Search

Rats were partially hepactectomized at various intervals after receiving a single injection of the carcinogen, methylazoxymethanol acetate. In treated rats, there was a delay and a reduction in the peak response of hepatic DNA synthesis. At 48 hr after partial hepatectomy, following completion of the first mitoses, almost all hepatocytes were enlarged (megalocytes) and many contained enlarged nuclei. Although at 7 days after the hepatectomy many megalocytes could still be found in centrilobular zones, the majority of the hepatocytes were of normal size or smaller. Abnormal anaphase and telophase figures containing chromosomal bridges and acentric fragments were found during the period of regeneration. In addition, discrete nests of small cells with increased cytoplasmic basophilia were evident. Megalocytes also appeared when rats were partially hepatectomized as late as 26 weeks after injection of the carcinogen. These results show that a single dose of methylazoxymethanol acetate can affect almost all hepatocytes and that latent effects persist for long periods of time.

Previous work has shown that single injections of methylazoxymethanol acetate in rats induce tumors predominantly in the colon, occasionally in the duodenum, and rarely in the jejunum and ileum. These studies describe the acute pathological and biochemical, alterations induced by this carcinogen in the different segments of rat small intestine and colon. Karyorrhexis was found in crypts of duodenum, cecum, and all segments of colon at 6 hr after treatment. Much of the cellular debris was removed by 24 hr, although mitoses did not return to normal levels until the third day after treatment. No pathological alterations were found in jejunum or ileum, even as late as 24 hr after treatment. Studies of DNA synthesis at 24 hr after treatment indicated that jejunum and ileum were much less affected than were duodenum, cecum, or colon. In contrast, 5-fluorouracil and nitrogen mustard, agents that can inhibit proliferating cells but are not known to be intestinal carcinogens, affected all of the segments equally. The results indicate that a correlation exists between those segments of intestine acutely affected by methylazoxymethanol acetate and the sites of eventual tumor development. The level of deacetylase activity in the various intestinal segments did not correlate with sensitivity to methylazoxymethanol acetate-induced inhibition of DNA synthesis. We also found that methylazoxy-methanol acetate inhibited DNA synthesis in the duodenum and colon in rats with cannulated bile ducts. These data indicate that the carcinogen does not require biliary transport to the intestinal lumen to exert its biological effects. Mechanisms that might account for the observed selectivity in action of methylazoxymethanol acetate in the various rat intestinal segments are discussed.

The two anthracycline antitumor antibiotics, adriamycin and daunomycin, have been tested for tumorigenic activity, and the results confirm previous findings that they can induce mammary tumors in female rats receiving single i.v. doses. Both substances are highly potent in producing malignant transformation and mutation in mammalian cell systems in vitro. Their transformming activity is comparable to that of the potent carcinogen, N-methyl-N'-nitro-N-nitro-soguanidine. Actinomycin D, although similar to the anthracyclines in having high binding affinity for DNA, is only minimally effective in the same in vitro systems and its direct carcinogenic activity in vivo is moot. These results suggest that satisfactory correlations may be obtainable between tests for tumorigenicity in vivo, and assays for transformation and mutagenesis in vitro, and that adriamycin, and daunomycin may have carcinogenic potential in man.

Pseudoisocytidine (psi ICyd) is a C-nucleoside with enhanced stability and resistance to enzymatic deamination when compared to 5-azacytidine and 1-beta-D-arabinofuranosylcytosine. Elimination kinetics in plasma using [14C]psi ICyd showed a beta-phase for t1/2 for 14C of 2 hr and a beta-phase t1/2 of unchanged psi ICyd of 1.5 hr. Net recovery of radioactivity in urine over 24 hr varied between 40 and 80% of the administered dose; 50 to 90% was unchanged drug and the rest was pseudouridine. Human leukemic cells in vitro deaminated psi ICyd very slowly, formed appreciable quantities of pseudoisocytidine triphosphate, and incorporated small amounts into RNA and DNA. Clinical trials were done using a daily i.v. injection for 5 consecutive days. Hematological or intestine toxicities were not seen, nor was depression of white blood cell count observed in leukemic patients. Hepatic toxicity proved to be dose limiting; this was characterized by an early phase with elevation of prothrombin time and aspartate aminotransferase. A later phase with cirrhosis was observed in two patients. Autopsy showed massive hepatic necrosis in patients dying of acute toxicity and micronodular cirrhosis in one patient dying with the chronic form.

