A phase 1 Bayesian dose selection study of bortezomib and sunitinib in patients with refractory solid tumor malignancies.

BACKGROUND: This phase 1 trial utilising a Bayesian continual reassessment method evaluated bortezomib and sunitinib to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and recommended doses of the combination. METHODS: Patients with advanced solid organ malignancies were enrolled and received bortezomib weekly with sunitinib daily for 4 weeks, every 6 weeks. Initial doses were sunitinib 25 mg and bortezomib 1 mg m(-2). Cohort size and dose level estimation was performed utilising the Escalation with Overdose Control (EWOC) adaptive method. Seven dose levels were evaluated; initially, sunitinib was increased to a goal dose of 50 mg with fixed bortezomib, then bortezomib was increased. Efficacy assessment occurred after each cycle using RECIST criteria. RESULTS: Thirty patients were evaluable. During sunitinib escalation, DLTs of grade 4 thrombocytopenia (14%) and neutropenia (6%) at sunitinib 50 mg and bortezomib 1.3 mg m(-2) were seen. Subsequent experience showed tolerability and activity for sunitinib 37.5 mg and bortezomib 1.9 mg m(-2). Common grade 3/4 toxicities were neutropenia, thrombocytopenia, hypertension, and diarrhoea. The recommended doses for further study are bortezomib 1.9 mg m(-2) and sunitinib 37.5 mg. Four partial responses were seen. Stable disease >6 months was noted in an additional six patients. CONCLUSION: Bortezomib and sunitinib are well tolerated and have anticancer activity, particularly in thyroid cancer. A phase 2 study of this combination in thyroid cancer patients is planned.

Lung effects of inhaled corticosteroids in a rhesus monkey model of childhood asthma.

BACKGROUND: The risks for infants and young children receiving inhaled corticosteroid (ICS) therapy are largely unknown. Recent clinical studies indicate that ICS therapy in pre-school children with symptoms of asthma result in decreased symptoms without influencing the clinical disease course, but potentially affect postnatal growth and development. The current study employs a primate experimental model to identify the risks posed by ICS therapy. OBJECTIVE: To (1) establish whether ICS therapy in developing primate lungs reverses pulmonary pathobiology associated with allergic airway disease (AAD) and (2) define the impact of ICS on postnatal lung growth and development in primates. METHODS: Infant rhesus monkeys were exposed, from 1 through 6 months, to filtered air (FA) with house dust mite allergen and ozone using a protocol that produces AAD (AAD monkeys), or to FA alone (Control monkeys). From three through 6 months, the monkeys were treated daily with ICS (budesonide) or saline. RESULTS: Several AAD manifestations (airflow restrictions, lavage eosinophilia, basement membrane zone thickening, epithelial mucin composition) were reduced with ICS treatment, without adverse effects on body growth or adrenal function; however, airway branching abnormalities and intraepithelial innervation were not reduced. In addition, several indicators of postnatal lung growth and differentiation: vital capacity, inspiratory capacity, compliance, non-parenchymal lung volume and alveolarization, were increased in both AAD and Control monkeys that received ICS treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Incomplete prevention of pathobiological changes in the airways and disruption of postnatal growth and differentiation of airways and lung parenchyma in response to ICS pose risks for developing primate lungs. These responses also represent two mechanisms that could compromise ICS therapy's ability to alter clinical disease course in young children.

Phase I and clinical pharmacology study of trimetrexate administered weekly for three weeks.

Trimetrexate, a new antifolate compound, was administered by 30-min infusions weekly for 3 weeks to 29 patients with solid tumors in a Phase I study. Thrombocytopenia was dose limiting, but highly variable among patients at a given dose level; other toxicity was mild and uncommon. Twenty-three patients participated in pharmacokinetic studies and five patients participated in a study of the effects of trimetrexate on [6-3H]-deoxyuridine incorporation into hematopoietic cell DNA. The median total body clearance of trimetrexate for each dose level was independent of dose but the total body clearance varied widely among patients at a given dose level. The magnitude of the fall in platelet count in individual patients correlated well with the amount of exposure to trimetrexate, but not with the extent of prior therapy. The amount of [6-3H]deoxyuridine incorporation into hematopoietic cell DNA at 72 h after drug administration correlated with the total body clearance of trimetrexate. The total body clearance of trimetrexate was reduced in patients with impaired hepatic synthetic function, as judged by low pretreatment serum albumin concentrations. The recommended Phase II starting dose on this schedule is 130 mg/m2 weekly for 3 weeks; patients with hypoalbuminemia should be treated at lower doses.

