Extravasation injury potential of CI-980, a novel synthetic mitotic inhibitor.

Severe soft-tissue ulceration is known to result from inadvertent extravasation of a number of anticancer drugs, including tubulin-binding vinca alkaloids, during intravenous administration. CI-980 is a novel anticancer drug candidate that also inhibits mitosis by binding to tubulin. Intradermal administration of CI-980 to mice at doses of 0.02 and 0.05 mg produced ulcerative lesions in 3/5 and 2/5 animals, respectively, that were significantly smaller than those produced in all animals at vinblastine doses of 0.05 and 0.1 mg. Ulcerative lesions resulting from CI-980 treatment were also less persistent, resolving in 2-8 days versus 7-16 days following vinblastine administration. As based on the common dose of 0.05 mg, CI-980 appears to have significantly less vesicant activity than vinblastine.

Biochemical alterations in guinea pig adrenal cortex following administration of PD 132301-2, an inhibitor of acyl-CoA:cholesterol acyltransferase.

To assess whether previously reported ultrastructural alterations of adrenocortical mitochondria induced by the acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor PD 132301-2 are accompanied by functional deficits in tissue energy stores, phosphorylated adenine nucleotide levels in guinea pig adrenal cortex were quantitated. Adrenals of male guinea pigs were obtained at 1, 2, 6, or 24 hours after oral administration of 100 mg/kg PD 132301-2 or 0.5% methylcellulose vehicle. In treated animals, ATP levels and ATP/ADP ratios were decreased approximately 50% with concurrent increases in AMP. Calculated energy charge was also decreased; these decreases were maximal by 6 hours. Cholesterol esterification in adrenal cortex was inhibited, resulting in progressive accumulation of free cholesterol up to 3-fold over control by 24 hours, consistent with the ACAT inhibitory activity of the drug. These data suggest that PD 132301-2 distributes to the adrenal cortex where early alterations of tissue bioenergetics occur in a time frame consistent with ultrastructural alterations of mitochondria.

Differential toxicity of an inhibitor of mitochondrial respiration in canine hepatocytes and adrenocortical cell cultures.

PD132301-2, a novel inhibitor of acyl-CoA: cholesterol acyltransferase, was previously shown to be an inhibitor of mitochondrial respiration and an adrenal toxicant in several species. To investigate potential mechanisms of tissue-specific toxicity in vivo, dog adrenocortical and hepatocyte cell cultures were exposed to 0.01-30 mum PD132301-2 for 0-24 hr. Cell viability was assessed by neutral red uptake or release assays. Cytotoxicity was observed in adrenocortical cells at 0.01 mum or above after 2hr of exposure, while 30 mum was not toxic to hepatocytes after 24 hr of exposure. Decreases in adrenocortical cell viability were attenuated in the presence of 20 mm fructose, a glycolytic substrate, and fructose protection was in turn blocked by the glycolytic inhibitor NaF (1 mm). In contrast, PD132301-2-induced hepatocellular toxicity was evident only following pretreatment with NaF or metyrapone, a broad-spectrum cytochrome P-450 inhibitor. With either co-treatment, hepatocyte viability was reduced 50% after 6 hr at 1 mum or more PD132301-2. These data indicate that the relative sensitivity of adrenocortical cells to the cytotoxic effects of PD132301-2 may be due, in part, to their relative lack of the metabolic detoxification and glycolytic reserve capacities that appear to protect hepatocytes from PD132301-2 toxicity.

Preclinical toxicology studies with the angiotensin-converting enzyme inhibitor quinapril hydrochloride (Accupril).

Acute, subacute, and chronic toxicity studies, carcinogenicity bioassays, and reproductive and genetic toxicology studies were performed with quinapril, an ACE inhibitor used in the treatment of hypertension. Acute toxicity is minimal in rodents, and repeated dosing elicits gastric irritation, juxtaglomerular apparatus (JGA) hypertrophy and hyperplasia and tubular degenerative changes in the kidney, and reduced red cell parameters and heart weights in rodents and/or dogs. Other manifestations of toxicity, including hepatic lesions in dogs, reduced offspring weights in rats, marked sensitivity of the rabbit, and clastogenic effects at cytotoxic doses in the in vitro V79 chromosome aberration assay, have been reported with other drugs of this class.

