Evaluation of naphthalmustine, a nitrogen mustard derivative of naphthalimide as a rationally-designed anticancer agent

Naphthalmustine, 2-[2-[bis-(2-chloroethyl)amino]ethyl]-1H-benz[de]isoquinoline-1,3-dione (Compound 1) has been synthesized as a rationally designed new anticancer agent from N-(2-bromoethyl)naphthalimide. Its chemical alkylating activity exceeded that of nor-HN2 used as standard compound for comparison. Its antitumour efficacy was assessed in vivo in two murine ascites tumours namely Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) by measuring the increase in median survival times (MST) of drug treated (T) over untreated control (C) mice. The clinical drug cyclophosphamide and the experimental compound mitonafide were used as positive controls for comparison. Compound 1 has displayed substantial and reproducible antitumoural activity in these tumours since very high remission times of treated animals were observed. Significant increase in the life span of mice bearing highly advanced tumour for 10 days before the drug challenge was also noted after its treatment. Its LD50 value was 200 mg/Kg by single i.p. injection. Its toxicity was also assessed in vivo in normal and in S-180 bearing mice by measuring drug-induced changes in hematological parameters, femoral bone marrow and splenic cellularity sequentially on days 9, 15 and 21 following drug treatment at the optimum dose of 12 mg/kg from day 1 to 7. The results indicated that the compound did not adversely affect hematopoiesis. Drug-induced hepatotoxicity and nephrotoxicity were also evaluated on those days but no such toxicities were detected. Naphthalmustine inhibits the synthesis of DNA and RNA in S-180 tumour cells. It was further screened in vitro in 4 different human tumour cell lines but no significant activity was observed in those lines.     

Evaluation of beta-tethymustine, a new anticancer compound, in murine tumour models

beta-Tethymustine, 1-[2- {bis(2'-chloroethyl)amino}ethyl]spiro[imidazolidine-4,2'-(1'H),3',4'-dihydronaphthalene]-2,5-dione, has been synthesised and LD50 value determined in Swiss male mice, which was found to be 100.00 mg/kg by single i.p. injection. The following three criteria, namely ascites cell count, ascites fluid measurement and increase in median survival times (MST) of drug-treated (T) over untreated control (C) mice, were studied for evaluation of its antitumour efficacy in vivo in three murine ascites tumours, namely Ehrlich ascites carcinoma (EAC), sarcoma-180 (S-180) and Dalton's lymphoma (DL). At the optimum dose range of 8.0 mg/kg (higher) to 4.0 mg/kg (lower) for 1-7 days treatment following tumour transplantation on day 0, it exhibited a very high percentage of inhibition of both the ascites cell and fluid in these models and displayed excellent ILS(max) value of 80 in EAC, 224 in S-180 and 240 in DL, respectively, showing 'curative' effect (2-3/6 mice having 90 days survival rate). It also demonstrated a high ILS value of 150 with one cure/six mice bearing S-180 for 6 days prior to drug therapy. Screening results were compared with two clinical drugs, cyclophosphamide and 5-fluorouracil, serving as positive controls. Its chemical alkylating activity was compared with nor-HN2 (NSC 10873) and spiromustine (NSC 172112). The results indicate that it possesses greater alkylating activity than nor-HN2 and comparable activity with spiromustine.     

Antitumor activity of Nitronaphthal-NU, a novel mixed-function agent

Nitronaphthal-NU (Compound 1) was synthesized as a mixed-function antitumor agent based on the structures of the clinical drug CCNU and experimental compound Mitonafide. In vitro screening in four human tumor cell lines namely SNB-78 CNS, HOP-62 Lung, T47D Breast and SiHa - cervix revealed significant cytotoxicity in the former two cell lines much greater than CCNU and comparable to Mitonafide used as standards. In vivo antitumoral potency assessed in the murine ascites tumors Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) by measuring the increase in median survival times of drug treated (T) over untreated control (C) mice, revealed highly significant (p<0.001) tumor regression effects greater than standards. Life span of mice bearing advanced tumor for 10 days before the drug challenge was also considerably increased. Its toxicity was assessed in vivo in normal and S-180 bearing mice by measuring drug-induced changes in haematological parameters, femoral bone marrow and splenic cellularities as well as hepatotoxicity and nephrotoxicity sequentially on days 9, 15 and 21 following drug treatment at the optimum dose of 50 mg/kg from day 1 to 7. Results indicate that it did not adversely affect haematopoiesis. The other parameters were within normal limit. The compound comparable to standards inhibited the synthesis of DNA and RNA in S-1 80 tumor cells.     