Toxicity, elimination, and metabolism of 10-ethyl-10-deazaaminopterin in rats and dogs.

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.

Phase I trial and clinical pharmacological evaluation of hexamethylene bisacetamide administration by ten-day continuous intravenous infusion at twenty-eight-day intervals.

We have treated 33 patients with different types of advanced cancer by 10-day continuous i.v. infusion courses of hexamethylene bisacetamide (HMBA), a drug that produces differentiation of a variety of transformed cell lines on prolonged exposure in vitro to drug concentrations of 3 to 5 mM. In this dose-finding and pharmacokinetic study, five dosage levels were explored from 12 to 28 g/m2/day. Patients who had not shown progression of disease were given repeat courses of therapy at 28-day intervals. Seventy-two courses of therapy were administered; 17 patients received one course; eight patients received two; six patients received three; and one patient each received four and 17+ courses, respectively. The maximal tolerated dose was 28 g/m2/day for 10 days; the dose-limiting toxic effects were thrombocytopenia with hemorrhage and central nervous system dysfunction manifesting as disorientation and confusion. Based on these studies the recommended dosage for Phase II studies by the 10-day schedule is 24 g/m2/day. Pharmacokinetic studies demonstrated rapid clearance of HMBA from plasma; the decay phase data fit a one compartment model with a mean plasma half-life of 2.5 h and a range from 0.6 to 5.8 h. Mean plasma steady-state levels in our patients were 0.37, 0.58, 0.86, 0.88, and 1.42 mM, at the 12-, 16-, 20-, 24-, and 28-g/m2/day dosage levels, respectively. The data indicate that plasma HMBA concentrations of 1 mM can be maintained for 10 days with acceptable patient tolerance, but that HMBA concentrations in excess of 1.4 mM for 10 days are associated with substantial hematological and central nervous system toxicity. Objective antitumor effects were observed in five patients; one woman with non-small cell lung cancer, who has received 17+ courses over a period of 28+ mo, achieved a partial remission that continues at 28+ mo on therapy. Transient regression of cutaneous metastases was observed in three patients with breast carcinoma and one patient with colorectal carcinoma.

Phase I trial and clinical pharmacological evaluation of 10-ethyl-10-deazaaminopterin in adult patients with advanced cancer.

10-Ethyl-10-deazaaminopterin (10-EDAM) is an analogue of methotrexate with improved preclinical anticancer activity, more selective entry, and greater conversion to polyglutamate forms in neoplastic cells. In this Phase I trial, we have treated 62 adults with advanced solid tumors, giving 10-EDAM i.v. on either a weekly x 3 schedule (35 patients) or a weekly schedule (27 patients). The dosage levels ranged from 5 to 120 mg/m2. The toxicity observed with 10-EDAM was qualitatively similar to that of methotrexate. Oral mucositis was the dose-limiting toxicity; diarrhea, skin rash, leukopenia, thrombocytopenia, and mild elevations of serum glutamic-oxaloacetic transaminase, prothrombin, and partial thromboplastin times were also observed, but were not dose limiting. A weekly dosage of 80 mg/m2 with escalation or attenuation in accordance with patient tolerance, or 100 mg/m2 weekly for 3 weeks, followed by a 2-week "rest period" are recommended for Phase II assessment. 10-EDAM produced partial remissions in three patients with non-small cell lung cancer and one patient with breast cancer lasting 6, 40+, 26+, and 15 months, respectively. Pharmacokinetic studies carried out at the 5, 30, and 100 mg/m2 dosage levels demonstrated the drug to have a triphasic disappearance from plasma. Elimination was independent of dose over the range tested, with mean plasma half-lives of: alpha = 12.9 min, beta = 1.5 h, and gamma = 11.9 h. Cumulative urinary excretion of the drug ranged from 13 to 55% of the administered dose (mean = 33%); 88% of the urinary drug appeared within the first 4 h following drug administration. The pharmacokinetic behavior of the first and second weekly dosages were consistent within a given patient. The metabolites 7-hydroxy-10-EDAM, and 10-ethyl-10-deaza-2,4-diamino-pteroic acid were demonstrated in the plasma and urine of treated patients. In studies of tissue homogenates from two patients with skin metastases, more extensive retention of the drug and of its polyglutamates was observed in the breast cancer metastases than in the metastases from a kidney cancer or in normal skin.

