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D L McCormick

Publications and source records attributed to D L McCormick.

At least 55 records · Page 3Linked to original sources
PubMed1985

Modulation of rat mammary carcinogenesis by indomethacin.

Indomethacin, a nonsteroidal antiinflammatory agent which inhibits prostaglandin biosynthesis, has significant activity in inhibiting the growth and/or inducing the regression of transplantable tumors. The present study was designed to determine if, in addition to its chemotherapeutic effects, indomethacin also acts as a cancer chemopreventive agent. Fifty-day-old virgin female Sprague-Dawley rats were given a single intragastric dose of either 8 or 16 mg of 7,12-dimethylbenz(a)anthracene (time 0). Basal diet was supplemented with 25 or 50 mg of indomethacin per kg of diet by the following protocol: (a) -2 to +1 week; (b) +1 week to end; or (c) none. Administration of indomethacin by both protocols resulted in an inhibition of mammary tumorigenesis; however, the effect of -2 to +1 week indomethacin exposure was primarily on the induction of benign mammary tumors, while +1 week to end indomethacin administration inhibited the induction of both benign mammary tumors and mammary cancers. These data indicate that indomethacin has significant protective activity when administered either during the "early" stage (comprising the carcinogen-target cell interaction) or the "late" stage (postcarcinogen tumor development) of mammary carcinogenesis in rats. Possible mechanisms of indomethacin action include both local and systemic effects.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1984

Inhibition of 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinogenesis by concomitant or postcarcinogen antioxidant exposure.

When administered prior to or at the time of carcinogen exposure, the phenolic antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are effective inhibitors of carcinogenesis in several target organs. However, chronic, postcarcinogen administration of BHT apparently enhances tumorigenesis in certain animal models for liver and lung cancer. The present study was performed to determine the effects of BHA and BHT on mammary carcinogenesis when antioxidant exposure is limited to defined periods encompassing or following carcinogen availability. At 50 days of age (Time O), virgin female Sprague-Dawley rats (25/group) were given a single intragastric dose of 8 mg of 7,12-dimethylbenz(a) athracene . Basal diet (Wayne Lab Meal) was supplemented with 5000 or 2500 mg of BHA or BHT/kg by the following protocol: 2 weeks before until 1 week after carcinogen administration; 1 week after carcinogen administration until the end of the study; or none. The experiment was terminated 210 days after 7,12-dimethylbenz(a)anthracene administration, and all mammary tumors were confirmed histologically. When administered by the 2 weeks before to 1 week after schedule, both BHA and BHT were effective inhibitors of mammary carcinogenesis. However, the compounds also were active in chemoprevention when administered by the 1 week after to end protocol. These data indicate that the anticarcinogenic activity of antioxidants is not limited to influences on carcinogen metabolism, since both BHA and BHT inhibited mammary tumor induction when their administration was begun following clearance of the carcinogen from the mammary gland. The anticarcinogenic activity of postcarcinogen administration of BHA and BHT in the mammary gland is in contrast to the apparent tumor-enhancing activity of BHT in the liver and lung.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1983

Inhibition by retinoid and ovariectomy of additional primary malignancies in rats following surgical removal of the first mammary cancer.

Retinoids are highly effective inhibitors of mammary carcinogenesis in the rat. This study was designed to determine the influence of retinyl acetate and bilateral ovariectomy on the rate of new tumor appearance when treatment is started at the time of removal of an animal's first mammary tumor. Fifty-day-old virgin female Sprague-Dawley rats received a single intravenous injection of 35 mg N-methyl-N-nitrosourea per kg body weight. When an animal's first mammary tumor reached a diameter of 0.5 cm it was excised and the animal was entered into a treatment group: (1) intact, placebo diet; (2) intact, 328 mg retinyl acetate/kg diet; (3) ovariectomy, placebo diet; (4) ovariectomy, 328 mg retinyl acetate/kg diet. New tumor incidence was reduced from 94% in Group 1 to 15% in Group 4. Groups 2 and 3 had an intermediate tumor response. These data indicate that retinyl acetate and ovariectomy are active in cancer prevention when treatment is began after removal of a palpable tumor, a time at which preneoplastic lesions are present in the mammary glands.

Animals↗
PubMed1983

Inhibition of carcinogenesis by retinoids.