Evaluation of dimethoxydop-NU as a novel anti-tumor agent

Dimethoxydop-NU, 1-[2-{3-(2-Chloroethyl)-3-nitrosoureido}ethyl]-3,4-dimethoxy-benzene (Compound 1), was synthesized from 3,4-dimethoxy-phenethylamine as a novel anti-tumor agent based on the structures of the clinical drug CCNU and dopamine, an important endogenous biological amine having anti-angiogenesis property. In vitro screening in two human tumor cell lines, namely promyelocytic leukemia HL-60 and histiocytic lymphoma U-937, revealed its cytotoxicity greater than that of hydroxyurea and comparable to BCNU used as standards. Its in vivo anti-tumoral potency was assessed in the murine ascites tumors Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) by measuring the increase in median survival times of drug treated (T) over untreated control (C) mice. Results revealed significant tumor regression effects in these tumors. The survival time of treated mice was markedly increased by combination of the compound 1 with dopamine hydrochloride. Its toxicity was assessed in vivo in normal and EAC bearing mice by measuring drug-induced changes in hematological parameters, femoral bone marrow and splenic cellularities as well as biochemical parameters sequentially on days 9, 14 and 19 following drug treatment at the optimum dose of 30 mg/kg from day 1 to 7. Results indicated that initial suppression in the femoral bone marrow cellularity seen on day 9 reached normalcy by day 19. Other parameters were within normal limit. Histopathological studies of liver revealed mild hepatotoxicity on day 9 in treated groups that substantially recovered on day 19. Similar studies with heart and kidney revealed no cardio toxicity or nephrotoxicity. Compound 1 comparable to standards inhibited the synthesis of DNA and RNA in S-180 tumor cells.     

Antitumour activity of saffron (Crocus sativus)

Antitumor activity of saffron (Crocus sativus) extract a commonly used spice in India was studied against intraperitoneally transplanted sarcoma-180 (S-180), Ehrlich ascites Carcinoma (EAC) and Dalton's lymphoma ascites (DLA) tumours in mice. Oral administration of 200 mg/kg body weight of the extract increased the life span of S-180, EAC, DLA tumour bearing mice to 111.0%, 83.5% and 112.5%, respectively. The same extract was found to be cytotoxic to P38B, S-180, EAC and DLA tumour cells in vitro. Thymidine uptake studies indicated the mechanism of action of the extract at the site of DNA synthesis. Toxicity studies showed that the hematological and biochemical parameters were within normal range. These results indicate the potential use of saffron as an anticancer agent.     

Superior antitumour activity of S-1 in tumours with a high dihydropyrimidine dehydrogenase activity

To elucidate the mechanism of the enhanced antitumour activity of S-1 (1 M tegafur, 0.4 M 5-chloro-2, 4-dihydroxypyridine, and 1 M potassium oxonate) in terms of the phosphorylation and degradation pathways of 5-fluorouracil (5-FU) metabolism, we investigated tumoral thymidylate synthase (TS) content, dihydropyrimidine dehydrogenase (DPD) activity, the TS inhibition rate (TS-IR), and 5-FU incorporated into RNA (F-RNA) in four human gastric cancer xenografts (MKN-28, MKN-74, GCIY and GT3TKB) and compared the results obtained with S-1 with those obtained with 5-FU and UFT (1 M tegafur, 4 M uracil). 5-FU was administered intraperitoneally (i.p.) to mice at a dose of 50 mg/kg, three times, on days 0, 4 and 8. S-1 and UFT were administered orally at doses of 10 and 24 mg/kg, respectively, once a day, for 9 consecutive days. Antitumour activity was evaluated as the maximum inhibition of tumour growth in each animal. S-1 showed a better antitumour activity than 5-FU and UFT in tumours with a high DPD activity (GCIY and GT3TKB). There were inverse correlations between the antitumour activity and both TS content and DPD activity in the 5-FU and UFT groups. However, no such correlations were observed in the S-1 group. In GCIY and GT3TKB xenografts, TS-IR was significantly higher in the S-1 group than in the 5-FU or UFT groups. In GT3TKB xenografts, the F-RNA level was significantly higher in the S-1 group than in the 5-FU or UFT groups. The superior cytotoxicity of S-1 appears to be attributable to both an increased inhibition of DNA synthesis and an enhanced blockade of RNA function against tumours with a high DPD activity.     