Pharmacodynamic analysis of substrate stimulation of p-aminohippurate transport by newborn rabbit kidney.

Penicillin pretreatment of 2-week-old New Zealand White rabbits significantly increased the ability of renal cortical slices to transport p-aminohippuric acid (PAH). The PAH slice/medium ratio increased with dose to a maximum at 90,000 I.U. of procaine penicillin G. Sodium penicillin G (180,000 I.U.) produced no greater increase. Stimulation was maximal after four penicillin injections at 12-hour intervals. The maximal response was observed 24 hours after the final injection, whereas after 72 hours the capacity of slices from treated animals to transport PAH was no different than control. To determine the effect of a maximal substrate challenge on the development of transport capacity, pregnant does were treated with 90,000 I.U. of procaine penicillin i.m. twice daily through the last half of gestation. Young animals received four penicillin injections before sacrifice. The PAH slice/medium ratio from pups 3 days, 1 and 2 weeks old were not significantly different from that normally observed at 4 weeks. Animals 4 weeks old did not respond to penicillin treatment. Thus, intrinsic transport capacity for PAH is mature at 4 weeks of age. Only before this age may transport be enhanced by substrate. Maximal enhancement of PAH transport capacity occurs when four injections of 90,000 I.U. of procaine penicillin G are administered at 12-hour intervals followed by sacrifice 24 hours after the final injection.

Disappearance of p-aminohippurate and inulin from plasma of newborn and adult rats.

The ability of newborn and adult rats to eliminate p-aminohippuric acid and inulin from plasma was determined. The pattern of development is similar to that observed in vitro using renal cortical slices. The fact that function increases to a peak and then declines over the developmental period while organ weight and histology mature progressively suggests a divergence of functional and antomical maturation. Inulin elimination, unlike PAH, increased over the ages tested, and is apparently more closely related to organ growth.

Glutathione S-transferases: an evaluation of their role in renal organic anion transport.

Organic anion transport capacity measured as accumulation of p-aminohippurate by renal cortical slices was less in kidneys from newborn rats and rabbits than adults and increased with age. Glutathione (GSH) S-aryltransferase activity in 100,000 X g supernatant of renal homogenates, an estimate of GSH-S-transferase concentration in the tissue, was also less in newborn of both species. Enzyme activity increased to adult values by 1 week of age in rats, prior to maturation of transport capacity. Enzyme activity in rabbit kidney was not different at 1 day and 2 weeks but was increased by 4 weeks coincident with transport maturation. In rats, 25 mg/kg of 3-methylcholanthrene administered once a day for 3 days significantly increased enzyme activity but had no effect on transport capacity. Chronic ammonium chloride acidosis increased enzyme activity 8-fold but decreased transport capacity. Forty-eight hours after unilateral nephrectomy in rats transport capacity was significantly increased with little effect on enzyme activity. L-Methionine-SR-sulfoximine (1.85 mmol/kg) significantly reduced glutathione concentration in renal cortex but had no effect on transport capacity. Organic anion transport was greater in male than in in female mice yet there was no difference in enzyme activity between sexes. 3-Methylcholanthrene (10,20, 30 and 40 mg/kg) administered to 2-week-old rabbits twice daily for 3 days increased transport in a dose-dependent manner. GSH S-transferase activity was also increased. Penicillin (90,000 I.U. twice daily for 2 days) similarly increased transport but had no stimulating effect on enzyme activity. The apparent lack of correlation between transport capacity and GSH S-transferase in several instances suggests that GSH S-transferase concentration is probably not the rate-limiting step in renal organic anion transport.

Leucovorin protection against repeated daily dose toxicity of trimetrexate in rats.