Retinoids are effective inhibitors of chemical carcinogenesis in the mammary gland and urinary bladder of experimental animals. Modification of the basic retinoid structure has produced retinoids with increased target organ specificity, resulting in increased anticancer activity with reduced systemic toxicity. Combining retinoid treatment with hormonal manipulation results in a synergistic inhibition of mammary carcinogenesis; this combination approach also inhibits development of additional mammary cancers following surgical removal of the first mammary cancer. Retinoids are most effective when administered shortly after the carcinogenic insult. However, even when retinoid treatment is delayed, the compounds are still effective cancer chemopreventive agents for the mammary gland and urinary bladder. The length of time that retinoid exposure can be delayed and retain an anticancer effect is directly related to tumor latency, with a longer delay permissible against tumors with long latent periods.

Adenocarcinoma↗
PubMed1982

Temporal association between arterial cholesterol deposition, thymidine incorporation into DNA, and atherosclerosis in Japanese quail fed an atherogenic diet.

Male Japanese quail (strain SEA) rapidly develop atherosclerotic lesions in the aorta and brachiocephalic arteries when fed an atherogenic diet containing 1.0% cholesterol and 0.5% cholic acid. The present study was conducted to determine the parameters of the atherosclerotic response. Groups of 20 quail fed the atherogenic diet were killed at 0 days, 1 day, 3 days, or weekly from 1 to 12 weeks. Quail fed the atherogenic diet for 1 day showed a significant increase in serum cholesterol; a plateau was reached by 2 weeks. A significant increase in arterial cholesterol was seen after 2 weeks on the atherogenic diet, and arterial cholesterol showed a linear increase with time from 2 to 12 weeks. Increased incorporation of tritiated thymidine into the DNA of arterial cells was first seen at 2 weeks; thymidine incorporation increased to a maximum value at 9 weeks, then declined to 50-60% of the 9-week value at weeks 11 and 12. Grossly visible atherosclerotic lesions were first seen at 3 weeks, and 90% of birds showed gross atherosclerotic lesions by 8 weeks. Atherosclerosis induced in Japanese quail by feeding cholesterol and cholic acid is characterized initially by lipid deposition in the arterial wall, followed by increased incorporation of tritiated thymidine and the appearance of gross lesions.

Animals↗
PubMed1982

Inhibition of chemical carcinogenesis by retinoids.

Retinoids are effective inhibitors of chemical carcinogenesis in the mammary gland, esophagus, and urinary bladder of experimental animals. Modification of the basic retinoid structure has produced retinoids with increased target organ specificity, resulting in increased anticancer activity with reduced systemic toxicity. Combining retinoid treatment with hormonal manipulation results in a synergistic inhibition of mammary carcinogenesis; this combination approach also inhibits mammary tumor recurrence following surgical removal of the first mammary tumor. Retinoids are most effective when administered shortly after the carcinogenic insult. However, even when retinoid treatment if delayed, the compounds are still effective cancer chemopreventive agents for the mammary gland and urinary bladder. The length of time that retinoid exposure can be delayed and retain an anticancer effect is directly related to tumor latency, with a longer delay permissible against tumors with long latent periods. Current research focuses on the identification of new retinoids with increased chemopreventive activity and decreased toxicity, and combination studies which will provide treatment regimens with increased anticancer activity as well as information pertaining to mechanisms of retinoid action.

Animals↗
PubMed1982

Correlation between retinoid inhibition of N-methyl-N-nitrosourea-induced mammary carcinogenesis and levels of retinoic acid binding proteins.

A correlation was made between the ability of retinoids to suppress N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis and the levels of cytosolic retinoic acid binding proteins (cRABP) in the cytosol of MNU-induced mammary tumors. Although retinyl acetate and N-(4-hydroxyphenyl)-retinamide were found to be effective inhibitors of mammary carcinogenesis in intact hosts, both retinoids were significantly more active in ovariectomized rats than in intact animals. Quantitative analysis of cRABP in the tumors indicated that mammary cancers arising in animals which were ovariectomized one week after MNU administration contained significantly increased concentrations of cRABP compared to cancers appearing in intact rats. In addition, when animals bearing palpable mammary tumors were ovariectomized, the tumors which continued to grow contained significantly higher levels of cRABP than did tumors which stopped growing or regressed. These data suggest that the selective inhibition of ovarian hormone-independent mammary cancer by retinyl acetate and N-(4-hydroxyphenyl)retinamide may be mediated through an increased level of cRABP in tumor cells of ovariectomized hosts.

Animals↗
PubMed1982

Influence of 15 retinoic acid amides on urinary bladder carcinogenesis in the mouse.