Classification of anticancer chemotherapeutic drugs according to their immunopotentiating activity

Both melphalan (L-PAM: L phenylalanine mustard) and 5-fluorouracil (5-FU) expressed a cytotoxic effect in vitro on MOPC-315 plasmacytoma tumour cells. However, they differed in their chemotherapeutic effectiveness in BALB/c mice bearing large MOPC-315 plasmacytoma tumours. Therapy with L-PAM, 7.5 mg/kg induced permanent regression of tumours, whereas regression induced by 5-FU, 200 mg/kg, was only transient and the mice dies finally with tumours. Moreover, spleen cells of tumour bearing mice treated with L-PAM exhibited high specific cytotoxic potential in vitro whereas spleen cells from tumour bearing 5-FU treated mice were devoid of cytotoxic potential. Effectiveness of chemotherapy with L-PAM was antagonized by treatment in combination with 5-FU. L-PAM, but not 5-FU potentiated cell mediated contact sensitivity response in vivo and impaired induction of T-suppressor cells by ConA. The parameters mentioned above indicate that L-PAM behaves as an "immunopromoting" drug and 5-FU as a "nonimmunopromoting" drug.     

Three alkaloids as selective destroyers of cancer cells in mice. Synergy with classic anticancer drugs

Alstonine, serpentine and sempervirine, when used at appropriate concentrations cure a relatively important proportion of BALB/C mice inoculated with transplantable YC8 lymphoma ascites cells, as well as Swiss mice bearing Ehrlich ascites carcinoma cells. The development of some solid tumors was only partially prevented. However, when one alkaloid was administered in association with either 5-FU, daunorubicin, 1-(2-chloroethyl) nitrosourea (CCNU) or cyclophosphamide (CP) to mice bearing either ascites carcinoma cells or solid tumors, a high rate of cure was obtained without toxicity. The role of the three alkaloids in the curing of mice and prevention of carcinogenesis is discussed.     

Dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine S-1 may be effective against peritoneal dissemination in gastric cancer

The effects of a novel oral fluoropyrimidine derivative S-1 on peritoneal metastasis from gastric cancer were investigated. OCUM-2MD3 cells, a highly peritoneal-metastatic cell line, were injected intraperitoneally in nude mice. These mice were allocated to the following three groups (each group, n=10): the S-1 group, to which 10 mg/kg body weight of S-1 was administered per os daily; the FT group, to which 100 mg/kg body weight of tegafur (FT) was administered per os daily; the control group, to which no anticancer drug was administered. Drug administration was starting the day after inoculation. The median survival time of the S-1 group was found to be significantly longer than that of the FT group (30 days vs. 23 days; P<0.005) and the control group (vs. 24 days; P<0.005). The mean values of 5-fluorouracil (5-FU) concentrations in ascites of the S-1 group at 1-4 h were 414-580 ng/ml (n=5), and those of FT group were 70-87 ng/ml (n=5), with significant differences between the two groups at each observation time. The high CDHP concentrations in ascites of the S-1 group were observed at 1-6 h after drug administration. DPD was expressed strongly in fibrous tissue around peritoneal metastasis and weakly in tumor cells of peritoneal metastasis themselves. The high concentrations and long duration of 5-FU in the peritoneal cavity after S-1 administration suggest that S-1 may be effective against peritoneal dissemination. High concentrations of CDHP may prevent 5-FU degradation in peritoneal dissemination and its surrounding fibrous tissue.     

Evaluation of toxicity of beta-tethymustine, a new anticancer compound, in mice.

The toxicity of beta-tethymustine, a potential anticancer compound 1 ((Cancer Lett., 119 (1997) 7-12) was assessed in normal as well as in Ehrlich ascites carcinoma (EAC), Sarcoma-180 (S-180) and Dalton' s Lymphoma (DL) tumour-bearing Swiss male mice by measuring drug-induced changes in haematological parameters, femoral bone marrow cellularity and splenic cellularity on days 9, 15 and 21 following drug treatment at the optimum dose of 8.0 mg/kg body weight from days 1 to 7. Detailed studies were also made by noting sequential changes in the above parameters in normal and EAC-bearing mice on days 12 and 18, respectively. The results indicate that the compound did not adversely affect haematopoiesis as it was observed that no significant decrease in haematological parameters and femoral marrow cellularity occurred in treated groups. Initial hyposplenic activity was, however, noted in EAC and normal treated groups on day 9 which soon reached normal count within 7-10 days after termination of drug therapy. Drug-induced hepatotoxicity and nephrotoxicity were also sequentially evaluated in normal and tumour-bearing mice on days 9, 15 and 21 but no such toxicities were detected. Also, body weight, skin and hair texture, and behavioural pattern (food and water intake and activity) did not reflect any toxic reaction in host mice at this optimum dose.     