Antagonistic interactions of hexamethylene bisacetamide in combination with 1-beta-D-arabinofuranosylcytosine, adriamycin and harringtonine on the growth and differentiation of HL-60 cells in vitro.

Selective killing of cancer cells by cytotoxic agents and the conversion of cancerous cells to normal state by differentiation agents represent two basically different approaches in chemotherapy. In this study, we examined the combination of the cell differentiation inducer, hexamethylene bisacetamide (HMBA), and the cytotoxic agents, 1-beta-D-arabinofuranosylcytosine (Ara-C), adriamycin (Adr) and harringtonine (HT), for cytotoxicity and induction of cell differentiation in HL-60 cells by measuring cell growth inhibition, morphological maturation and nitroblue tetrazolium (NBT) reduction. To determine quantitatively whether the effects produced by these combinations were additive, synergistic or antagonistic, we used a computer program based on the median-effect principle and isobologram equations (Adv. Enz. Reg. 22, 27-55, 1984), After 5-day exposure to each drug alone we found that the ED50s for cell growth inhibition were 0.01 microM for Ara-C, 0.012 microM for Adr, 0.017 microM for HT and 2.53 mM for HMBA. ED50s for differentiation were 0.089 microM (morphology), 0.06 microM (NBT) for Ara-C; 0.12 microM (morphology), 0.09 microM (NBT) for Adr; 0.04 microM (morphology) 0.06 microM (NBT) for HT; and 2.55 mM (morphology), 2.43 mM (NBT) for HMBA, respectively. At dose levels from ED50 to ED95, the combinations of Adr/HMBA and HT/HMBA produced antagonistic cytotoxic and cell differentiation effects. The combination of Ara-C/HMBA produced antagonistic cytotoxic and cell differentiation effects. The combination of Ara-C/HMBA produced antagonistic cytotoxic effects but slight synergistic cell differentiation effects. On the basis of this study, we conclude that the equipotency combinations of the above three pairs of drugs do not synergistically enhance cytotoxicity or cell differentiation effects in vitro at effect levels high enough for the successful treatment of acute leukemia. Other combinations of cell differentiation agents with cytotoxic agents or biological response modifiers remain to be explored.

Cell differentiation effects of 2'-fluoro-1-beta-D-arabinofuranosyl pyrimidines in HL-60 cells.

A group of 2'-fluoro and 5-substituted arabinosyl pyrimidines and a group of base-substituted pseudoisocytidine analogs were evaluated for their capacity to induce differentiation in the human promyelocytic leukemia cell line, HL-60. These compounds were compared to 1-beta-D-arabinofuranosylcytosine (Ara-C) by monitoring: (1) inhibition of cell growth; (2) morphological maturation; (3) nitroblue tetrazolium (NBT) reduction; (4) expression of a myeloid differentiation antigen, Mo1; and (5) inhibition of colony formation. Exposure of logarithmically growing cells for 5 days to Ara-C, 2'-fluoro-Ara-C (FAC), 2'-fluoro-5-methyl-Ara-C (FMAC) and 2'-fluoro-5-ethyl-Ara-C (FEAC) resulted in cell growth inhibition at ED50 concentrations of 0.007, 0.11, 1.7 and 18 microM, and at cytostatic concentrations of 0.1, 0.5, 5.0 and 50 microM, respectively. These compounds induced granulocytic and monocytic maturation, reduction of NBT, increased expression of Mo1 antigen and a decrease or loss of both cell proliferation and colony formation in semisolid medium. There were few, if any, cell differentiation effects for the uracil nucleosides and pseudoisonucleosides tested. We found that Ara-C was the most cytotoxic of the compounds, and that when comparing absolute numbers of differentiated cells, i.e. percent of positive cells multiplied by the number of viable cells, FAC, FMAC and FEAC were superior to Ara-C inducing differentiation of HL-60 cells.

