D-19575 is a glucose derivative of ifosfamide mustard with a broad spectrum of antitumor activity in animal models. In comparison with ifosfamide, D-19575 is less toxic and is better tolerated by tumor-bearing animals, achieving a better therapeutic efficacy. D-19575 is directly cytotoxic in vitro--in contrast to ifosfamide--and it is possible to modulate this cytotoxicity by inhibition of transmembrane glucose transporters. Correspondingly, renal reabsorption of filtered D-19575 could be blocked by pre- and cotreatment with phlorizin, resulting in a higher urinary excretion of the unchanged drug. The toxicity to white blood cells, colony-forming units (CFU-C), and spleen-cell colony-forming units (CFU-S) is considerably lower for D-19575 as compared with ifosfamide. In conclusion, D-19575 is a new alkylating cytotoxic agent with increased antitumor selectivity, probably caused by an active transmembrane transport mechanism.
In a comprehensive experimental study on rats, the carcinogenicity of various therapeutically important antitumor drugs was investigated. The influences of strain, sex, dose and time of administration were systematically varied. The tested compounds showed remarkable differences in their carcinogenic potential. These differences were particularly obvious, not only when the total tumor rate was analyzed, but also when the distribution of tumor rates to the various localizations was considered (tumor spectrum). Three classes of carcinogenic substances were identified: (1) Substances showing a specific carcinogenicity: they lead to tumorogenesis primarily in organs or organ systems that, in the untreated control animals, remain virtually tumor-free for life. One example of such a substance is chlormethine. (2) Substances with non-specific carcinogenicity: they lead to an increase in tumors in organs that are also stricken in the control animals, however, to a clearly reduced extent. Oxazaphosphorine carcinogenicity is typical for this class. (3) Substances of mixed-type carcinogenicity: this group shows non-specific carcinogenicity, as well as a carcinogenic action with marked organ specificity. One example of this class is procarbazine. The antimetabolites tested were shown to be practically non-carcinogenic. Characteristic differences occurred between the two rat strains used in the investigation, Sprague-Dawley and BD II, with regard to the spontaneous tumor spectrum and the organ-related extent of carcinogenicity under the influence of the substances tested. In an experiment involving short-term application (up to 17% LD50, five times i.v. at 14-day intervals), the carcinogenic effects were substantially lower than in an experiment involving long-term application (up to 7% LD50, once a week for 52 weeks, i.v.), although the strain- and substance-specific characteristics in both experiments were rather similar.
The antitumor activity of ASTA Z 7557, a stabilized primary metabolite of cyclophosphamide, was evaluated in comparison with cyclophosphamide (CP) against different rodent tumor systems. At equimolar doses, which corresponded in mg/kg to the optimal doses of each compound, Z 7557 showed a higher therapeutic activity than CP when both drugs were administered intraperitoneally (ip) during 5 consecutive days. The drug remained active against a P388 subline totally resistant to CP, but to a much lesser extent. The ip-implanted B16 melanoma was highly sensitive to 100 and 50 mg/kg administered during 9 consecutive days: an increase in lifespan (ILS) of 244% was produced and 5 mice out of 10 were cured. This treatment administered against Lewis lung carcinoma (LL) transplanted intravenously (iv) induced an ILS of 179% and 3 mice out of 10 survived on day 60. This effect was slightly inferior to that produced by 50 mg/kg of CP, but is balanced by the number of long-term survivors recorded after administration of low doses of Z 7557. When mice bearing the subcutaneously (sc) implanted colon 38 (C38) tumor were treated with 200 mg/kg on days 2 and 9, the tumor growth was inhibited by 83% in comparison to the control mice. The wide range of activity of Z 7557, its stability and its different chemical reactivity as compared to CP appear to justify interest in this activated oxazaphosphorine.
The LD 50 of Z 7557 in mice was between 500 and 625 mg/kg after i.v. and around 2310 mg/kg after oral administration. The corresponding LD 10 was around 435 mg/kg (i.v.) or 1100-1250 mg/kg (p.o.), respectively. The LD 50 values in rats were in the range of 250-310 mg/kg after i.v. administration and around 1000-1250 mg/kg if given orally. With repeated daily i.v. injections only 70% of the daily dose contributed to lethality. A second administration of Z 7557 to rats after reversal of all toxic signs from the first administration induced the same symptoms and degree of toxicity as the initial injection. Reversible myelosuppression was the predominant feature of toxicity in mice and rats, but at equimolar doses this myelotoxicity was less than half that of cyclophosphamide (CP). First signs of immunosuppression were seen only at 100 mg/kg i.v.. No severe urotoxicity was observed in rats with single i.v. doses up to 192 mg/kg. This might be due to the fast and complete renal excretion of the thiol moiety of Z 7557, whereas the activated oxazaphosphorine component occurred in the urine only to a much smaller amount, as could be shown by a pilot pharmacokinetic study. In conclusion, Z 7557 appeared to have an overall tolerance in rats and mice similar to cyclophosphamide but was clearly less toxic with respect to the bone marrow, the immune system and the urinary tract.
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