缩氨基硫脲过渡金属配合物抗癌活性研究

［目的］研究3－硝基苯乙酮缩氨基硫脲（HL）过渡金属配合物的抗癌活性。［方法］测试了配体和6个配合物对S180腹水癌细胞的体外抗癌活性及配合物Cu（L）2、Zn（L）2对S180腹水癌小鼠的生命延长作用和对S180实体瘤的抑制作用。［结果］配合物Cu（L）Cl、Cu（L）2、Zn（HL）2Cl2、Zn（L）2对S180腹水癌细胞有强的杀伤作用。配合物Cu（L）2、Zn（L）2剂量为10mg/kg时,对S180荷瘤小鼠的存活时间延长率分别为132．4％和55．2％,对S180实体瘤的抑癌率分别为81.59％和62.11％。［结论］配合物Cu（L）2是一种抗癌活性较好的物质。     

Changes in anatomical distribution of tumour lesions induced by platelet-active drugs

To examine the effect of platelet-active drugs on the spread of blood-borne tumour cells, two murine tumours, sarcoma 180 (S-180) and TLX-5 lymphoma, were selected. Following intravenous (IV) injection into CBA mice the former elicited thrombocytopenia and formed discrete pulmonary tumours, whereas the latter failed to elicit thrombocytopenia and formed discrete tumours in all visceral organs examined except the lungs. S-180 cells were injected IV into mice pre-treated with RA233 (known to prevent thrombocytopenia and thrombus formation) and TLX-5 cells were injected IV into mice pre-treated with Corynebacterium parvum (known to induce thrombocytopenia and thrombus formation). RA233 pre-treatment did not change survival time or incidence of S-180 pulmonary tumours but did result in a higher incidence of extrapulmonary tumours and a lower tumour cell burden immediately after injection. Pre-treatment with C. parvum resulted in a higher TLX-5 tumour cell burden but not discrete tumours in the lungs. On the basis of known drug activities it is proposed that thrombocytopenia induced in these experiments is in part a reflection of thrombus formation in the lungs which influences the speed of passage of tumour cells through capillaries. In some cases this may lead to a changed anatomical distribution of tumour lesions.     

Antitumour action of 1,5-dihalogeno-, and 1, 2-4, 5-dianhydro-xylitol derivatives

The antitumour action of some xylitol compounds possessing alkylating potency at 1 and 5 position of the sugar skeleton was investigated. Unlike the hexitol derivatives, bi-halogenated xylitols showed no antitumour action. The modest therapeutic index of 1, 2-4,5-dianhydroxylitol on the NK/Ly ascites tumour could be substantially increased by the addition of a phenyl-benzoyl group at the 3 position. This latter compound appeared to be active against L1210 leukaemia, S-180, and Yoshida solid sarcoma; and furthermore, against metastasis formation of the Lewis lung tumour.     

Application of fusogenic liposomes containing fragment A of diphtheria toxin to cancer therapy.

Previously we reported that fusogenic liposomes, prepared by fusing simple liposomes with Sendai virus particles, could introduce their contents directly and efficiently into the cytoplasm. In this study, we examined the anti-tumour activity of fusogenic liposomes containing fragment A of diphtheria toxin (DTA). Fusogenic liposomes containing DTA showed high cytotoxicity against sarcoma-180 (S-180) cells in vitro. When these liposomes were administered into the abdominal cavity of ddY mice carrying S-180, tumour cells completely disappeared in four of six tumour-bearing mice without decrease in body weight. Neither simple liposomes containing DTA nor empty fusogenic liposomes had any effect on tumour suppression. We conclude that fusogenic liposomes containing DTA are new and potentially effective tools for the treatment of ascites tumours without any severe side-effects.     

Kinetic alterations induced by 5-fluorouracil in bone marrow, intestinal mucosa, and tumor.