Respiratory illness and hypophosphatemia.

We retrospectively reviewed the charts of 308 admissions to a pulmonary disease ward and 100 admissions to the general medical service over one year to find the prevalence, sequelae, and etiology of hypophosphatemia. The overall prevalence of low serum phosphate levels (less than 2.4 mg/dl) occurring at least once during hospitalization in chest patients was 17 percent, but was higher in patients with respiratory infections (28 percent). Moreover, the prevalence of hypophosphatemia on admission (before institution of intravenous fluid or drug therapy) was ten times higher in patients with respiratory infections than in patients with noninfectious respiratory illness or general medical patients (21 vs 2 percent, p less than 0.001). Serum phosphate less than 2.0 mg/dl occurred in 4 percent of patients. Twenty-seven percent of the patients (including two with ventilatory failure) with abnormally low serum phosphate levels had symptoms or signs of uncertain etiology later explicable by the presence of hypophosphatemia. The most common additional laboratory finding associated with hypophosphatemia was elevation of muscle enzymes. Although mortality was no higher in hypophosphatemic patients, hospital stay was twice as long as that of patients with normal levels of serum phosphate. No correlation was found between simultaneous arterial blood gases and serum phosphate levels. Two patients given antacids had severe hypophosphatemia and worsened ventilatory function; phosphate-binding antacids should be used judiciously in patients with severe respiratory disease, since they may lead to the development or worsening of hypophosphatemia and diminished ventilatory function.

Incorporation and metabolism of 2'-fluoro-5-substituted arabinosyl pyrimidines and their selective inhibition of viral DNA synthesis in herpes simplex virus type 1 (HSV-1)-infected and mock-infected Vero cells.

The incorporation and metabolism of 2'-fluoro-5-substituted arabinosyl pyrimidine analogs, and their selective inhibition of viral DNA synthesis in herpes simplex virus type 1 (HSV-1)-infected and mock-infected Vero cells were studied by HPLC and CsCl isopycnic density gradient analysis of isolated DNAs. The amounts of radiolabeled analogs incorporated as parent compound following 10 microM exposure for 4 h were 10-fold higher in HSV-1-infected vs mock-infected cells for 2'-fluoro-5-difluoromethyl-Ara-U (F2FMAU); 4.3-fold higher for 5-ethyl deoxyuridine (EdU); 2.6-fold higher for 2'-fluoro-5-methyl-Ara-U (FMAU) and 1.7-fold higher for dThd. For 2'-fluoro-5-ethyl-Ara-U (FEAU), 3.0 pmole of unchanged moiety was incorporated per 10(6) HSV-1-infected cells but no incorporation was detected in mock-infected cells. HPLC profiles showed that the percentages of radiolabeled analogs incorporated as parent compound in the DNA extracted from HSV-1-infected cells were 31.0% for F2FMAU, 99.6% for EdU, 83.5% for FEAU and 98.3% for FMAU; from mock-infected cells, they were 63.6% for F2FMAU, 96.7% for EdU, 97.3% for FMAU and no incorporation into DNA for FEAU was detected. CsCl density gradient analyses of isolated DNA showed that viral DNA synthesis was inhibited 98% by 10 microM FEAU, 92% by 10 microM F2FMAU, 90% by 2 microM FMAU and 80% by 50 microM EdU, whereas cellular DNA synthesis was inhibited by 53, 44, 61, 66 and 54%, respectively. We conclude that: (a) FEAU incorporation into host-cell DNA was not detectable but FEAU was selectively incorporated into HSV-infected cells; (b) FMAU and FEAU were metabolically stable; however, F2FMAU was extensively metabolized; (c) FEAU and F2FMAU were among the most selective inhibitors of HSV-1 DNA synthesis while allowing cellular DNA synthesis to continue.

