Phorbol 12-myristate 13-acetate

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.；SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. IMMEDIATELY call a hospital or poison control center even if no symptoms (such as redness or irritation) develop. IMMEDIATELY transport the victim to a hospital for treatment after washing the affected areas.；INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. IMMEDIATELY call a physician and be prepared to transport the victim to a hospital even if no symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing.；INGESTION: If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Generally, the induction of vomiting is NOT recommended outside of a physician's care due to the risk of aspirating the chemical into the victim's lungs. However, if the victim is conscious and not convulsing and if medical help is not readily available, consider the risk of inducing vomiting because of the high toxicity of the chemical ingested. Ipecac syrup or salt water may be used in such an emergency. IMMEDIATELY transport the victim to a hospital. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust; Environmental precautions: Do not let product enter drains; Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

SMALL SPILLS AND LEAKAGE: If a spill of this chemical occurs, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with acetone and transfer the dampened material to a suitable container. Use absorbent paper dampened with acetone to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with acetone followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.；STORAGE PRECAUTIONS: You should protect this chemical from exposure to light. Keep the container tightly closed under an inert atmosphere, and store it in a freezer. (NTP, 1992)

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material; Contaminated packaging: Dispose of as unused product.

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed.

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]:；IMMEDIATE PRECAUTIONARY MEASURE: Isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids.；SPILL: Increase the immediate precautionary measure distance, in the downwind direction, as necessary.；FIRE: If tank, rail tank car or highway tank is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2024)

MINIMUM PROTECTIVE CLOTHING: If Tyvek-type disposable protective clothing is not worn during handling of this chemical, wear disposable Tyvek-type sleeves taped to your gloves.；RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter). (NTP, 1992)

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Impervious clothing. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

To determine effect of interval between initiation & promotion & the effect of aging of mice in two-stage carcinogenesis, 20 ug 7,12-dimethylbenz(a)anthracene (initiator) was applied once only & 2.5 ug PMA was applied 3 times/wk to dorsal skin of 5 groups of female ICR/ha Swiss mice. For groups 1, 2, 3, 4 & 5, age (in wk) at primary treatment (initiator) was 6, 44, 56, 6 & 6 respectively; interval (in wk) to secondary treatment (promotor) was 2, 2, 2, 36 & 56 respectively; number of mice/group were 120, 20, 50, 35 & 35 respectively; % mice with papillomas was 100, 100, 56, 90 & 57 respectively; % mice with squamous carcinoma was 50, 30, 6, 25 & 11 respectively. Appropriate control groups consisted of one agent only given at various time intervals. Results show that skin carcinomas are induced whether interval between initiation & promotion is 2, 36 or 56 wk. Carcinoma incidences are significantly lower in groups 3 & 5 where secondary treatment was started when animals were 58 & 62 wk old. /From table/

Because endogenous proteases may play role in mechanism of action of tumor promotors, 3 known protease inhibitors were tested for ... inhibitory effects in two-stage carcinogenesis. Protease inhibitors ... tosyl chloromethyl ketone, tosyl phenylalanine chloromethyl ketone, & tosyl arginine methyl ester ... were applied to mouse ears after initiation with single dose of 7,12-dimethylbenz(a)anthracene followed by promotion with ... PMA. Inhibitors were applied 3 times/wk immediately after application of promoting agent. Protease inhibitors delayed appearance of 1st tumors, changed general pattern of rate of tumor appearance, & caused some decr in tumor incidences.

Low dosages of sulfur mustard, bis(beta-chloroethyl)sulfide completely inhibited two-stage carcinogenesis in mouse skin. 30 Female ICR/ha mice per group received either control applications or different combinations of initiator, promotor & inhibitor test compd for 400 days. 7,12-Dimethylbenz(a)anthracene (DMBA), 20 ug/0.1 mL acetone, applied once only was used as initiator. PMA, the promotor, was applied at 2.5 ug/0.1 mL acetone 3 times/wk. BCS, bis(beta-chloroethyl)sulfide, at 20 ug/0.1 mL acetone was applied beginning 14 days after initiator. DMBA + PMA + BCS (2 times/wk) produced papillomas in 1 mouse with 1st tumor occurring at 90 days; DMBA + PMA + BCS (3 times/wk) produced papillomas in 2 mice occurring at 209 days; DMBA + PMA only produced papillomas in 27 mice & squamous cell carcinomas in 16 occurring at 40 days; PMA alone produced papillomas in 4 mice occurring at 218 days; DMBA + BCS (2 times/wk) produced papillomas in 1 mouse at 385 days; DMBA + BCS (3 times/wk) produced no papillomas; BCS alone (3 times/wk) produced papillomas in 1 mouse at 323 days; DMBA + acetone only produced papillomas in 1 mouse at 219 days; no papillomas were observed in control group admin acetone alone or in group which did not receive either of the test compd. /From table/