In order to provide a more rational approach to the design of chemotherapeutic programs involving 5-fluorouracil (5-FU), the kinetic effect of this drug on bone marrow, gastrointestinal epithelium, and tumorous tissues in mice was monitored by determining the rate of incorporation of labeled deoxyuridine (UdR) into DNA following doses of 15, 50, and 100 mg/kg i.p: In BALB/c x DBA/2 F1 (hereafter called CD2F1) mice bearing P1534 ascites tumor, the magnitude and duration of suppression of [3H]UdR incorporation into DNA were directly related to drug dose for both the normal and tumorous tissues. However, the impact of 5-FU was clearly greater upon the P1534 ascites tumor than on either normal tissue, so that, after a dose of 100 mg/kg, the tumor did not initiate recovery until Day 5, while duodenal mucosa and bone marrow returned to 50% of control levels of UdR incorporation at 2 and 3 days, respectively. In order to determine whether the duration of suppression of [3H]UdR incorporation, such as observed in the P1534 ascites tumor, correlated with sensitivity of Ehrlich ascites tumor to 5-FU, the effect of 50 and 100 mg/kg of 5-FU i.p. on this less 5-FU-sensitive tumor was determined. No difference was observed in the time course of suppression and recovery between Ehrlich ascites tumor and the duodenal mucosa and bone marrow of the G.P. Swiss host. In non-tumor-bearing CD2F1 mice, the toxicity of a 2nd dose of 100 mg/kg 5-FU i.p. was found to be predictably related to the kinetic effect of a 1st dose of 100 mg/kg on [3H]UdR incorporation in the bone marrow and duodenal mucosa. In the time period from 12 hr through Day 6, when [3H]UdR incorporation into DNA rose to a maximum, administration of a 2nd dose of 5-FU was associated with 95% lethality. In contrast, during the period between 0 and 12 hr that preceded recovery of UdR incorporation, a 2nd dose resulted in less than 40% lethality, and, in the period from Day 6 through Day 8, when UdR incorporation was declining, lethality of a 2nd dose also declined to less than 25% lethality. In addition, the antitumor effectiveness of a 2nd dose of 5-FU, 100 mg/kg i.p., was predictably related to the differential effect of the 1st dose of 100 mg/kg on [3H]UdR incorporation in the P1534 tumor as compared to the host bone marrow and duodenal mucosa. Administration of a 2nd dose of 5-FU was maximally effective on Day 7, at a time when [3H]UdR incorporation was declining in the host target tissues and increasing to a maximum in the P1534 ascites tumor. Thus, the present study has demonstrated that [3H]UdR incorporation into DNA may be used to monitor the differential effect of 5-FU on tumor versus normal proliferating host tissues and, where such differences exist, to provide an in vivo method of value in designing a schedule of optimum therapeutic benefit.     

Some new aryl-sydnones: effects on murine tumours.

The effects of new aryl-sydnones: 3-[4-X-3-nitrophenyl]-1,2,3-oxadiazolium-5-olates, where X = Cl (SYD-1); pyrrolidino (SYD-2); piperidino (SYD-3) and morpholino (SYD-4) on the survival of mice bearing Sarcoma 180, Ehrlich carcinoma, B10MCII (Fibrous histiocytoma) and L1210 leukemia ascitic tumours, on the proliferation of cultured tumour cells and on the synthesis of DNA in L1210 leukemia were determined. SYD-1 and SYD-2 in vivo significantly enhanced the survival of S180, Ehrilich and B10MCII tumour-bearing mice. Furthermore, SYD-2 showed significant activity against L1210. SYD-3 and SYD-4 did not show antitumour activity. SYD-1, in vitro was the most cytotoxic against all the above tumour cells. All of the drugs tested inhibited thymidine uptake by L1210 cells, SYD-4 being the least active.     