Successful treatment of a patient with acute nonlymphoblastic leukemia (ANLL) and anthracycline cardiomyopathy with 4' (9-acridinylamino) methanesulfon-m-anisidide (AMSA).

A patient with acute nonlymphoblastic leukemia in relapse and anthracycline cardiomyopathy was treated with AMSA in combination with cytosine arabinoside and thioguanine (AAT). Induction of remission was accomplished after one course of therapy without development of congestive heart failure. Radionuclide studies done prior to and subsequent to the reinduction with AAT revealed that the combination did not induce further deterioration of myocardial function. Although the exact risk of AMSA causing additional cardiac damage will require more extensive experience, this case suggests that AMSA may be safely given to patients with anthracycline cardiomyopathy and may be the treatment of choice for this group of patients.

Phase I/II trial of intravesical methotrexate for superficial bladder tumors.

Twenty-one patients with superficial transitional cell carcinoma of the bladder received a total of 121 doses of intravesical methotrexate (MTX) at 11 different concentrations of drug, ranging from 40 mg/m2 (mean concentration of 2.9 X 10(-3) M) to 500 mg/m2 (4.9 X 10(-2) M). Biochemical evidence of absorption was minimal in all cases. The maximum serum level was observed within 0.5-2 h in all patients and ranged from 1.8 X 10(-8) M to 5.0 X 10(-7) M. By 24 h the serum levels were negligible and ranged from 5.5 X 10(-9) M (the lowest limit detectable by the assay) to 4.4 X 10(-8) M in the patient who received the highest dosage of 500 mg/m2. Biologic evidence of absorption was minimal. Myelosuppression, mucositis, and nausea were not observed. Eighteen patients received six consecutive weekly doses ranging from 40 to 500 mg/m2. All patients had repeat cytoscopy performed within 2-4 weeks after six consecutive doses to evaluate local toxicity and efficacy. Flow cytometry was performed on the bladder washings of 22 patients, illustrating the use of flow cytometry, in conjunction with conventional cytology, as an additional means of objectively quantifying results. Despite MTX's established activity in systemic treatment of advanced bladder carcinoma, this study failed to demonstrate any clinical response to intravesically administered MTX, in doses of up to 500 mg/m2, and in concentrations of up to 4.9 X 10(-2) M.

Factors modulating the epithelial response to toxicants in tracheobronchial airways.

As one of the principal interfaces between the organism and the environment, the respiratory system is a target for a wide variety of toxicants and carcinogens. The cellular and architectural complexity of the respiratory system appears to play a major role in defining the focal nature of the pulmonary response to environmental stressors. This review will address the biological factors that modulate the response of one of the major target compartments within the respiratory system, the tracheobronchial airway tree. Individual airway segments respond uniquely to toxic stress and this response involves not only the target cell population, e.g. epithelium, but also other components of the airway wall suggesting a trophic interaction within all components of the airway wall in maintaining steady state and responding to injury. A number of biological factors modulate the nature of the response, including: (1) metabolic potential at specific sites for activation and detoxification; (2) the nature of the local inflammatory response; (3) age of the organism at the time of exposure; (4) gender of the exposed organism; (5) history of previous exposure; and (6) species and strain of the organism exposed.

Clear cell carcinoma of the ovary: a remarkable case.

Clear cell carcinoma of the ovary is uncommon, and there are few reports of successful long-term therapy. In this case report, a previously healthy preadolescent presented with clear cell carcinoma of the ovary. After progressing through two regimens of chemotherapy, she was given topotecan, which arrested the disease. Nearly 3 years later, she continues to lead a near-normal life as a high school student. Our treatment plan is to continue to administer this therapy at monthly intervals until relapse. Although the achievement of stable disease with topotecan is frequently observed in patients relapsing with epithelial ovarian cancer, durable stable disease in clear cell carcinoma of the ovary is unusual. Treatment--and long-term maintenance therapy--with topotecan may be an option in such patients. In this case, the lack of cumulative toxicities allows the patient to maintain her usual daily activities.

Phase II trial of trimetrexate in patients with stage III and IV non-small-cell lung cancer.