The aim of the present study was to determine the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) and diethyldithiocarbamate (DDTC) alone or in combination on human pancreatic cancer cells cultured in vitro and grown as xenograft tumors in nude mice. Pancreatic cancer cells were treated with either DDTC or TPA alone, or in combination and the number of viable cells was then determined by trypan blue ecxlusion assay and the number of apoptotic cells was determined by morphological assessment by staining the cells with propidium iodide and examining them under a fluorescence microscope. Treatment with DDTC or TPA alone inhibited the growth and promoted the apoptosis of pancreatic cancer cells in a concentration-dependent manner. These effects were more prominent following treatment with TPA in combination with DDTC than following treatment with either agent alone in PANC-1 cells in monolayer cultures and in 3 dimensional (3D) cultures. The potent effects of the combination treatment on PANC-1 cells were associated with the inhibition of nuclear factor-kappaB (NF-kappaB) activation and the decreased expression of Bcl-2 induced by DDTC, as shown by NF-kappaB-dependent reporter gene expression assay and western blot analysis. Furthermore, treatment of nude mice with DDTC + TPA strongly inhibited the growth of PANC-1 xenograft tumors. The results of the present study indicate that the administration of TPA and DDTC in combination may be an effective strategy for inhibiting the growth of pancreatic cancer.

For more Interactions (Complete) data for 12-O-TETRADECANOYLPHORBOL-13-ACETATE (16 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.1X10+5(SRC), determined from a structure estimation method(2), indicates that 12-O-tetradecanoylphorbol-13-acetate is expected to be immobile in soil(SRC). Volatilization of 12-O-tetradecanoylphorbol-13-acetate from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 4.7X10-12 atm-cu m/mole(SRC), using a fragment constant estimation method(1). 12-O-Tetradecanoylphorbol-13-acetate is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.8X10-17 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2016).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.1X10+5(SRC), determined from a structure estimation method(2), indicates that 12-O-tetradecanoylphorbol-13-acetate is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 4.7X10-12 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). According to a classification scheme(4), an estimated BCF of 2300(SRC), from an estimated log Kow of 7.36(2), suggests the potential for bioconcentration in aquatic organisms is very high(SRC), provided the compound is not metabolized by the organism(SRC). Biodegradation data in water were not available(SRC, 2016). A base-catalyzed second-order hydrolysis rate constant of 0.042 L/mole-sec(SRC) was estimated using a structure estimation method(2); this corresponds to half-lives of 5.3 years and 192 days at pH values of 7 and 8, respectively(2).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 12-O-tetradecanoylphorbol-13-acetate, which has an estimated vapor pressure of 1.8X10-17 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase 12-O-tetradecanoylphorbol-13-acetate may be removed from the air by wet and dry deposition(SRC). 12-O-Tetradecanoylphorbol-13-acetate absorbs at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Reproductive Toxin - A chemical that is toxic to the reproductive system, including defects in the progeny and injury to male or female reproductive function. Reproductive toxicity includes developmental effects. See Guidelines for Reproductive Toxicity Risk Assessment.

