maximum increase in life span produced by iso-pentyl (75%) and heptyl (68%) disulfides of 6-MP and sec-butyl (83%), pentyl (78%), and naphthyryl (90%) disulfides of 6-TG were higher than that of parent compounds (6-MP: 53%, 6-TG: 64%). Compounds with higher therapeutic ratio than respective parent compound were decyl and naphthyryl disulfide derivatives of 6-MP and almost all the derivatives of 6-TG tested (propyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, decyl, benzyl, and naphthyryl disulfides of 6-TG).

Excretion of 1-hexylcarbamoyl-5-fluorouracil in urine of mice.

Excretion and metabolites in urine and feces of mice after oral administration of l-hexylcarbamoyl-5-fluorouracil-6-14C (14C-HCFU) or 5-fluorouracil-6-14C (14C-FU) were examined. After oral administration, about 90% of 14C-HCFU was excreted in urine within 48 h but not in feces. Major radioactive compounds in urine were 1-(3-carboxypropylcarbamoyl)-5-fluorouracil (CPRFU), FU, 5, 6-dihydro-5-fluorouracil (DHFU) and alpha-fluoro-beta-alanine (FBAL).

Antitumor activity of 1-alkoxycarbonylalkylcarbamoyl-5-fluorouracil derivatives by oral administration.

Antitumor activity of seven 5-fluorouracil derivatives having carbamoyl linkage with amino acid was examined against L-1210 leukemia, adenocarcinoma 755, ascites sarcoma 180, Ehrlich ascites carcinoma and Lewis lung carcinoma by oral administration. These compounds showed more than 30% increase in life-span (ILS) against L-1210 at optimal doses when given by oral administration. Therapeutic ratios (ILSmax/ILS30) of 1-methoxycarbonylmethylcarbamoyl and 1-(1-ethoxycarbonyl-3-methylthiopropylcarbamoyl) derivatives of 5-fluorouracil in L-1210 system were 4.

Metabolic fate on 1-hexylcarbamoyl-5-fluorouracil and 5-fluorouracil in mice bearing ascites sarcoma 180.

Patterns of metabolism and disposition in plasma of tumor-bearing mice after oral administration of [6(-14)C]1-hexylcarbamoyl-5-fluorouracil ([6(-14)C]HCFU) resembled those in plasma of normal mice, but elimination of [6(-14)C]HCFU and 5-fluorouracil (FUra) was slower in tumor-bearing mice. The level of 1-(5-hydroxyhexylcarbamoyl)-5-fluorouracil (HHCFU) was lower in tumor-bearing mice. Also detected in plasma were [6(-14)C]HCFU, HHCFU, 1-(3-carboxypropylcarbamoyl)-5-fluorouracil, FUra, 5,6-dihydro-5-fluorouracil, and alpha-fluoro-beta-alanine.

Structure-antitumor activity relationship of purin-6-yl alkyl disulfides.

Antitumor activity and toxicity to host of newly synthesized disulfide derivatives of 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) were examined in murine ascites sarcoma-180 system (total packed cell volume method) by parenteral administration. The compounds tested were 6-alkyl disulfides (carbon number of alkyl group: 2, 3, 4, 5, 6, 7, 8, 10, and 14), 6-branched-alkyl disulfides (iso-propyl, sec-butyl, and tert-butyl), and 6-aralkyl disulfide (naphthyryl). Most disulfide derivatives of 6-MP and 6-TG showed higher antitumor activity (lower ED50) and higher toxicity to host (lower LD50) than parent compounds, but ratios of increase in activity and toxicity were different with each other.

Antitumor activity of 3',5'-diesters of 5-fluoro-2'-deoxyuridine against murine leukemia L1210 cells.

Antitumor activity of several 3',5'-diesters of 5-fluoro-2'-deoxyuridine (FUdR) against L1210 leukemia cells following intraperitoneal administration was examined. Esters of FUdR with aromatic acid or aliphatic acid of longer chain length were markedly active. Their activities, with respect to ILS30, were as much as 100 times that of unesterified FUdR.

Metabolic fate of 1-hexylcarbamoyl-5-fluorouracil after oral administration in mice.

1. The metabolic fate of a new antitumour agent, 1-hexylcarbamoyl-5-fluoro[6-14C]uracil (14C-HCFU) was compared with that of 5-fluoro[6-14C]uracil (14C-FU) after oral administration to mice. 2.