Trimetrexate is a nonclassical antifolate with greater preclinical antitumor activity than methotrexate. Fourteen patients with stage III or IV non-small-cell lung cancer who had not previously received chemotherapy were given trimetrexate (12 mg/m2 intravenously daily for 5 days) every 3 weeks. No major objective responses were observed (95% confidence limits: 0-20%). Ten of the 14 patients had grade 2 or greater toxicity, with 50% experiencing grade 2 or greater leukopenia and/or thrombocytopenia. Nausea, vomiting, rash, mucositis, diarrhea, and serum glutamic-oxaloacetic transaminase (SGOT) elevations were also seen. At the dosage and schedule of trimetrexate used, no responses occurred in this population of patients with non-small-cell lung cancer. With the low response rate and the observed degree of myelosuppression, trimetrexate appears to have limited utility in this disease.

Endotoxin potentiates ozone-induced mucous cell metaplasia in rat nasal epithelium.

People are exposed to a combination of environmental pollutants throughout their lives. Repeated exposures of one common pollutant, ozone, have been reported to cause the development of mucous cell metaplasia in the nasal transitional epithelium (NTE) of rats. The present study was designed to test the hypothesis that exposure to bacterial endotoxin, another toxicant ubiquitous to the environment, potentiates this metaplastic response in rat NTE. Rats were exposed to 0 or 0.5 ppm ozone 8 h/day for 3 days. After ozone exposure, rats were intranasally instilled with saline containing 0 or 100 micrograms endotoxin once daily for 2 days. Rats were killed 6 h or 3 days after the last intranasal instillation. Nasal tissue was processed for light microscopy and image analysis, or for isolation of total RNA. Mucous cell metaplasia was not detected in air/endotoxin-exposed rats, was observed in ozone/saline-exposed rats, and was most severe in ozone/endotoxin-exposed rats. At 6 h after instillation, amounts of intraepithelial mucosubstances (IM) were 4-fold greater in NTE of ozone/endotoxin-exposed rats as compared to controls. These IM levels were similar to those of ozone/saline-exposed rats. Mucin-specific mRNA (rMuc-5AC) levels were elevated in all treatment groups at this timepoint. At 3 days after instillation, amounts of IM in ozone/endotoxin-exposed rats were 10-fold greater than in controls and 5-fold greater than in ozone/saline-exposed rats. rMuc-5AC mRNA levels remained elevated in the ozone/endotoxin-exposed rats. Despite the fact that bacterial endotoxin alone does not cause a phenotypic change in rat NTE, it can augment the mucous cell metaplasia induced by a previous exposure to ozone.

Naphthalene cytotoxicity of differentiating Clara cells in neonatal mice.

Selective Clara cell injury produced by many bioactivated lung toxicants is thought to result from high levels of activating enzymes found in differentiated Clara cells. A recent study found an elevated susceptibility to the Clara cell toxicant 4-ipomeanol in neonatal rabbits when Clara cell P450 activity is low. To determine whether differentiating Clara cells in another species (mouse) are more susceptible to injury by a different bioactivated Clara cell toxicant (naphthalene), adult, 14-day postnatal (DPN) and 7DPN male mice were given a single intraperitoneal dose (25, 50, or 100 mg/kg) of naphthalene and killed 24 hr later. Epithelial damage, as assessed by quantitative histopathology, included cellular swelling, vacuolization, and exfoliation. In 7DPN mice, bronchiolar epithelium was severely injured at the lowest dose of naphthalene tested, 25 mg/kg. Bronchiolar epithelium in 14DPN mice was moderately injured at 25 mg/kg; injury severity was greatest at 50 and 100 mg/kg. Minimal bronchiolar epithelial injury occurred in adult mice at 50 mg/kg and moderate injury at 100 mg/kg. In proximal bronchi, epithelium of 7DPN mice showed signs of injury only at 100 mg/kg. Bronchial epithelium of adult mice was not injured at any dose. Isolated distal airways from 7DPN and 14DPN mice were more sensitive to naphthalene exposure than isolated distal airways from adult mice. Despite the low levels of P450 activity, differentiating Clara cells in neonatal mice are more susceptible to injury by the bioactivated cytotoxicant naphthalene than are differentiated Clara cells in adult mice.