Succinylated Acinetobacter glutaminase-asparaginase (SAGA) has broader antitumor activity than Escherichia coli L-asparaginase in experimental systems; moreover, drug resistance does not develop in tumor cell lines initially sensitive to this enzyme. We have investigated the pharmacology and toxicology of SAGA after both single-dose and serial daily dose injections in 20 adult patients. Glutaminase activity in plasma after i.v. injection of single doses did not follow simple first-order kinetics (half-life during the initial 24 hr was 21 +/- 9 hr. A linear relation was observed between increasing doses of SAGA and resultant levels of plasma enzyme activity and blood glutamate. Assay of whole blood which had been deproteinized immediately following phlebotomy showed that single doses of SAGA lowered glutamine only transiently to nondetectable levels; serial daily doses were required to achieve and maintain continuous glutamine depletion. Reversible depression of the central nervous system, ranging from encephalopathy to coma, occurred in a dose-related manner and was dose limiting. Other prominent reactions included respiratory alkalosis, hyperglycemia, nausea, and vomiting. Transient antitumor effects were noted in two patients with solid tumors and in two patients with leukemia. SAGA causes considerable neurotoxicity in adults which requires close patient monitoring. Phase II studies in leukemic patients are in progress.

Adriamycin induces an inhibition of DNA synthesis in mouse tissues within one hr after treatment. While the effects are short-lived in liver and small intestine, DNA synthesis in heart remains below control values for up to 7 days. After this period DNA synthesis in hearts of treated mice is elevated and remains above control values for as long as 4 weeks. Both 1-beta-D-arabinofuranosylcytosine and actinomycin D also induce inhibition of cardiac DNA synthesis soon after treatment; the effects of 1-beta-D-arabinofuranosylcytosine are over by the end of 24 hr while the effects of actinomycin D persist for at least 4 days. Actinomycin D treatment also induces an "over-shoot" of DNA synthesis in mouse heart. Adriamycin can induce a loss of prelabeled DNA from heart, although no pathological alterations are immediately obvious. The small intestine, however, shows extensive karyorrhexis. The initial effects on cardiac DNA synthesis occur in adrenalectomized animals, indicating that the effects are not mediated via the adrenal gland. We did find, however, that DNA synthesis in heart was sensitive to the effects of starvation. The results of this study indicate that inhibition of mouse heart DNA synthesis is not specific for Adriamycin and that the effects of Adriamycin in heart following a single treatment are long-lived.

10-Ethyl-10-deazaaminopterin (10-EdAM) is an antifolate compound with greater therapeutic activity than methotrexate against transplanted tumors in mice. When given weekly for 3 weeks, the 10% lethal dose in rats was 125 mg/kg (i.p.) and in dogs it was 2.5 mg/kg (i.v.). The major histopathological findings in intoxicated animals were damage to the mucosa of the gastrointestinal tract in rats and dogs and hypocellularity of the marrow in rats. The elimination of 50 mg/kg of 10-EdAM from the plasma of rats was triexponential with a terminal phase t1/2 of 18.5 h but a mean residence time of 0.7 h. The primary route of elimination in rats was biliary secretion of parent compound and eventual excretion of the parent compound and the deglutamate metabolite in the feces; the 7-hydroxy metabolite was also present in plasma, bile, and feces. Biliary elimination was independent of dose over a 5-fold range. The elimination of 10-EdAM from the plasma of dogs was also triexponential with a mean terminal phase t1/2 of 9.1 h and a mean residence time of 2.5 h; nonrenal clearance was the primary route of elimination. The pharmacokinetic parameters were independent of dose over the range of 0.25 to 5.0 mg/kg. High tissue concentrations of 10-EdAM were observed initially in liver, kidney, and small intestine of rats, while concentrations in bone marrow were low. Some polyglutamate formation was observed in these tissues as early as 0.5 h after drug administration but declined over 72 h.