Toxicity and Antitumor Activity

The LDp values obtained for the four cyclophosphathiazenes studied are given in Table 9 in which two points are worthy of particular attention  

The activities of SOF, SOPHi, SOAz and DISOF under various conditions are shown in Table 10. 

10 P388 cells implanted i.p.,i.p.treatment(10mice/group) median survival timeof control lO.Odays a This ILS figure was actually vitiated by the mortality of 4 mice out of 10 which were not included in the calculation of %ILS. 

1) The three compounds of series (I), namely SOF, SOPHi and SOAz, are found to be active, but DISOF does not exhibit any antitumor activity at all. The delayed toxicity of DISOF may however conceal an eventual antitumoral activity. It appears therefore that at least two geminal aziridino pairs are necessary in these compounds for antitumoral activity. 

2) SOAz appears to be the most active member of series (I) indeed a single dose of 200 mg/kg resulted in 40% cured mice on Day 60. 

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Perez-Soler, R., Khokhar, A. R., Hacker, M. P., and Lopez-Berestein, G. (1986). Toxicity and antitumor activity of cis-bis-cyclopentenecarboxylato-1,2-diaminocyclohexane platinum(II) encapsulated in multilamellar vesicles. Cancer Res., 46. 6269-6273. 

Yokoyama M, Okano T, Sakurai Y, Ekimoto H, Shibazaki C, Kataoka K (1991) Toxicity and antitumor activity against solid tumors of micelle-forming polymeric anticancer drug and its extremely long circulation in blood. Cancer Res 51 3229-3236... 

As might be expected, the lipophilicity increases with increasing chain length of the carboxylato ligands alkyl group. This increases the body burden of rhodium, which in turn increases both the toxicity and antitumor activity of the rhodium complex. However, it has been stated that too great an increase in the chain length (i.e. beyond the pentanoate) reduces the therapeutic properties.24 It seems that optimal properties are shown by the butyrate.25,26... 

A convenient synthesis was reported for l,3-bis(tetrahydro-2-fur-anyl)-5-fluorouracil (Thf2 FU), whose toxicity and antitumor activity were compared with Ftorafur (Thf-FU) and FU. The oral LDc in mice was approximately 3-fold greater than that observed for Thf-FU, ich was much less toxic than FU. Thf -FU slowly hydrolyzed to FU in vivo and showed significant antitumor effects at 0.15-0.45 mmol/kg (p.o.) against Ehrlich and AH-130 carcinomas, sarcoma 180, Yoshida sarcoma and Walker 256 carcinosarcoma. The most active in a series of 1-alkyIcarbamoyl derivatives of FU was the 1-jt-butylcarbamoyl compound, which gave an of... 

Hart MM, Smith CE, Yancey ST and Adamson RH (1971) Toxicity and antitumor activity of gallium nitrate and periodically related metal salts. J Natl Cancer Inst 47 1121-1127. 

Toxicity. Acute toxicity and antitumor activity data for the chloroammineplatlnum(II) complexes is tabulated in Table VIII. 

Chen Y, Yu DC, Charlton D, Henderson DR. Pre- existent adenovims antibody inhibits systemic toxicity and antitumor activity of CN706 in the nude mouse LNCaP xenograft model implications and proposals for human therapy. Hum Gene Ther2000 11 1553-1567. 

Biomedical Uses. The molybdate ion is added to total parenteral nutrition protocols and appears to alleviate toxicity of some of the amino acid components in these preparations (see Mineral NUTRIENTS) (97). Molybdenum supplements have been shown to reduce iiitrosarnine-induced mammary carcinomas in rats (50). A number of studies have shown that certain heteropolymolybdates (98) and organometaUic molybdenum compounds (99) have antiviral, including anti-AIDS, and antitumor activity (see Antiviral agents Chemotherapeutics, anticancer). 

A.n log ue Synthesis. Two notable examples, in which analogues have greater therapeutic indexes than the parent dmgs, have been identified in Phase I trials. These are carboplatin (29) and ado2elesin (37) (35). Carboplatin s approval was based on its comparable efficacy to cis-platinum (28) and its more favorable toxicity profile, ie, reduced and delayed episodes of emesis, reduced ototoxicity, etc. On the other hand, ado2elesin, a totally synthetic analogue of natural product CC1065, has demonstrated a similar potency and antitumor activity profile as its natural prototype but is devoid of the delayed death UabiUty associated with the parent dmg in animals (36). 

The investigation of microorganisms has also resulted in the isolation of numerous indole derivatives with antibiotic and antitumor activity as well as substances primarily noteworthy for toxicity. One example is the mitomycin family, which has antitumor activity. Mitomycin... 

The cytotoxic effect and antitumor activity of triethyltin lupinyl sulfide hydrochloride have been investigated133. Different patterns of antiproliferative effects have been observed in a panel of human cell lines in vitro. Acute toxicity at doses of 21 and 17.5 mg kg-1 in mice was reported and disappeared progressively at lower concentrations. On this base, the doses of 3.5, 7 and 14 mgkg-1 were selected to assess the antitumor activity in vivo against the P388 leukemic cells xenografted in mice. This compound was able to induce a dose-dependent significant reduction of tumor volume, up to 46%. 

The doses of retinol that are protective in animals are in the toxic range (Section 2.5.1) and are unlikely to be useful in cancer therapy or prevention. A number of synthetic retinoids have been developed, in a search for compounds that show anticancer activity, but are metabolized, stored, and transported differently, or bind to different subtypes of retinoid receptor and are less toxic. RXR-selective ligands are less toxic and more active in animal cancer models than RAR ligands (Lippman and Lotan, 2000). Fenretinamide, and possibly other retinoids that have antitumor activity, exerts at least part of its action by induction of apoptosis by a receptor-independent mechanism (Wu et al., 2001). 

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