Efficacy of 5-fluorouracil in combination with methoxyphenyl maleamic acid in murine tumors.

Combination chemotherapy studies were carried out in vivo against sarcoma 180 (ascites)(S180) and Ehrlich (ascites) carcinoma (EAC) tumours using cytotoxic drugs and methoxyphenyl maleamic acid (MPMA), an intermediate in the synthesis of pyrrolidine-nitrogen-mustards. Preliminary data have suggested that the combination of 5-fluorouracil (5-FU) and methoxyphenyl maleamic acid (MPMA) was more active than 5-FU used singly against EAC tumour. The possible therapeutic potential of this combination was further investigated in EAC tumour.

Anti-tumor effect of 3-amino-N-substituted-pyrrolidine-2,5-dione-N-mustard hydrochloride.

The anti-tumor effect of 3-amino-N-substituted pyrrolidine-2,5-dione-N-mustard hydrochloride (PNM.HCl) against Ehrlich (ascites) carcinoma (EAC) was studied. A substantial increase in the survival of mice bearing EAC tumor was achieved following daily administration of PNM.HCl at subtoxic dosages. The therapeutic efficacy of PNM.HCl was maintained with changes in dosages and the schedules of administration. The effect of PNM.HCl when administered with conventional anti-cancer drugs at different time schedules against EAC was also studied. The results demonstrated an augmentation of anti-tumor activity in the case of certain anti-cancer drugs against EAC tumor, thereby suggesting a potential usefulness of PNM.HCl in multi-drug therapy.

Influence of N-(o-methoxyphenyl)-maleimide on 5-fluorouracil cytotoxicity in Ehrlich (ascites) carcinoma.

N-(o-methoxyphenyl)-maleimide (I), an intermediate obtained during the synthesis of pyrrolidinedione-N-mustards, did not exhibit antitumor activity against Ehrlich (ascites) carcinoma. The effect of co-administration of (I), with established anticancer drugs was studied against P388 leukemia, S180 (ascites) and Ehrlich (ascites) carcinoma. A significant potentiation in the activity of 5-Fluorouracil (5-FU) against Ehrlich (ascites) carcinoma by (I) was observed. The possible mechanisms responsible for potentiation of the activity of 5-FU are presented.

Methoxyphenyl maleamic acid augments the activity of cytotoxic drugs against murine tumours.

The anti-tumour effects of methoxyphenyl maleamic acid (MPMA) and cytotoxic drugs, in combination were investigated on P388 leukaemia and S180 (ascites) tumours. Simultaneous administration of MPMA with CTX or HN2 resulted in enhancement of anti-tumour activity. The increased activity was observed against P388 leukaemia, whereas S180 (ascites) tumour was not responsive to the combined treatment. The possible mechanism (s) of action, responsible for the modulation of activity of CTX and HN2 against P388 tumour have been postulated.

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.

Enhanced activity of anticancer drugs in murine tumours by co-administration with 3-amino-pyrrolidine-2,5-dione-N-mustard derivative.

(R,S)3-(N,N-[bis-(2-chloroethyl)]-amino)-1-(2'-methoxyphenyl)- pyrrolidine-2,5-dione hydrochloride (I) has shown antitumor activity against P388 and L1210 leukaemias and Sarcoma 180 (ascites). The effect of (I), when co-administered with anticancer drugs, was studied in these murine tumours. Although co-administration of (I) with methotrexate showed a significant increase of the activity against P388 and L1210 leukaemias and Sarcoma 180 (ascites), co-administration of (I) with 5-fluorouracil, mitomycin C, adriamycin or vincristine did not exhibit any enhancing, synergistic or additive effect in the activity of these drugs.

Pharmacokinetics of methotrexate in Indian children and its relationship to nutritional status.

Any significant change in the pharmacokinetics of an anticancer drug would have a bearing on its therapeutic efficacy and toxicity. Nutritional deficiencies have been shown to affect the pharmacokinetics of a drug. Since malnutrition and undernutrition are widely prevalent in India, the effect of initial nutritional status on the overall kinetics of methotrexate (MTX) administered to cancer patients appeared to be of practical importance. A study of 6 Indian children with malignancies was made to examine the pharmacokinetics of low dose MTX and its relationship to the nutritional status. The results indicate that the relative weight correlates well with the anthropometric parameters, nutritional parameters and dietary intake and may be used as a marker of nutritional status.

Anticancer activity of new 3-amino-pyrrolidinedione-nitrogen mustard derivatives on murine sarcoma 180.

A 2,5-pyrrolidinedione linked nitrogen mustard derivative, (R,S)3-[N,N-bis(2-chloroethyl)]-amino-1-(2'-methoxyphenyl)pyrrolidine- 2,5-dione hydrochloride (I) showed a marked antiproliferative effect on mouse Sarcoma 180. Since (I) is also active against L1210 and P388 leukaemias, its toxicity in mice was evaluated. A study of acute toxicity revealed focal liver cell necrosis. Another derivative, (R,S)3-[N,N-bis-(2-chloroethyl)]amino-1-(4'-n-butoxyphenyl)pyrrolidine- 2,5-dione dihydrate (II), which also possessed significant anticancer effect on P388 and L1210 leukaemias, was inactive against Sarcoma 180.