Repeated high doses of trimetrexate (TMX), a potent non-classical antifolate, have been administered as an experimental treatment for life-threatening Pneumocystis carinii infections in man. This therapy includes the coadministration of leucovorin, a reduced folate cofactor, to prevent antifolate toxicity in the host. The purpose of this investigation was to assess possible toxicologic sequelae of this combination regimen in an animal model. TMX at daily oral doses of 25, 35, and 45 mg/kg produced dose-related myelosuppression, thymic lymphoid depletion, seminiferous tubular atrophy, and degenerative lesions of the gastrointestinal tract. Mortality observed with TMX alone occurred earlier at higher doses and was specifically associated with severe degenerative enteropathy of the cecum. Oral leucovorin doses of 1, 5, 20, or 50 mg/kg administered twice daily, at the time of TMX administration and 6 hr later, protected against TMX lethality and target organ toxicity in a dose-related manner. Leucovorin was only partially protective against TMX-induced macrocytic anemia and the degree of protection was not dose-related. Leucovorin protection against cecal enteropathy was associated with increased DNA synthetic rates and higher mitotic activity of cecal epithelium than those in rats administered TMX alone. Importantly, the combination of daily administration of high dose TMX for 4 weeks with protective coadministration of leucovorin did not result in target organ toxicities that differed from TMX alone.

Substrate stimulation of para-aminohippuric acid transport: effect on uptake and runout.

The ability of penicillin pretreatment to increase PAH accumulation by slices of newborn rabbit renal cortex was dissected into two components, uptake and runout. The oxygen-requiring component of the uptake process was significantly enhanced by penicillin treatment, whereas runout was unaffected. Kinetically, the data suggest that penicillin alters the affinity of the transport system for PAH. Due to the limitations of such a kinetic analysis, no conclusions may be drawn from such a suggestion. However, it may be concluded that penicillin pretreatment increases renal accumulation of PAH solely by stimulating the uptake process. Elucidation of the molecular changes involved will require techniques more sophisticated than uptake into renal cortical slices.

Effect of substrate pretreatment on renal organic ion transport in the adult rat.

The ability of renal cortical slices to accumulate PAH and NMN was not significantly affected by pretreatment of adult rats with large doses of PAH. Pretreatment of adult rats with THAM significantly increased PAH accumulation but had no effect on NMN. Inulin and PAH clearance and filtration fraction were significantly decreased by PAH pretreatment but unaffected by THAM pretreatment. The effects of pretreatment on transport are probably due to non-specific toxicity.

Biochemical and ultrastructural correlates of substrate stimulation of renal organic anion transport.

Penicillin pretreatment enhanced the rate of PAH uptake into separated proximal tubules (collagenase digestion) from 2-week New Zealand white rabbits. A double reciprocal plot of these data suggests that penicillin increases the maximal velocity of PAH uptake. Na, K-ATPase was less in adult tissue but was unaffected by penicillin. No ultrastructural changes could be attributed to the treatment. Thus substrate stimulation of PAH transport does not involve Na, K-ATPase and probably involves soluble, rather than structural proteins.

Preclinical toxicological evaluation of fostriecin, a novel anticancer antibiotic, in rats.

Fostriecin, a novel anticancer antibiotic produced by Streptomyces pulveraecus, is believed to act via inhibition of topoisomerase II. Single-dose intravenous administration to rats at dose levels of 8.8 to 48 mg/kg resulted in lethality at dose levels of 35 mg/kg and higher. Major toxic effects were observed primarily at 17.5 mg/kg and higher, were reversible, and consisted of bone marrow hypocellularity, leukopenia, neutropenia, thrombocytopenia, and diffuse necrosis of various lymphoid tissues. The kidney was also identified as a target organ. Renal effects were observed primarily at 20 mg/kg, were reversible, and included increases in serum BUN, creatinine, and 24-hr glucose excretion. Twenty-four-hour excretion of Na+, K+ and urine osmolality were decreased postdosing at 10 and 20 mg/kg. Renal lesions, observed primarily at 20 mg/kg, consisted of vacuolization and necrosis of proximal and distal tubular epithelium at the corticomedullary junction extending into the medulla. Repeated daily intravenous administration of fostriecin for 5 days to rats at dose levels of 2.5 to 26.5 mg/kg resulted in death at 10 mg/kg and above and similar hematologic, bone marrow, lymphoid tissue, and renal changes as observed in the single-dose study. Hematological, bone marrow, lymphoid, and renal changes observed in rats were consistent with the cytotoxic mechanism of action of the compound.

