Treatment of solid P815x2 murine mastocytoma with adriamycin (NSC-1231127): toxity limitations.

The efficacy of adriamycin (NSC-123127), given as weekly or as 5-day-per-week doses, on the control of solid P815X2 murine mastocytomas was severely limited by hematopoietic and gastrointestinal toxicity. Although daily or weekly drug schedules both elicited dose responsiveness in terms of tumor control, no dose level of drug increased the life-span of tumor bearing animals.

Combined-modality oncotherapy with cyclophosphamide (NSC-26271) and radiotherapy: control of murine mastocytoma.

We investigated the effects of cyclophosphamide, alone and in combination with a 1,000-R/week radiotherapy schedule, on the growth of solid P815X2 tumors in 12-week-old male DBA/2 mice. Single-dose treatments of 150 mg cyclophosphamide/kg were given to animals bearing tumors of different ages. Such treatment of young tumors resulted in proportionately greater degrees of regression and steeper regrowth curves than did treatment of older tumors. Although slopes of regrowth curves differed greatly, time to regrowth (to pretreatment size) was the same for all age classes of tumors. Graded weekly exposures of 50-250 mg/kg for 4 weeks resulted in dose-dependent increases in incidence of complete remission, duration of remission (time to regrowth), and mean animal life-spans. The combination of radiotherapy to the tumor and 75, 150, or 225 mg cyclophosphamide/kg/week resulted in better local tumor control than occurred with radiotherapy or the drug alone. However, a dose-dependent increase in radiosensitivity of the gastrointestinal mucosa included in radiotherapy fields was observed. A 3-week course of radiotherapy plus 75 mg cyclophosphamide/kg/week (which is tolerated by the mucosa) increased animal lifespans to 165% of those of controls.

Control of local tumor growth with combined fractionated radiotherapeutic and chemotherapeutic regimens.

A treatment concept for the control of tumor growth utilized weekday radiotherapy and weekend chemotherapy. Mice were given sc injections of P815X2 mastocytoma cells on the lower back (day 0) and separated into the following treatment groups: 5-day/week X-irradiation, adriamycin alone at either 5 mg/kg body wt (days 6 and 13) or 2 mg/kg (days 5, 12, and 19), and combined radiotherapy and chemotherapy. Untreated controls had a mean tumor volume of 2.77 cm-3 and a mean survival time of 24 days. Adriamycin alone at 5 mg/kg resulted in an eventual tumor of 70 percent of the control value at death, whereas at 2mg/kg the tumor volume was 60 percent of control. After radiotherapy only, tumor size was 52 percent of control. Irradiation plus either 5 or 2 mg drug per kg body wt resulted in tumor volumes of 23 and 30 percent, respectively, of control values. Although no treatment regimen prolonged survival, the marked reduction in local tumor growth with combination therapy indicates that it may be a useful concept in future cancer therapy.

Influence of adriamycin and adriamycin-radiation combination on jejunal proliferation in the mouse.

The influence of adriamycin and adriamycin-radiation combinations on posttreatment proliferative activity of the mouse jejunum was examined by measuring [3H]thymidine incorporation. Single doses of 5 or 10 mg/kg produced a transient reduction in the proliferative activity, while 1 mg/kg had little effect. After 10 mg/kg, there was a rapid decrease in the number of mitotic figures, followed by a gradual decrease in the number of and rate of DNA synthesis in S-phase cells. A compensatory epithelial hyperplasia characterized by an enlarged crypt proliferative population and shortened mitotic cycle duration was observed beginning 48 hr after treatment. Multiple doses of adriamycin totalling 10 mg/kg inhibited cell production to a greater extent than the equivalent single dose. In combination with 1000 R, adriamycin (5 mg/kg) given from 96 hr before to 72 hr after irradiation reduced the amount of postirradiation proliferation.

A comprehensive evaluation of the mechanism of skin tumorigenesis by straight-run and cracked petroleum middle distillates.