A series of experiments was conducted to determine the efficacy of 15 synthetic retinoic acid amides (retinamides) as inhibitors of chemical carcinogenesis of the urinary bladder in C57BL/6 x DBA/2F1 mice. Eight of the retinamides tested had significant protective activity when administered at nontoxic levels in the diet. Minor structural alterations, such as the addition of a methyl or hydroxyl group to the terminal amide moiety had a major influence on the anticarcinogenic activity of the retinamides. Although 13-cis retinamides generally were less toxic on a molar basis than were their all-trans isomers, no consistent pattern of differential anticarcinogenic activity was noted among the six pairs of all-trans and 13-cis isomers tested. All-trans-4-hydroxyphenyl retinamide was among the most active and least toxic of the retinoids tested, and appears to be the compound of choice for further study.

Animals↗
PubMed1982

Inhibition of mammary and urinary bladder carcinogenesis by a retinoid and a maleic anhydride-divinyl ether copolymer (MVE-2).

N-(4-hydroxyphenyl)retinamide (4-HPR), a synthetic retinoid, and MVE-2, a maleic anhydride-divinyl ether copolymer, were both effective inhibitors of mammary carcinogenesis induced in Sprague-Dawley rats by N-methyl-N-nitrosourea and of urinary bladder carcinogenesis induced in C57BL/6 x DBA/2F1 mice by N-butyl-N-(4-hydroxybutyl)-nitrosamine. However, combined administration of 4-HPR and MVE-2 was no more effective in cancer inhibition than was either agent alone. Retinoids and maleic anhydridedivinyl ethers may exhibit a mechanistic or metabolic antagonism which precludes an additive or synergistic interaction in inhibiting chemical carcinogenesis.

Animals↗
PubMed1982

Enhanced inhibition of mammary carcinogenesis by combined treatment with N-(4-hydroxyphenyl)retinamide and ovariectomy.

Bilateral ovariectomy and dietary administration of the retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) are both effective inhibitors of chemical carcinogenesis in the rat mammary gland. The present study was designed to determine whether an enhanced inhibitory effect is obtained with combined ovariectomy and 4-HPR administration, compared to either treatment alone. In separate experiments, 50-day-old virgin female Sprague-Dawley rats received either a single i.v. injection of 50 mg N-methyl-N-nitrosourea per kg body weight or a single intragastric dose of 20 mg 7,12-dimethylbenz(a)anthracene. The experimental design was the same in both the N-methyl-N-nitrosourea and 7,12-dimethylbenz(a)anthracene experiments: Group 1, 25 intact rats, placebo diet; Group 2, 25 intact rats, supplement of 782 mg 4-HPR per kg diet; Group 3, 50 ovariectomized rats, placebo diet; Group 4, 50 ovariectomized rats, supplement of 782 mg 4-HPR per kg diet. Feeding of the 4-HPR supplement was begun 7 days after carcinogen administration; ovariectomy was performed 7 days post-7,12-dimethylbenz(a)anthracene or 14 days post-N-methyl-N-nitrosourea. In both experiments, combined ovariectomy plus 4-HPR was significantly more active in suppressing mammary cancer induction than was either manipulation alone. 4-HPR was a more effective inhibitor of carcinogenesis in ovariectomized rats than in intact animals. These data indicate that 4-HPR is highly effective in inhibiting ovarian hormone-independent cancers and suggest that retinoid inhibition of mammary carcinogenesis does not involve an influence on ovarian hormone action.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1982

Influence of delayed administration of retinyl acetate on mammary carcinogenesis.

Administration of a dietary retinoid supplement beginning 1 week after carcinogen administration is highly effective in the inhibition of rat mammary carcinogenesis. A study was designed at two carcinogen dose levels to determine to what extent retinoid feeding can be delayed and retain its chemoprotective effect. In the high-dose experiment, groups of 30 virgin female Sprague-Dawley rats received a single i.v. dose of 50 mg N-methyl-N-nitrosourea (MNU) per kg body weight and were fed a dietary supplement of 328 mg retinyl acetate per kg diet beginning at 1, 4, or 8 weeks after MNU administration. In the low-dose experiment, groups of 50 rats received 25 mg MNU per kg, and the retinoid was begun at 1, 4, 8, 12, 16, or 20 weeks post-MNU. Controls at both dose levels received a placebo diet beginning 1 week after carcinogen treatment. At the high MNU dose, retinyl acetate was most effective in inhibition of carcinogenesis when treatment was begun 1 week after MNU administration. Delaying retinyl acetate feeding until 4 weeks post-MNU resulted in slightly reduced chemoprotective efficacy, while an 8-week delay caused a complement loss of anticancer activity. At the low MNU dose, delaying retinyl acetate administration for up to 12 weeks after MNU administration caused no loss of chemopreventive efficacy. A 16-week delay resulted in decreased anticancer activity, while retinoid treatment begun 20 weeks post-MNU had no effect on cancer induction. Retinoid administration can be delayed beyond 1 week and retain its activity against rat mammary carcinogenesis; the length of delay allowable without loss of activity is a function of tumor latency.

