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α-[N,N-[bis(2-hydroxyethyl)]-amino]-N-(o-methoxyphenyl)pyrrolidin-2,5-dione (I), an intermediate in the synthesis of pyrrolidine-dione-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.

The scope of the structure-anticancer activity relationship among various aliphatic and aromatic hydrazones containing the N,N,N′,N′ -bis(1,2-ethanediyl)-phosphoric diamide moiety was studied. A total of 19 compounds were tested in vivo, using murine lymphocytic leukemia P388. At optimum dose all these compounds were active. The highest activity was exhibited by the N,N;N′,N′ -bis(1,2-ethanediyl)-[ N 2 -( p -chlorobenzylidene)- N 1 -hydrazin-1-yl]phosphoric triamide, N,N;N′,N′ -bis(1,2-ethanediyl)- N 2 -( p -chlorobenzylidene)- N 1 -methyl-hydrazin-1-yl]phosphoric triamide and N,N;N′,N′ -bis(1,2-ethanediyl)-[ N 2 -( p -chlorobenzylidene)- N 1 -phenylhydrazin-1-yl]phosphoric triamide as is evidenced by the percent T/C of 212, 194 and 192, respectively. An attempt was made to correlate the anticancer activities with the corresponding lipophilicities. On the basis of the activity-lipophilicity results, it is concluded that, in general, the activity scale follows the lipophilicity scale in the reverse order, i.e. the more active compounds possess lower lipophilicity than the less active compounds.

Some new di-n-butyltin and tin(IV) complexes of the type Bu2SnL, Bu2SnL2 and SnL2 (where L = anions of Schiff bases derived from S-substituted dithiocarbazates and fluoro-aniline) have been prepared and screened for their antitumor activity in P 388 Lymphocyte Leukaemia system. These complexes do not show any toxicity at low dose levels and display T/C values in the range 94-124. Di-n-butyltin complex derived from salicylaldehyde-S-methyl dithiocarbazate has been found to be the most active in this series.

The combined effects of fractionated administration of the antiviral agent (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and fractionated (4 injections at a 48-h interval) administration or continuous (7-day) infusion of 5-fluorouracil (FU) have been investigated in P388 leukemia-bearing mice. The LD50 of continuous FU infusion in normal mice was approximately 330 mg/kg, while that for the fractionated treatment was 160 mg/kg. When combined with BVDU (200 mumol/kg, 90 min before each FU injection; 4 injections at a 48-h interval), the LD50 of FU was decreased from 330 to 115 mg/kg and from 160 to 30 mg/kg, respectively. The 7-day continuous infusion of FU (up to a dose of 210 mg/kg) did not exert a therapeutic effect in P388-leukemic mice, and, similarly, combination of continuous FU infusion (at lower doses) with BVDU failed to increase the survival of the leukemic mice. If, however, FU was administered in fractionated doses, there was a dose-dependent increase in survival time of P388-leukemic mice, and simultaneous fractionated BVDU treatment allowed a 4-6-fold lower dose of FU to achieve the same increase in survival time, indicating that BVDU effectively increased the antitumor activity of FU in the leukemic mice.

The antitumor effect of dicyclohexylammonium sulfate (DCHA), a potent inhibitor of spermidine synthase, was tested on BDF1 mice inoculated i.p. with P388 leukemia (1 × 106 cells/mouse). DCHA prolonged the survival time of mice bearing P388 leukemia at the doses of 10–100 mg/kg administered daily for 6 days. The spleen weight increased by 30% at 7 days after tumor inoculation. DCHA treatment had no effect on the tumor-induced increase in splenic weight. The spermidine concentration of the ascites tumor cells and spleens of mice bearing the tumor was lowered by the treatment, while spermine concentration hardly changed. The depletion of spermidine in the ascites tumor cells and spleens might be a cause of the suppression of tumor growth.

In vitro cross-resistance of adriamycin-resistant subline of P388 leukemia to non-anthracycline agents-actinomycin D, vincristine and vinblastine was elucidated. Decreased uptake of these 3 drugs was observed with the resistant cells. In addition, 2,4-dinitrophenol, a metabolic inhibitor, greatly enhanced the uptake of these drugs by the sensitive and resistant cell lines, particularly by the latter, abolishing a difference in drug uptake between the 2 which was observed under the normal condition. These results suggest that adriamycin-resistant cells are endowed with an enhanced capacity for outward transport of not only anthracycline antibiotics, but chemically and pharmacologically dissimilar agents such as the aforementioned agents.

The structure-anticancer activity and the activity-lipophilicity relationship of 8 mono- and bis-anthraquinone hydrazones containing the N,N;N′,N′-bis-(1,2-ethanediyl) phosphoric diamide moiety were evaluated. These compounds were tested in vivo, using murine lymphocytic leukemia P388. Seven of these compounds were active and one was marginal at optimum doses. The highest activity was exhibited by the bis[N,N;N′,N′-bis(1,2-ethanediyl)-[N2-(1′,4′,5′,8′-tetrahydroxy anthracenylidene)-N1-methyl hydrazin-1-yl]]-phosphoric triamide, bis[N,N;N′,N′-bis(1,2-ethanediyl)-[N2-(1′,4′-dihydroxy anthracenylidene)-N1-methylhydrazin-1-yl]]phosphoric triamide and bis- [N,N;N′,N′-bis(1,2-ethanediyl)-[N2-(1′,4′,5′,8′-tetrahydroxy anthracenylidene)-N1-phenylhydrazin-1-yl]]phosphoric triamide as is evidenced by their percent T C of 183, 175 and 172, respectively. The correlation of the anti-cancer activities of these compounds with their lipophilicities leads to the general hypothesis that the intercalating and alkylating capabilities of a potential drug may play only a secondary role as compared to the selective permeability of the drug through normal and cancerous membranes.