The role of skin irritation and other factors on the tumorigenic activity of petroleum middle distillates (PMDs) in mice was examined in a comprehensive research program. The program culminated in a 2-year dermal carcinogenicity study which compared the effects of equal weekly doses of irritating and nonirritating PMDs. Modified Ames mutagenicity studies and three- to seven-ring polycyclic aromatic compound (PAC) analyses indicated that the mutagenic activity of PMDs was correlated to PAC content. In subchronic and subacute studies, PMDs produced marked skin irritation which was ameliorated if the test samples were diluted in mineral oil. The reduction in irritation level was not a result of reduced dermal absorption. Straight-run kerosine (SRK), straight-run gas oil (SRGO), and catalytically cracked light cycle oil (LCO) were evaluated in the dermal carcinogenicity study. Test materials were applied either undiluted (2x/week) or as 28.5% (7x/week) or 50% (4x/week) concentrations in mineral oil for a total weekly dose of 100 microliters PMD per animal. All three materials produced moderate to marked skin irritation and increased tumor frequency when applied undiluted. When diluted, the irritant effects of SRK and SRGO, which contain low levels of PACs, were ameliorated, and there were no significant increases in tumors relative to controls. LCO, containing 8.7% three- to seven-ring PACs, increased tumor frequency when diluted, even when skin irritation was limited. These data indicate that the tumorigenic activity of straight-run MDs is likely a consequence of a nongenotoxic process, associated with frequent cell damage and repair. PMDs which contain low levels of three- to seven-ring PACs are unlikely to cause tumors in the absence of prolonged skin irritation. In addition, genotoxic mechanisms may also contribute to tumor formation for other PMDs containing higher levels of PACs, e.g., products blended with cracked stocks.

The adjuvant activity of diesel exhaust particles and carbon black on systemic IgE production to ovalbumin in mice after intranasal instillation.

The adjuvant activity of diesel exhaust particles (DEP) on systemic IgE production to ovalbumin (OA) was studied in mice after intranasal administration. The main purpose was to elucidate which part of the particles was responsible for the effect, the carbon core and/or the adsorbed organic substances. Female Balb/cA mice were immunized with OA either alone or in combination with DEP or carbon black particles (CB), the latter used as a surrogate for the non-extractable carbon core of DEP. Controls were given DEP, CB or buffer alone. The animals were immunized four times. 1 and 2 weeks after the last immunization anti OA IgE antibody in serum was analysed by enzyme linked immunosorbent assay (ELISA). An increased response to the antigen was observed in animals receiving OA together with DEP or CB, compared with animals receiving OA alone. The increased response was seen as both increased number of responding animals and increased serum anti OA IgE antibody. For OA + DEP 37% of the animals showed a serum anti OA IgE response, whereas 22% of the OA + CB animals and 10% of the OA animals responded. In conclusion, this work shows that not only DEP, but also CB have an adjuvant activity for specific IgE production after intranasal instillation. However, the activity of DEP may be more pronounced than that of CB. The results imply that both the organic matter adsorbed to DEP and the non-extractable carbon core are responsible for the observed adjuvant effect.

Diesel exhaust particles and carbon black have adjuvant activity on the local lymph node response and systemic IgE production to ovalbumin.

The possible adjuvant effect of diesel exhaust particles (DEP) on the response to the model allergen ovalbumin (OA) was studied in BALB/c mice using the popliteal lymph node (PLN) assay. In addition to changes in PLN weight, cell numbers and cell proliferation, specific serum IgE anti-OA antibody levels were measured. OA inoculated together with DEP into one hind footpad gave a significantly augmented response (increase in weight, cell numbers and cell proliferation) in the draining popliteal lymph node as compared to DEP or OA alone. Also, the local lymph node response was of longer duration when DEP were given with the allergen. Experiments in thymus-deficient nu/nu mice indicated that the lymph node response observed in BALB/c mice was of a specific immunologic character and not an unspecific inflammatory reaction. The OA-specific IgE response was increased in mice receiving OA together with DEP as compared to the response in mice receiving OA without DEP. Carbon black (CB) was given with and without OA in some experiments, as a surrogate for the non-extractable core of DEP. CB was found to resemble DEP in its capacity to increase the local lymph node response and serum specific IgE response to OA, but CB appeared to be slightly less potent than DEP. Thus, both DEP and CB had a significant adjuvant effect on the local immune-mediated inflammatory response and on the systemic specific IgE response to allergen. The results indicate that the non-extractable particle core contributes substantially to the adjuvant activity of DEP.

Assessment in rats of the reproductive toxicity of gasoline from a gasoline vapor recovery unit.