Anti-tumour effect of alpha-amino N-substituted-pyrrolidin-2,5-dione-N-mustards on the growth of P388 lymphocytic leukaemia.

(R,S)alpha-[N,N-[bis (2-chloroethyl)]-amino]-N-(o-methoxyphenyl)-pyrrolidin-2,5-dione hydrochloride (I), a new nitrogen mustard incorporated into a 2,5-pyrrolidinedione ring system, was found to be active against P388 lymphocytic leukaemia when administered by i.p., s.c. and p.o. routes. The anti-tumour activity, exhibited by compound (I), against intracerebrally grafted P388 tumour is of interest. However, (R,S)alpha-[N,N-[bis (2-chloroethyl)]-amino]-N-(p-n-butoxyphenyl)-pyrrolidin-2,5-dione dihydrate (II), was found to be active against the P388 tumour following i.p. administration only.

Acute toxicity of folic acid in mice.

The toxicity of folic acid (PGA) was studied in different inbred strains of mice. LD50 values of PGA by the i.p. route showed a unique toxicity pattern. In some strains, convulsions, ataxia and weakness were observed. Histopathological study in strains S/RVCri, BDF1, DBA/2 and DBA/2fNCri showed acute renal tubular necrosis.

Combination of anticancer agents with folic acid in the treatment of murine leukaemia P388.

Folic acid (FA) was combined with anticancer agents such as (i) antimetabolites like methotrexate (MTX), 5-fluorouracil (5-FU), arabinosyl cytosine (Ara-C) and 6-mercaptopurine (6-MP); (ii) plant-derived mitotic inhibitor, vincristine (VCR), and (iii) an antibiotic, mitomycin C (Mit-C). This combination modality was used for the treatment of P388 lymphocytic leukaemia. Large doses of FA were administered to the tumour-bearing mice either prior to or simultaneously with different anticancer agents. Pre-treatment with FA significantly improved the therapeutic efficacy of 5-FU, Ara-C and Mit-C; while MTX was more effective when given simultaneously with FA. The efficacy of 6-MP and VCR was not enhanced by FA when tested similarly. Large doses of FA can potentiate the activity of certain anticancer agents when administered to P388-bearing mice at critical times that vary according to the particular drug used.

Cytotoxicity of the acetylated oil of Semecarpus anacardium Linn. f.

The cytotoxic effects of acetylated oil of Semecarpus anacardium nuts on the cells of P388 lymphocytic leukemia were tested in vitro. The product was tested at the concentrations ranging from 15-75 micrograms/ml. The cell kill was observed as early as three hr after the treatment. The effects of acetylated oil on the biosynthesis of DNA, RNA and protein using labelled thymidine, uridine and leucine respectively showed that the product inhibited the biosynthesis of all the three. This was indicated by the inhibition of the incorporation of their precursors. The uptake of 3H-thymidine was inhibited 15 min after treatment; while that of 3H-uridine and 14C-leucine took 30 and 45 min respectively. Since the S. anacardium oil was unstable due to air-oxidation, the studies were confined to its acetylated product.

Anti tumour and pharmacological effects of the oil from Semecarpus anacardium Linn. f.

Semecarpus anacardium Linn.f. nuts were extracted by using non-polar and polar organic solvents. Hot methanol extract and a resinous fraction, isolated from it, showed antitumour activity against P388 lymphocytic leukaemia in BDF1 mice as judged by their median survival time. Petroleum ether extract and its chromatographically isolated fraction were obtained. The latter fraction was distilled under reduced pressure to get an orange-coloured oil, (b.p. 200-20 degrees/2-3 mm). Both had antitumour activity. The orange-coloured oil, on further distillation under reduced pressure, yielded Bhilawanol. An acetyl derivative of the oil was also obtained. The latter two also had antitumour activity.

Experimental studies on betel nut and tobacco carcinogenicity.

Sun-dried Mangalore betel nut extracts in water and in DMSO, and sun-cured Vadakkan tobacco extract in DMSO, were tested for their carcinogenic potency. Inbred Swiss and C17 mice and golden hamsters were used for the experiments. Control animals treated with either DMSO or water did not show any changes at the sites of administration. On subcutaneous administration of betel nut extract, 60% of Swiss mice developed transplantable fibrosarcomas at the site of injection. Skin application of DMSO extracts of tobacco and of betel nut separately did not result in skin lesions in C17 mice; but when a mixed DMSO extract of tobacco and betel nut was used, skin papilloma and epidermoid carcinoma developed in some animals. Similarly, hamster cheek pouches painted with a DMSO extract of tobacco alone did not develop malignant atypia whereas those painted with a DMSO extract of betel nut showed early malignant changes. DMSO extract of a mixture of tobacco and betel nut positively increased the incidence of early malignant changes in the hamster cheek pouch, indicating the enhancing effect of betel nut in carcinogenesis.