Diflubenzuron: Intestinal absorption and metabolism in the rat

Willems, A. G. M.; Overmars, H.; Scherpenisse, Peter; Lange, Nikola; Post, L. C.

doi:10.3109/00498258009033736

Cited by 11 publications

(9 citation statements)

References 5 publications

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“…Other workers (Metcalf et al, 1975;Ivie, 1978;Willems et al, 1980) have all reported identification of hydroxylated diflubenzuron metabolites in sheep, cattle, and rats. Tentative identification of metabolites III and/or IV as hydroxylated products based on TLC chromatography in some solvent systems suggests that chickens are able to hydroxylate diflubenzuron.…”

Section: Discussionmentioning

confidence: 96%

In vivo and liver microsomal metabolism of diflubenzuron by two breeds of chickens

Opdycke¹,

Miller²,

Menzer³

1982

J. Agric. Food Chem.

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Section: Discussionmentioning

confidence: 96%

In vivo and liver microsomal metabolism of diflubenzuron by two breeds of chickens

Opdycke¹,

Miller²,

Menzer³

1982

J. Agric. Food Chem.

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“…An obvious question is why each of the repeat injections of DFB did not reduce tumor volume accordingly and delay resumption of the growth curve to the same extent as the initial injection. One possibility relates to differential sensitivities of cells (10) such as selective sensitive or partial synchrony of cells into resistant stages, but the subject of this study relates to rapid metabolic degradation of the compound in rodents (11). If DFB requires metabolic alteration to be effective, repeated daily injections could rapidly reduce the pool of enzymes necessary for the alteration and tumors in the animals would appear less susceptible or refractory to further injections of DFB.…”

Section: Discussionmentioning

confidence: 99%

“…The metabolite chlorophenylurea (CPU) was quite toxic and excess deaths began to occur about 5 days after the initial injection, therefore, the data were limited to 5 days after the initial injection. Selection of metabolites for injection was based on studies by Willems et al (11) who showed that initial metabolic alteration of DFB in rodents was either by aromatic hydroxylation or by cleavage at the benzoyl-ureido bridge (Fig. 1).…”

Section: -Oh-dfbmentioning

confidence: 99%

“…Tumors resumed a normal (control-like) pattern of volume increase after an intitial decrease of 10 to 20% within 24 hours and a delay of 2 or 3 days. The temporary effects were attributed, possibly, to a rapid degradation of DFB in rodents and excretion of the products within 72 hours after injection (10,11). Since response of tumors to DFB may depend on metabolic alteration of DFB, studies were performed to determine the influence of in vivo suppression or induction of mixed function oxidase on tumor responses to DFB.…”

Section: Introductionmentioning

confidence: 99%

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Role of metabolism in effects of diflubenzuron on growth of B16 melanomas in mice

Jenkins¹,

Perry²,

Ahmed³

et al. 1986

Invest New Drugs

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The insect growth regulator diflubenzuron (DFB), which also inhibits growth of experimental tumors in mice, was studied to determine the influence of in vivo microsomal metabolism on its antitumor activity. DFB inhibits chitin synthesis and growth of imaginal epidermis in insects and suppresses melanogenesis and uptake of nucleosides in mouse melanoma cells, but the means of cell growth regulation and the role of metabolism of DFB in such regulation have not been established. Five daily injections of DFB (total of 4000 mg/kg) into C57BL/6 mice with B16 melanomas induced an acute 11-20% decrease in tumor volume and a 2-3 day increase in the initial tumor volume doubling time (Td), but at mid-treatment tumors regained maximum (control-like) rate of volume increase. Tumors in mice conditioned with a mixed function oxidase inhibitor (CoCl2) and treated with DFB did not decrease in mean volume, but their rate of volume increase was reduced by about 75% and the Td was increased by 4.2 days. In contrast, induction of mixed function oxidase with 3-methylcholanthrene (3-MC) or beta-napthaflavone (B-NF) enhanced the effects of DFB by a factor of 1.5 to 2.0. Therefore, aromatic hydroxylation of DFB may be required for tumor growth regulation. Three metabolites of DFB--two hydroxylated forms and a scission product, 4-chlorophenylurea (CPU), were also tested for tumor growth regulation. CPU was ineffective; a form oxidized at the 3 carbon of the phenyl ring (3-OH-DFB) was only marginally effective; but the 2-carbon form (2-OH-DFB) induced a 24% decrease in mean tumor volume and a 2.4 day increase in Td. Pretreatment with 3-MC and treatment with 2-OH-DFB also resulted in a 24% decrease in tumor volume and a 2.2 day increase in Td, but also reduced tumor volume increase to 20% between the 5th and 10th days after the initial 2-OH-DFB injection, compared to a 125% increase without 3-MC. Further, 3-MC pretreatment caused the otherwise marginally effective 3-OH-DFB to become almost as effective as 2-OH-DFB. These data support our previous report that DFB alters tumor growth and show that mixed function oxidase enhances effects of DFB, 2-OH-DFB and 3-OH-DFB.

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“…Decrease in volume does not adequately reflect changes in the number of viable cells since loss of non-viable cells and repopulation by viable ceils are taking place simultaneously. It was not surprising that the effects of DFB occurred rapidly in the mouse since it has been shown that DFB is completely and rapidly metabolized in rats and the metabolites are almost completely excreted within 72 h after oral administration (16).…”

Section: Discussionmentioning

confidence: 99%

Effects of diflubenzuron on growth of malignant melanoma and skin carcinoma tumors in mice

1984

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The insect growth regulator diflubenzuron (DFB), which may also inhibit growth of imaginal epidermal cells in insects, was studied for antitumor activity in two mouse tumor models of epidermal origin. DFB inhibits chitin deposition, but the mechanisms by which DFB controls chitin deposition or regulates growth of insect epidermal cells are unknown. A single injection of 20 mg (800 mg/kg) of DFB into C57BL/6 mice with B16 malignant melanomas or AKR mice with skin tumors (CA 1025) induced a rapid (24 h) decrease in tumor volume in 78% and 66% of the tumors, respectively. In contrast, 85% of the melanomas and 91% of skin tumors in control mice increased in volume during the same 24-h period. Tumor volume decreased by as much as 55% for about 1% of the tumors, but the median decrease was 20% for both types of tumors. Since control tumors concommitantly increased, DFB-treated tumors decreased, relatively, to 60% of the volume of matched control tumors. After the initial volume decrease, both types of tumors resumed exponential growth resulting in an average growth curve delay, calculated for 12-14 days, of about 2.0 days. Subsequent treatment of melanomas with DFB 24 h after the initial treatment resulted in a further decrease in relative tumor volume to 40-50% of control tumor volume and a growth curve delay of 2.6 days. The most effective regimen used was 5 daily, 20-mg doses of DFB. Melanomas decreased to 40% of control tumor volume after the third injection and the mean growth curve delay was extended to 4.3 days.(ABSTRACT TRUNCATED AT 250 WORDS)

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Diflubenzuron: Intestinal absorption and metabolism in the rat

Cited by 11 publications

References 5 publications

In vivo and liver microsomal metabolism of diflubenzuron by two breeds of chickens

In vivo and liver microsomal metabolism of diflubenzuron by two breeds of chickens

Role of metabolism in effects of diflubenzuron on growth of B16 melanomas in mice

Effects of diflubenzuron on growth of malignant melanoma and skin carcinoma tumors in mice

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