Susan M. Sieber

Toxicity of antineoplastic agents in man, chromosomal aberrations antifertility effects, congenital malformations, and carcinogenic potential.

Publisher Summary This chapter consolidates and quantitates some deleterious effects of cancer chemotherapeutic agents in humans—namely, their ability to induce chromosomal aberrations, their antifertility effects, their ability to produce congenital malformations under certain conditions, and their carcinogenic potential when used to treat neoplastic and nonneoplastic diseases. It discusses the three classes of antitumor compounds: alkylating agents, antimetabolites, and antitumor antibiotics. These compounds have been extensively studied in vitro and in vivo and they induce chromosomal aberrations; these abnormalities vary according to the agent and the test system used. Combinations of agents or agents plus irradiation also produce cytogenetic damage in human cells. It also provides information on the possible adverse effects of the antimetabolites, antitumor antibiotics, and miscellaneous synthetic agents on spermatogenesis. The current evidence indicates that these effects are related to the dose and duration of chemotherapy, both for single alkylating agents and for combination chemotherapy in which the alkylating agent is one of the components. Anticancer drugs other than the alkylating agents should be more thoroughly studied for possible effects on the fertility in the human female.

Effect of liposome encapsulation of a fluorescent dye on its uptake by the lymphatics of the rat

The fluorescent dye carboxyfluorescein (CF), entrapped in liposomes and administered by intraduodenal injection to thoracic duct-cannulated rats, was not detected in thoracic duct lymph at any time after dosing. However, the dye was present in blood, and in higher concentration in portal than in systemic blood. Similarly, free CF given intraperitoneally (i.p.) appeared to be absorbed into portal blood and was quickly cleared from the circulation, with less than 1% of the injected dye being recovered in thoracic duct lymph within 24 h after dosing. In contrast, 27% of the injected CF was recovered in thoracic duct lymph of rats receiving CF/liposomes i.p. These findings indicate that liposomal entrapment effectively limits passage of CF into the splanchnic blood vessels while enhancing the lymphatic uptake of the dye from the peritoneal cavity.

Effects of long-term oral administration of DDT on nonhuman primates

Abstract Because of reports on tumorigenic activity in different animal species exposed to DDT a decision was made in 1969 to evaluate the long-term effects of DDT on 24 cynomolgus and rhesus monkeys. DDT (20 mg/kg) was given in the diet for 130 months, followed by an observation period that ended in 1994. The two cases of malignant tumor detected in the DDT group included a metastatic hepatocellular carcinoma in a 233-month-old male and a well-differentiated adenocarcinoma of the prostate in a 212-month-old monkey. Benign tumors detected in the DDT group included three cases of leiomyoma, two of which were uterine and one, esophageal. No tumor was detected in the control group of 17 monkeys. Fatty changes in the liver were observed in 52.9% of the DDT group and 29.4% of the control group. More specific signs of hepatotoxicity were documented microscopically in seven DDT monkeys. Severe tremors and histological evidence of CNS and spinal cord abnormalities were observed in six DDT monkeys. The present findings show clear evidence of hepatic and CNS toxicity following long-term DDT administration to cynomolgus and rhesus monkeys. However, the two cases involving malignant tumors of different types are inconclusive with respect to a carcinogenic effect of DDT in nonhuman primates.

Effects of hycanthone on rapidly proliferating cells

Abstract The effects of hvcanthone on various types of rapidly proliferating tissue, including tumor cells in vitro and in vivo , phytohemagglutinin (PHA)-stimulated lymphocytes, and embryonic cells, have been investigated. Hycanthone was cytotoxic to several tumor cell lines in tissue culture and exerted antitumor activity in vivo against Walker 256 carcinosarcoma, leukemia L1210 and mast cell P815. Human PHA-stimulated lymphocytes incubated in the presence of hycanthone showed a 50 per cent depression in mitotic index, and a marked increase in number of chromosomal aberrations. Hycanthone administered to pregnant mice was not teratogenic, but its embryotoxicity was manifested by an increased incidence of intrauterine death and a decrease in average fetal body weights. Mechanism studies have shown that hycanthone inhibits both DNA and RNA, but not protein synthesis, in human PHA-stimulated lymphocytes. Furthermore, hycanthone was found to inhibit aldehyde oxidase and this inhibition was greater than that previously reported for the N -alkylphenothiazines. These studies suggest that hycanthone may have promise as an antitumor agent, either alone or in combination with antitumor agents known to be inactivated by aldehyde oxidase.

Lymphatic Delivery of Monoclonal Antibodies: Potential for Detection and Treatment of Lymph Node Metastases

AbstractTwo roads diverged in a wood, and I—I took the one less traveled by, And that has made all the difference.

Cardiotoxic and Possible Leukemogenic Effects of Adriamycin in Nonhuman Primates

10 monkeys (macaques) received adriamycin by monthly intravenous injections at 12 mg/m2 (1 mg/kg). 8 of the 10 monkeys developed congestive heart failure at an average cumulative adriamycin dose (310 mg/m2) well below that considered the safe upper limit (550 mg/m2) in man. Histologically, the myocardial lesions resembled those found in human anthracycline-induced cardiomyopathy. 1 of the 10 monkeys developed acute myeloblastic leukemia after receiving 324 mg/m2 of adriamycin; the 10th monkey is alive and well 26 months after the last dose of drug. Our results suggest that adriamycin is a more potent cardiotoxin in monkeys than in man, and that leukemia may be a consequence of prolonged treatment with this drug.

Nonhuman Primate Models for Lymphoma, Leukemia, and Other Neoplasms

Herpesvirus saimiri (HVS) is an oncogenic virus for a variety of nonhuman primates. HVS does not produce overt disease upon inoculation in the natural host (squirrel monkey) but consistently induces neoplasms including lymphomas and lymphocytic leukemias in 4 other species of monkeys. Various drugs inhibit replication of HVS in vitro including cytosine arabinoside and adenine arabinoside. In addition, the lymphoma and leukemia induced in owl monkeys responds to vincristine and prednisolone, cyclophosphamide, cytosine arabinoside, and human interferon. Of the various chemical carcinogens studied, the antitumor agent procarbazine induces neoplasms in a variety of species including monkeys. Thus far this compound has induced acute myelogenous leukemia (AML), lymphoma, and hemangiosarcomas in macaques. We have induced primary liver tumors in macaques with several nitrosamines and aflatoxin B1 and these tumors produce alpha-fetoprotein (AFP) which can be assayed for both diagnosis and therapy. Thus far, therapy of hepatocellular carcinoma has been most successful with surgical resection; and the tumor mass and serum AFP have been less responsive to single agent chemotherapy. These nonhuman primate models are useful for an understanding of the cause, diagnosis, prevention, and treatment of the human disease.