Effects of the angiotensin-converting enzyme inhibitor quinapril on renal function in rats.

Angiotensin-converting enzyme inhibitors induce hypertrophy of renal juxtaglomerular cells in laboratory animals, and, in some studies, also produced renal tubular lesions. The objective of the present study was to evaluate the effects of the new angiotensin-converting enzyme inhibitor quinapril on renal function in normotensive rats. Male rats were dosed orally with quinapril at 0 (vehicle control) or 400 mg/kg for 1, 3, 8, 17 or 29 days. This dose of quinapril is more than 1000-fold greater than the effective antihypertensive dose in rats. Parameters of renal function were measured approximately 24 hours after dosing in order to minimize interference from acute pharmacologically mediated effects. Mean arterial blood pressure was only mildly affected at this time: 126.7 +/- 6.0 and 100.0 +/- 8.7 mm/Hg (mean +/- S.E.; day 29) for the control and quinapril-treated animals, respectively. Microscopic analysis of kidney tissue showed pronounced juxtaglomerular cell hypertrophy and hypergranularity in the quinapril-treated animals. These changes were first observed on day 7 and reached a maximum response by day 14. There were no morphologic changes in renal tubules. Quinapril had no significant effect on serum biochemistry parameters (electrolytes, urea nitrogen, creatinine). Urine output in quinapril-treated animals was increased 65% to 197% over controls during the course of the study and correlated with increased water consumption (r = 0.96). Urine osmolality was reduced 31% to 55% on days 8, 17 and 29. However, except for minimal reductions (< 15%) on day 8, there were no significant effects of quinapril on total (24 hour) urinary excretion of electrolytes or creatinine. There were also minimal effects of quinapril on direct measurements of renal function in anesthetized animals. Mean values (+/- S.E.) for control and quinapril-treated animals on day 29 were, respectively: glomerular filtration rate: 2.93 +/- 0.37 and 2.70 +/- 0.53 ml/min; effective renal plasma flow: 11.14 +/- 2.06 and 11.22 +/- 2.35 ml/min; effective renal tubular secretion: 267 +/- 63 and 261 +/- 106 micrograms/min; filtration fraction: 27.1 +/- 2.5 and 24.0 +/- 0.4%; and fractional sodium excretion: 0.25 +/- 0.04 and 0.34 +/- 0.04%. There were also no significant differences between control and quinapril-treated animals when the above parameters were measured following plasma volume expansion on day 29. The results show that quinapril had no adverse effects on renal function in rats when administered at a suprapharmacological dose for up to 4 weeks.(ABSTRACT TRUNCATED AT 400 WORDS)

Renal morphology and function in dogs after treatment with the angiotensin-converting enzyme inhibitor quinapril.

Angiotensin-converting enzyme (ACE) inhibitors have proven to be effective therapeutic agents for treatment of hypertension and congestive heart failure (CHF). Because of the role the renin-angiotensin system (RAS) plays in maintaining renal homeostasis, the effect these compounds have on renal function has been of interest. We assessed the effect of toxicologically significant doses of the new ACE inhibitor, quinapril, on renal function and morphology in dogs. Groups of 3 male beagle dogs were administered quinapril orally at daily doses of 0, 25, 125, or 250 mg/kg for 13 weeks. After treatment, animals were anesthetized and assessed for clinical pathologic and renal functional disturbances under normal conditions and after volume expansion and diuresis. Renal histopathology was conducted on perfusion-fixed kidney. No adverse effects on sensitive measures of renal function were detected; changes observed were consistent with the pharmacologic consequences of ACE inhibition. Decreased serum Na+ and Cl- (< 10%) and hematocrit at 125 and 250 mg/kg, twofold increases in serum creatinine and blood urea nitrogen (BUN) at 250 mg/kg, and decreased arterial blood pressure (BP) (20%) were observed at all doses. Under baseline conditions, urine flow increased 81-123% in quinapril-treated animals as compared with controls and urine specific gravities decreased 16% relative to controls at 125 and 250 mg/kg. Microscopically, juxtaglomerular hypertrophy was observed at all doses. At 250 mg/kg, minimal, widely scattered cortical tubular alterations were observed; glomerular lesions were not. No significant adverse effects of quinapril on renal morphology or function were observed at doses approximately 250 times the therapeutic dose.