IDENTIFICATION AND USE: TPA is a colorless powder. It is used in cancer research to study mechanisms of tumor promotion, to screen for potential inhibiting agents, and as positive control for tumor promoting agents. It has been tested as experimental medication for the treatment of leukemias and lymphomas and other types of cancer. HUMAN EXPOSURE AND TOXICITY: TPA is a human platelet aggregating agent. TPA was used in clinical trials in humans suffering from recurrent malignancies, particularly hematological malignancies including severe forms of leukemia. The objective of this trial was the use of TPA as an agent to induce, at low doses,apoptosis and cell differentiation. The TPA application was based on current protocols for cytostatic agents, and involved 35 patients given a low dose constant rate infusion over a defined period. Various patients developed severe side effects following the treatment, such as transient fatigue, anemia, neutropenia and thrombocytopenia, mild dyspnea, nausea fever, rigor and cardiovascular effects with syncope and hypotension, but only one patient exhibited a tumor response, consisting in a reduction in mass dimensions. TPA is routinely used in human cell studies in vitro. ANIMAL STUDIES: TPA has been recognized as a tumor promoter in a mouse skin bioassay and in the mouse forestomach as well as in in vitro cell proliferation assays. However, there was no evidence for tumor-initiating properties of TPA. Tumor initiation and promotion was investigated in the epithelium of the forestomach of mice treated intragastrically with a single dose of 7,12-dimethylbenz [a]anthracene(DMBA) at 50 mg TPA/kg bw followed by repeated dosing (twice per week) for 35 weeks of TPA at 10 mg/kg bw. Forty-five out of 50 mice which received this treatment had tumors (papillomas) in the forestomach. There were no forestomach tumors noted for mice in the untreated control and the TPA-only groups, although in the DMBA-only group, papillomas were observed in the

12-O-Tetradecanoylphorbol-13-acetate occurs as the major phorbol diester constituent in croton oil, the seed oil of Croton tiglium L. (Euphorbiaceae)(1,2); 14.99% of the total phorbol weight in croton oil occurs as the diester(1).

Phorbol esters have been identified in Sapium indicum, S. japonicum, Euphorbia frankiana, E. cocrulescence, E. ticulli, Croton spareiflorus, C. tiglium, C. ciliatoglandulifer, Jatropha curcas, Excoecaria agallocha and Homalanthus nutans. These esters are toxic(1). /Phorbol esters/

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical.[Available from: http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=16561-29-8]

Using a structure estimation method based on molecular connectivity indices(1), the Koc of 12-O-tetradecanoylphorbol-13-acetate can be estimated to 1.1X10+5(SRC). According to a classification scheme(2), this estimated Koc value suggests that 12-O-tetradecanoylphorbol-13-acetate is expected to be immobile in soil.

12-O-Tetradecanoylphorbol-13-acetate occurs as the major phorbol diester constituent in croton oil, the seed oil of Croton tiglium L. (Euphorbiaceae)(1).

... croton oil.../derived/ from seeds of Croton tiglium L ... active constituents ... are diesters of a tetracyclic diterpene, phorbol. Fourteen diesters have been isolated from croton oil ... /of which/ most active biologically is 12-O-tetradecanoylphorbol-13-acetate ...

/HUMAN EXPOSURE STUDIES/ Phorbol esters activate protein kinase C and modulate a variety of downstream cell signaling pathways. 12-O-tetradecanoylphorbol-13-acetate (TPA) is a phorbol ester that induces differentiation or apoptosis in a variety of cell lines at low concentrations. A phase I dose escalation trial of TPA was undertaken for patients with relapsed or refractory malignancies. The starting dose was 0.063 mg/sq m and most patients were treated with an intravenous infusion of TPA on days 1-5 and 8-12 followed by a 2-week rest period prior to retreatment. Thirty-five patients were treated. A biological assay was used to monitor levels of TPA-like activity in the blood after treatment. Serious adverse events included individual episodes of gross hematuria, a grand mal seizure, syncope, and hypotension. Many patients had transient fatigue, mild dyspnea, fever, rigors, and muscular aches shortly after the infusion. Dose-limiting toxicities included syncope and hypotension at a dose of 0.188 mg/sq m. Only a single patient had evidence of tumor response. These studies establish 0.125 mg/sq m as the maximally tolerated dose when TPA is administered on this schedule.