Correlation between 5-fluorouracil metabolism and treatment response in two variants of C26 murine colon carcinoma

Following an i.p. dose of 150 mg x kg(-1) 5-fluorouracil (5-FU), drug uptake and metabolism over a 2-h period were studied by in vivo (19)F magnetic resonance spectroscopy (MRS) for the murine colon carcinoma lines C26-B (5-FU-insensitive; n=11) and C26-10 (5-FU-sensitive; n=15) implanted s.c. in Balb/C mice. Time courses for tumour growth, intracellular levels of FdUMP, thymidylate synthase (TS) activity, and 5-FU in RNA were also determined, and the effects of a 9.5-min period of carbogen breathing, starting 1 min before drug administration, on MRS-detected 5-FU metabolism and tumour growth curves were examined. Both tumour variants generated MRS-detectable 5-FU nucleotides and showed similar initial growth inhibition after treatment. However, the growth rate of C26-B tumours returned to normal, while the sensitive C26-10 tumours, which produced larger fluoronucleotide pools, still showed moderate growth inhibition. Carbogen breathing did not significantly influence 5-FU uptake or fluoronucleotide production but did significantly enhance growth inhibition in C26-10 tumours. While both tumour variants exhibited incorporation of 5-FU into RNA and inhibition of TS via FdUMP, clearance of 5-FU from RNA and recovery of TS activity were greater for the insensitive C26-B line, indicating that these processes, in addition to 5-FU uptake and metabolism, may be important determinants of drug sensitivity and treatment response.     

Modulating effect of alpha-[N,N-[bis(2-hydroxyethyl)]-amino-N- (o-methoxyphenyl)-pyrrolidin-2,5-dione on the chemotherapy of murine tumours

alpha-[N,N-[bis(2-hydroxyethyl)]-amino]-N- (o-methoxyphenyl)pyrrolidin-2,5-dione (I), an intermediate in the synthesis of pyrrolidinedione-N-mustards, did not exhibit antitumour activity against P388 lymphocytic leukemia, Sarcoma 180 (ascites) and Ehrlich (ascites) carcinoma tumours. The effect of co-administration of (I) with established anticancer drugs was studied against these murine tumours. The activity of 5-fluorouracil against Sarcoma 180 (ascites) and Ehrlich (ascites) carcinoma was significantly enhanced by co-administration with (I). Other anticancer drugs, when co-administered with (I), did not show any enhancing effect.     

Tumour volume response, initial cell kill and cellular repopulation in B16 melanoma treated with cyclophosphamide and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea.

The relationship between tumour volume response and cell kill in B16 melanoma following treatment in vivo with cyclophosphamide (CY) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) was investigated. Tumour volume response, expressed as growth delay, was estimated from measurements of tumour dimensions. Depression of in vitro colony-forming ability of cells from treated tumours was used as the measure of tumour cell kill. The relationship between these parameters was clearly different for the two agents studied. CY produced more growth delay (7.5 days) per decade of tumour cell kill than CCNU (2 to 3.5 days). The possibility that this was due to a technical artefact was rejected in favour of an alternative explanation that different rates of cellular repopulation in tumours treated with CY and CCNU might be responsible. Cellular repopulation was measured directly, by performing cell-survival assays at various times after treatment with doses of CY and CCNU which produced about 3 decades of cell kill. The rate of repopulation by clonogenic cells was much slower after treatment with CY than with CCNU, and this appears to account for the longer duration of the growth delay obtained with CY.     

Tissue distribution of [18F]-5-fluorouracil in mice: effects of route of administration,strain, tumour and dose

Summary In a study investigating the usefulness of 5-fluorouracil labelled with fluorine 18 ([¹⁸F]-5-FU) in cancer chemotherapy, the tissue distribution of the radiolabel was determined in mice at 2, 4 and 6 h after administration by varying several parameters such as the mode of administration, the strain of mouse, the presence of a tumour and the total dose of 5-FU. The tissue distribution of fluorine 18 after i. p. injection pointed to an altered behaviour of the drug and/or its metabolites when compared with values obtained after i.v. injection, but no difference was found in the accumulation of radiolabel in the tumour. A comparison of non-tumour-bearing BALB/c and C57Bl/6 mice revealed that the latter showed a higher radiolabel accumulation of the drug and its metabolites in the liver, kidney, intestines and coecum (P <0.05 at 2 and 4 h). In tumour-bearing mice, especially at 2 h, the tissue accumulation of radiolabel was found to be significantly higher than in non-tumour-bearing controls (in BALB/c mice bearing colon 26 carcinoma,P <0.05 for all tissues; in C57Bl/6 mice bearing colon 38 carcinoma,P <0.05 for the blood, lung, liver, kidney, large intestines, coecum and muscle). Finally, a comparison of injections of a tracer dose of [¹⁸F]-5-FU (2.5 mg/kg) vs a therapeutic dose (100 mg/kg) revealed only small differences in the accumulation of fluorine 18 in the liver and kidney.