Subchronic intravenous toxicity of the antineoplastic drug, amsacrine, in male Wistar rats.

Amsacrine, a DNA intercalator and topoisomerase II inhibitor, is efficacious as an antileukemogenic agent. This study was conducted to assess the subchronic toxicity of amsacrine in rats following a cyclic clinical dosing regimen and as a range-finding experiment for a subsequent carcinogenicity bioassay. Groups of 30 male Wistar rats were administered drug intravenously at doses of 0, 0.25, 1.0, and 3.0 mg/kg daily for 5 days followed by 23 days without treatment. This cycle of dosing and recovery was repeated six times to simulate human clinical usage of the drug. Assessments of hematology, clinical chemistry, and gross and microscopic pathology were conducted 3 and 21 days following completion of dosing in the first, third, and sixth cycles. There were no deaths during the study. Hair loss, diarrhea, tail injuries, chromodacryorrhea, and rhinorrhea were observed primarily in animals administered 3 mg/kg. Hair loss and diarrhea occurred during periods of dosing and generally resolved during the recovery phase of each cycle. Both of these signs became progressively more severe during the latter half of the study. Body weight loss and reduced food consumption also occurred in the 3 mg/kg group during each week of dosing. At study termination, mean body weight and food consumption of the 3 mg/kg group were significantly less than those of controls by approximately 20 and 50%, respectively. Marked, reversible leukopenia associated with reductions in both neutrophil and lymphocyte counts occurred in cycles one and three in animals administered 1 and 3 mg/kg, respectively. Reversible neutropenia was also observed in the 3 mg/kg group in cycle 6. Similar effects on platelet counts were seen in the 3 mg/kg group in all three cycles analyzed. Absolute and relative testes weights of the 3 mg/kg group were significantly less than the vehicle controls at all time points in the third and sixth cycles. Relative testes weights were also decreased in the 1 mg/kg group in cycle 6. Reversible decreases in absolute relative spleen weights occurred in all drug-treated groups in cycle 1 and for the 3 mg/kg group in cycle 3. Lymphoid depletion (spleen, thymus, lymph node), marked hypocellularity of bone marrow, segmental degeneration of seminiferous tubules, and intestinal epithelial cell degeneration were observed at 3 mg/kg. With the exception of testicular changes which remained evident at the end of cycle 6, pathologic lesions were reversible during the 23-day recovery period of each cycle. The results show that the subchronic toxicity of amsacrine is consistent with a cytotoxic mechanism and that target organs are generally tissues with the highest rates of cell turnover. The doses administered in this study induced a range of effects which were minimal at 0.25 mg/kg and dose-limiting at 3 mg/kg and therefore were considered appropriate for use in the subsequent carcinogenicity bioassay.

Renal structure and function in rats after suprapharmacologic doses of quinapril, an angiotensin-converting enzyme inhibitor.

Angiotensin-converting enzyme (ACE) inhibitors have adverse effects on renal function in some hypertensive patients, and some of them produce renal tubular lesions in animals at high doses. To assess the effect of quinapril on renal function and structure, a 4-week time-course study was conducted in male Wistar rats with daily oral gavage doses of 0, 10, 100, or 400 mg/kg. Glomerular filtration rate (GFR) estimated as creatinine clearance and fractional electrolyte excretion values were derived from urinalysis and blood chemistry data obtained at days 1, 7, 14, and 28. Renal sections were collected on these days for histopathologic evaluation, and cortical slices were obtained to assess organic ion transport in vitro. Expected pharmacologic effects of an ACE inhibitor were observed at all doses and included increased urine output, increased water consumption, decreased serum aldosterone (65 or 25% of control at 10 or 400 mg/kg, respectively, on day 28), increased plasma renin activity (PRA, up to two- to threefold higher than controls at day 28), and hypertrophy of the juxtaglomerular apparatus. Despite these expected class effects, quinapril administration to male rats for 28 days produced no functional alterations or renal tubular lesions suggestive of renal toxicity at doses up to 400-fold higher than the effective antihypertensive dose in rats.