/HUMAN EXPOSURE STUDIES/ Nine compounds, based on 4 biogenetically-related polycyclic diterpene skeletons, were subjected to open and closed patch testing on human volunteer subjects. The tigliane esters phorbol-12,13,20-triacetate, 12-O-2Z-4E-octadienoyl-4-deoxyphorbol-13-acetate and 12-O-tigloyl-4-deoxyphorbol-13-isobutyrate, in increasing order of potency, produced symptoms of toxicity in closed patch tests, with the dose of the most potent compound in this series being 0.5 ug in 5 uL acetone. Phorbol, a tigliane alcohol, was inactive in closed tests at a dose level of 50 ug/5 uL. The daphnane derivative, daphnetoxin, produced bullae and vesiculation in closed patch tests, but daphnetoxin-5,20-diacetate was devoid of these effects when applied at 10 times the dose of daphnetoxin. The ingenane compounds, ingenol-3,5,20-triacetate and 20-deoxy-16-hydroxyingenol-3,5,16-triacetate, and the lathyrane compound, ingol-3,7,8,12-tetraacetate, were obtained from the hydrolyzed, acetylated irritant latex of Euphorbia hermentiana. At the doses tested, ingenol-3,5,20-triacetate was the only compound derived from this plant to exhibit irritant activity in closed patch tests. This compound is inactive as an irritant to the mouse ear at dose up to 250 ug/ear. Only 3 compounds, 12-O-2Z-4E-octadienoyl-4-deoxyphorbol-13-acetate, 12-O-tigloyl-4-deoxyphorbol-13-isobutyrate and daphnetoxin, produced dermatological toxicity in open patch tests at the doses used. Inflammatory signs and symptoms for several of the compounds under test persisted for over 4 days in open patch tests and for a week or more after application in closed patch testing.

/ALTERNATIVE and IN VITRO TESTS/ PMA is a human platelet aggregating agent. Low concn...aggregated human platelets slowly at first, but then more rapidly as adenosine diphosphate (ADP) was released. ADP alone also induced platelet aggregation, but unlike ADP-induced aggregation PMA-induced effect could be readily inhibited by chelation of calcium ions. ...It was suggested that PMA-aggregating effect was mediated by platelet actomyosin. ... Blood platelet-aggregating effect is probably not related to tumor-promoting activity...

12-O-Tetradecanoylphorbol-13-acetate's production and use as a tumor promoter and activator of protein kinase C in cancer research(1,2) may result in its release to the environment through various waste streams(SRC). It is also known as purging cotton and used in traditional medicine(3).

An estimated BCF of 2300 was calculated in fish for 12-O-tetradecanoylphorbol-13-acetate(SRC), using an estimated log Kow of 7.36(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is very high(SRC), provided the compound is not metabolized by the organism(SRC).

The Henry's Law constant for 12-O-tetradecanoylphorbol-13-acetate is estimated as 4.7X10-12 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that 12-O-tetradecanoylphorbol-13-acetate is expected to be essentially nonvolatile from water surfaces(2). 12-O-Tetradecanoylphorbol-13-acetate's Henry's Law constant indicates that volatilization from moist soil surfaces is not expected to occur(SRC). 12-O-Tetradecanoylphorbol-13-acetate is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.8X10-17 mm Hg(SRC), determined from a fragment constant method(1).

Tetradecanoic acid, (1aR,1bS,4aR,7aS,7bS,8R,9R,9aS)-9a-(acetyloxy)-1a,1b,4,4a,5,7a,7b,8,9,9a-decahydro-4a,7b-dihydroxy-3-(hydroxymethyl)-1,1,6,8-tetramethyl-5-oxo-1H-cyclopropa3,4benz1,2-eazulen-9-yl ester: Does not have an individual approval but may be used under an appropriate group standard

Highly effective tumor promoter found in croton oil that stimulates DNA and RNA synthesis; [ChemIDplus] Used in cancer research for studying tumor promotion mechanisms, screening for potential inhibiting agents, and as a positive control for tumor promoting agents; [HSDB]

A phorbol ester with potential antineoplastic effects. Tetradecanoylphorbol acetate (TPA) induces maturation and differentiation of hematopoietic cell lines, including leukemic cells. This agent may induce gene expression and protein kinase C (PKC) activity. In addition to potential antineoplastic effects, TPA may exhibit tumor promoting activity.

A substance being studied in the treatment of leukemias and lymphomas. It is also being studied in the treatment of other types of cancer. Tetradecanoylphorbol acetate affects many cell actions and may cause tumor cells to die.

MEDICATION

/Used in/ molecular biology studies as standard; analytical studies of tumor promoters; /for/ promotion of cell growth.