Effect of 1-hexylcarbamoyl-5-fluorouracil on spontaneous mammary adenocarcinoma of mice.

The antitumor activity of 1-hexylcarbamoyl-5-fluorouracil (HCFU) in various schedules of long-term oral administration was examined in spontaneous mammary adenocarcinoma of SHN mice, an autochthonous tumor system. In the control group, the average time to local recurrence and average longevity after surgical intervention were 21 and 48 days, respectively. Oral administration of HCFU at 200 approximately 300 mg/kg/day, 3 times a week for 5 consecutive days every 2 or 3 weeks was markedly effective against the adenocarcinoma.

Antitumor activity of metabolites of 1-hexylcarbamoyl-5-fluorouracil and related compounds against L1210 leukemia in vivo and L5178Y lymphoma cells in vitro.

Antitumor activity of metabolites of 1-hexylcarbamoyl-5-fluorouracil (HCFU) and related compounds was examined in vivo and in vitro. Carboxypentyl and carboxypropyl carbamoyl derivatives of 5-fluorouracil (FU) were moderately active against L1210 by oral administration but less active by intraperitoneal administration. However, 5-hydroxy- and 5-oxo-hexylcarbamoyl derivatives of FU were markedly or moderately active against the leukemia by both oral and intraperitoneal administrations.

Isolation and characterization of the murine lymphoma L5178Y cell line highly resistant to 5-fluorouracil.

5-Fluorouracil-resistant cell line designated as L5178Y/FU was established in this experiment. This is one of the colonies derived from the subculture which acquired resistance to 5-fluorouracil by passing the L5178Y cells through ten successive episodes of culture in Fischer's medium containing 5-fluorouracil, in which each 5-fluorouracil treatment was followed by recovery intervals. The resistance of this line is about 80-fold that of the IC99 of 5-fluorouracil, and also shows a cross resistance to both 5-fluorouridine and 5-fluoro-2'-deoxyuridine.

The difference in mechanism of action of 5-fluorouracil and its nucleosides in L5178y cells.

The mechanism of antitumor activity of 5-fluorouracil (FU) was studied in mouse leukemia L5178Y cells in vitro. FU increased labeled-thymidine incorporation into acid-insoluble fraction and inhibited labeled-deoxycytidine incorporation as did 5-fluorouridine (FUR) and 5-fluoro-2'-deoxyuridine (FUdR). FU and FUR inhibited labeled-uridine incorporation but FUdR did not.

Pharmacokinetics of 1-alkylcarbamoyl-5-fluorouracils in plasma and ascites fluid after oral administration in mice.

Pharmacokinetics of 1-alkylcarbamoyl-5-fluorouracils was examined in mice bearing sarcoma 180. The alkylcarbamoyl derivatives were absorbed rapidly as intact form through the gastrointestinal tract and distributed into ascites fluid. Concentration-x-time (C-x-t) values of 5-fluorouracil formed in plasma and ascites fluid decreased in order by extension of the carbon chain of the alkyl moiety.

Inhibition of phosphoribosylation of 5-fluorouracil by purines.

The mechanism of the reversal of 5-fluorouracil cytotoxicity in L5178Y cells by hypoxanthine, adenine and inosine was examined in a cell-free system. A crude extract of the cells possessed high hypoxanthine and adenine phosphoribosyltransferase and purine nucleoside phosphorylase activities. Hypoxanthine (2 mM), adenine (5 mM) and inosine (5 mM) inhibited the nucleotide formation from 5-fluorouracil at 0.

Mechanism of cytotoxicity of 5-fluorouracil: distinction between the irreversible cytotoxic effect of 5-fluorouridine and the reversible cytotoxic effect of 5-fluoro-2'-deoxyuridine on murine lymphoma L5178Y cells in culture.

To determine the relative importance of the DNA and RNA effects in the cytotoxicity of 5-fluorouracil, we determined the effects of brief exposure to 5-fluorouridine and 5-fluoro-2'-deoxyuridine, compared with 5-fluorouracil, on the subsequent growth of murine lymphoma L 5178 Y cells during prolonged incubations following the removal of the drug from the culture medium. 5-Fluoro-2'-deoxyuridine markedly inhibited cell proliferation by continuous exposure. However, its inhibitory effect by exposure even at 1,000 muM for 1 h easily disappeared within 1 week after removal of the drug from the culture medium.