Nitro-imidazole radiosensitizer-induced toxicity in cynomolgus monkeys.

Intravenously administered nitro-imidazole radiosensitizer and alkylating anticancer compound CI-1010, designated as (R)-alpha-[[(2-bromoethyl)amino]methyl]-2-nitro-1H-imidazole-1-ethanol monohydrobromide, causes multiorgan toxicity in rodents, including retinal degeneration. This study determined the potential of CI-1010 to induce similar effects in nonhuman primates. One male and 1 female cynomolgus monkey were given single daily doses of CI-1010 intravenously for 5 consecutive days each week for 3 wk. Doses were escalated from 5 mg per kilogram of body weight in week 1 to 40 and 60 mg/kg in week 3. Postdosing emesis occurred in both monkeys at 5 mg/kg, and clinical signs at 40 and 60 mg/kg included more pronounced emesis, reduced food consumption, pallor, weakness, and body weight loss. At study termination, both monkeys had markedly reduced peripheral blood lymphocytes and moderately lowered erythrocyte, hemoglobin, and hematocrit levels, which correlate with a decreased total nucleated bone marrow cell count. At necropsy, the monkeys had pancytic bone marrow hypocellularity, multiorgan lymphoid depletion, pancreatic acinar cell apoptosis, testicular seminiferous tubular degeneration, and bilateral multifocal retinal degeneration involving the photoreceptor and outer nuclear layers. Ultrastructurally, selected inner and outer retinal rod segments were swollen and fragmented, a state associated with cytoplasmic condensation and pyknosis of the outer nuclear cell layer. Thus, CI-1010 induced toxicity of hematopoietic/lymphoid organs, retina, testes, and pancreas in monkeys, findings similar to those of previous studies in rodents.

ATP depletion is associated with cytotoxicity of a novel lipid regulator in guinea pig adrenocortical cells.

A novel lipid regulator (PD132301-2) produces degeneration and necrosis of adrenal fasciculata in guinea pigs. Primary adrenocortical cell cultures from male Hartley guinea pigs were utilized to investigate potential mechanisms of this toxicity. Concentration-dependent loss of viability, measured by neutral red (NR) accumulation or MTT reduction, was observed within 6 hr at concentrations of 0.01 to 10 microM PD132301-2. At 10 microM, NR and MTT indices were 50% of those of control after 6 hr exposure. Maximal decreases in NR and MTT indices to 20% of control values occurred by 24 hr at > or = 1 microM PD132301-2. Adenine nucleotide analysis after PD132301-2 challenge indicated that ATP depletion preceded loss of viability. At 10 microM PD132301-2, ATP levels were 80% of those of control after 30 min and 25% of those of control after 6 hr. Supplementation of glucose-free buffer with 20 mM fructose protected adrenocortical cells from PD132301-2-induced toxicity. Fructose protection was blocked by inhibiting glycolysis with 1 mM sodium fluoride. Pretreatment of cultures with 100 microM metyrapone, an inhibitor of cytochrome P-450, did not block cytotoxicity induced by 10 microM PD132301-2, but did block cytotoxicity of 100 microM o,p'-DDD. In adrenocortical mitochondrial preparations, inhibition of respiration by PD132301-2 was site II-specific. Both state 3 and state 4 respiration were inhibited 50-75% at 1-30 microM PD132301-2. Thus, ATP depletion resulting from direct inhibition of mitochondrial respiration is a critical early event in adrenocortical cytotoxicity of PD132301-2.

Comparative nephrotoxicity of a novel platinum compound, cisplatin, and carboplatin in male Wistar rats.