Animals↗
PubMed1981

Influence of total dose and dose schedule on induction of urinary bladder cancer in the mouse by N-butyl-N-(4-hydroxybutyl)nitrosamine.

Dose-response relationships in the induction of urinary bladder cancer in male C57BL/6 x DBA/2-F1 (BDF) mice by intragastric instillation of N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN) were studied. Administration of a total dose of 0 to 80 mg OH-BBN in 10 weekly fractions to groups of 25 mice resulted in a linear increase in carcinoma incidence with dose. OH-BBN administration schedule had a significant effect on cancer incidence: administration of a total dose of 30, 20, or 15 mg OH-BBN in 20 weekly fractions was more effective in cancer induction than was the same total dose given in 5 fractions. A 10 dose administration schedule was of intermediate efficacy. The data obtained indicate that OH-BBN induces urinary bladder cancers in BDF mice in a dose-related manner, with high target organ-specificity, little toxicity, and short tumor latency; induced tumors are primarily transitional cell carcinomas which morphologically resemble their human counterpart. Administration of OH-BBN mice provides a useful model for the experimental study of urinary bladder cancer.

Animals↗
PubMed1981

Inhibition of benz[a]pyrene-induced mammary carcinogenesis by retinyl acetate.

The administration of a 250-ppm retinyl acetate dietary supplement for various periods relative to intragastric administration of 50 mg benzo[a]pyrene (BP) significantly inhibited the induction of mammary cancers in virgin female inbred LEW/Mai rats. with day of BP administration taken as time 0, groups receiving the retinoid from weeks -2 to +1, +1 to +90, +20 to +90, and -2 to +90 showed a significant reduction in tumor response as compared to controls. The inhibition of carcinogenesis achieved by a +1 to +20 administration schedule was temporary; the tumor yield was suppressed initially but returned to control levels by week 60. Autoradiographic analysis of mammary glands from 50-day-old rats indicated that a 2-week exposure to supplemental retinyl acetate significantly reduced the mammary gland parenchymal cell labeling index in ductal, alveolar, and terminal end bud structures. Beginning the retinyl acetate supplement 1 week after the administration of BP significantly reduced the number of terminal ductal hyperplasias. The inhibition of carcinogenesis achieved by a short period of retinyl acetate administration before and during the period of carcinogen availability as well as the inhibition achieved by long-term postcarcinogen retinoid exposure may involve an antiproliferative effect on the rat mammary gland.

Animals↗
PubMed1981

Lifetime dose-response relationships for mammary tumor induction by a single administration of N-methyl-N-nitrosourea.

Dose-response relationships for the induction of mammary tumors by a single i.v. injection of N-methyl-N-nitrosourea (MNU) were studied. At 50 days of age, groups of 20 virgin female Sprague-Dawley rats received single doses of 50, 45, 40, 35, 30, 25, 20, 15, or 10 mg MNU per kg body weight; a group of 10 control rats received 0.85% NaCl solution only. Animals were observed for the appearance of mammary tumors over their life span or until 600 days after carcinogen administration. Both malignant and benign mammary tumors appeared in all groups; however, malignant tumors appeared earlier and at a faster rate than did benign tumors. Incidence of cancer and number of cancers per animal increased with increasing MNU dose; the latent period for cancer increased with decreasing dose. The number of benign tumors induced as a percentage of total tumors increased with decreasing dose, ranging from approximately 10% in groups receiving more than 30 mg MNU per kg to 58% in the group receiving 10 mg/kg. Foci of metastatic mammary carcinoma were found in lungs of animals in several MNU dose groups. Data from the present study indicate that a single i.v. administration of MNU induces mammary cancer in a dose-related fashion, with little toxicity and a short latent period; induced cancers metastasize to distant sites. The single-dose MNU model thus appears to be superior to both the 7,12-dimethylbenz(a)anthracene and multiple-dose MNU models, particularly for use in studies of modification of mammary carcinogenesis.

Adenocarcinoma↗