Gasoline (CAS 86290-81-5) is one of the world's largest volume commercial products. Although numerous toxicology studies have been conducted, the potential for reproductive toxicity has not been directly assessed. Accordingly, a two-generation reproductive toxicity study in rats was conducted to provide base data for hazard assessment and risk characterization. The test material, vapor recovery unit gasoline (68514-15-8), is the volatile fraction of formulated gasoline and the material with which humans are most likely to come in contact. The study was of standard design. Exposures were by inhalation at target concentrations of 5000, 10 000, and 20 000 mg/m(3). The highest exposure concentration was approximately 50% of the lower explosive limit and several orders of magnitude above anticipated exposure during refueling. There were no treatment-related clinical or systemic effects in the parental animals, and no microscopic changes other than hyaline droplet nephropathy in the kidneys of the male rats. None of the reproductive parameters were affected, and there were no deleterious effects on offspring survival and growth. The potential for endocrine modulation was also assessed by analysis of sperm count and quality as well as time to onset of developmental landmarks. No toxicologically important differences were found. Therefore, the NOAEL for reproductive toxicity in this study was > or =20 000 mg/m(3). The only systemic effects, in the kidneys of the male rats, were consistent with an alpha-2 u-globulin-mediated process. This is a male rat-specific effect and not relevant to human health risk assessment.

Intestinal cell proliferation during fractionated abdominal irradiation.

In the mouse, at normal steady state of cell proliferation, the compensatory proliferative response to intestinal irradiation is such that when radiation exposures totalling 1,000 R are concentrated over the first few days of the week, summated proliferative activity for the entire week is near control levels. Symmetrically distributed exposures over a five-day treatment week (200 R daily, and especially 333 R on Monday, Wednesday and Friday) result in depressed levels of overall weekly proliferation. In these instances, the weekend break is particularly crucial. Similar results were obtained when the one-week measurement period was inserted between the third and fifth week of abdominal therapy, except in this instance, 200 R per day did not result in sub-control levels of proliferation, whereas 333 R on M, W and F, continued to do so. The intestine seems able to maintain its barrier epithelium for extended periods of diminished cell input, provided such is not too severe and that it seems from decreased cell production rate per crypt rather than from crypt attrition. A partial explanation for this relative tolerance is given by the finding that the vast majority of proliferative cells, even those irradiated and rendered permanently incapable of further division, succeed in migrating up the villus and hence help to maintain a barrier epithelium. In that sense, nearly all cell divisions become useful, even in the face of repeated exposures.

Time/dose relationships in abdominal irradiation: a definition of principles and experimental evaluation.

We have drawn upon the work of numerous investigators to formulate a model describing the principles governing the acute response of the intestinal epithelium to cytotoxic agents. Tolerance (exposure required to kill 50 per cent of the animals) to abdomen-only irradiation was measured experimentally in the mouse using a total of 17 time/dose fractionation schedules. The principle determinants of intestinal response to fractionated radiation therapy were magnitude of each fraction and the introduction of regular recovery intervals during the course of treatment. The roles of exposure per week, exposures per day, and radiation days per week were also examined. The log-log plots of endpoint v. either number of fractions or overall treatment time yielded straight lines with slopes of 0 with 54 and 0 with 59 and y intercepts of 1,270 and 812 rets respectively. The single dose for 50 per cent acute intestinallethality (LD50/6 days) was 1,610 R. It would appear that the acute intestinal tolerance to fractionated irradiation is, in the mouse, extremely dependent upon fraction number and overall treatment time. The biological basis for intestinal tolerance to cytotoxic agents is discussed in light of the results of these studies and the model initially described.

Damage and recovery assessment of the mouse jejunum to abdominal X-ray and adriamycin treatment.

The influence of adriamycin on the post-irradiation proliferative response of the mouse jejunum was examined. Doses of either 5 or 10 mg/kg of adriamycin administered immediately after abdominal irradiation reduced the LD50/7 days by 300-400 R. Neither dosage of the drug reduced the number of surviving crypts, as measured by the crypt isolation and microcolony techniques, for a given radiation exposure. However, both drug dosages reduced the amount of post-irradiation compensatory hyperplasia, as measured by 3H-thymidine incorporation.

Chemical ionization pyrolytical spectra of DNA.

The chemical ionization-pyrolytical (CI-Py) spectra of DNA and deuterated DNA (Herring Sperm) are recorded. The 200-800 a.m.u. region is examined for CH4, NH3, ND3, electron-capture and OH- CI spectra. The origin of major ion species is discussed.