The nephrotoxicity of three platinum-containing antitumor agents was compared at doses that approximate the LD10 (cisplatin) or the LD50 (CI-973, carboplatin) doses. Male Wistar rats were administered single iv doses of 45 mg/kg CI-973, 6.5 mg/kg cisplatin, or 65 mg/kg carboplatin and observed for 4 days. Cisplatin treatment increased blood urea nitrogen (4x), creatinine (3x), glucose, and fractional electrolyte excretions, and decreased creatinine clearance by Day 4. These parameters were not significantly altered in CI-973- and carboplatin-treated animals. Cisplatin increased urinary excretion of LDH (six-fold), GGT (twofold), and NAG (twofold); CI-973 and carboplatin increased GGT excretion (approximately twofold). Cisplatin induced the following functional changes as a consequence of direct nephrotoxicity: decreases in GFR (84%), ERPF (97%), ERBF (96%), and ERTS (95%), and increases in FF (fivefold). Functional changes, attributed to prerenal effects of CI-973, included a decrease in ERPF (35%) and an increase in FF (48%). No changes were seen following carboplatin treatment. All cisplatin-treated rats had proximal tubular necrosis in the outer stripe of the outer medulla, extending multifocally into inner cortical medullary rays. No renal lesions were detected by light or electron microscopy in the control or CI-973- or carboplatin-treated rats. Cisplatin produced marked nephrotoxicity as determined by biochemical, functional, and histopathologic endpoints. CI-973 and carboplatin were significantly less nephrotoxic than cisplatin.

Carcinogenicity of the anticancer topoisomerase inhibitor, amsacrine, in Wistar rats.

Amsacrine is an antineoplastic drug used in the treatment of acute adult leukemias. To assess its carcinogenic potential, groups of 50 male and 50 female rats were administered amsacrine by lateral tail vein injection at 0 (vehicle control), 0.25, 1, or 3 mg/kg once daily for 5 days, followed by a 23-day recovery period. This cycle of dosing and recovery was repeated a total of six times. The animals were then maintained without dosing for an 18-month observation period. During the dosing phase, signs of toxicity were limited to the 3 mg/kg animals and included alopecia, diarrhea, injection site lesions, and skin and subcutaneous nodules. Statistically significant reductions in body weight gain and food consumption also occurred at 3 mg/kg during each 5-day dosing period followed by recovery during the latter 3 weeks of each cycle. Except for skin and subcutaneous nodules, signs of toxicity in the 3 mg/kg animals ultimately disappeared during the 18-month observation phase. Survival at study termination for the vehicle control, 0.25, 1, and 3 mg/kg groups was 56, 52, 34, and 0%, respectively, in males, and 64, 48, 54, and 4%, respectively, in females. Mortality was primarily due to bone marrow suppression during the dosing phase, chronic progressive nephropathy, or development of tumors. Incidences of the following tumors were significantly increased in the 3 mg/kg groups of both sexes (Fisher exact test, two-tailed, p < 0.01): all malignancies; all tumors of the small intestine, adenocarcinoma and adenoma of the small intestine, all tumors of the skin, and squamous cell papilloma. Other tumor incidences that were significantly increased in the 3 mg/kg males were thymoma and multiple neoplastic histotypes of the skin and adnexa including basal cell tumor, fibroma, sebaceous gland adenoma, and squamous cell carcinoma. A disproportionate number of the skin tumors were located on the tail, suggesting a localized tissue concentration effect. In the 3 mg/kg females, significantly increased tumor incidences also included all tumors of the mammary gland, adenocarcinoma of the mammary gland, all tumors of the uterine horn, and endometrial stromal polyps of the uterine horn. The 1 mg/kg males had significantly increased incidences of all tumors of the small intestine and skin, adenocarcinoma of the small intestine, and fibroma of the skin. Fibroma of the skin was also significantly increased in the 0.25 mg/kg males. Incidences of all tumors and all benign tumors were significantly increased in the 1 mg/kg females. There were no significantly increased tumor incidences in the 0.25 mg/kg females. The results of this study show that amsacrine is carcinogenic in Wistar rats. Target organs for tumorigenicity include small intestine, skin, mammary gland, thymus, and uterus.