Thio-TEPA

Thio-TEPA is a DNA alkylating agent, with antitumor activity.

Signaling Pathways >> Cell Cycle/DNA Damage >> DNA Alkylator/Crosslinker

Research Areas >> Cancer

DNA Alkylator[1]

Thio-TEPA exhibits alkylating activity in rat liver slice incubation. Thio-TEPA does not affect the viability of rat liver slices, and is not accumulated in the slices at all doses of 2, 5, 10 mM[1].

Thio-TEPA (20 mg/kg, i.p.) with total body irradiation (TBI) enhances donor-type blood chimerism during the first 10 weeks but is not dramatically higher than that of TBI group alone. Thio-TEPA alone improves both short- and long-term engraftment in mice[2].

The effect of Thio-TEPA on slice viability is studied by the determination of intracellular potassium (K+) leakage. Intracellular K+ is measured by flame photometry and is expressed in relation to the DNA content as measured using fluorometry. Thio-TEPA is added at concentrations of 1, 2, 5, and 10 mM and slices are incubated for 6, 12, and 24 h. The results are compared with the values found for drug-free controls. Thio-TEPA in medium and slices is measured following 3, 6, and 9 h incubation at the three highest concentrations. Krebs-HEPES buffer is used as the slicing buffer and Waymouth's MB 752/1 medium supplemented with 10 μg gentamycin is used as the incubation medium[1].

Mice[2] Male C57BL/6JIco mice, 19 weeks old, 25 to 30 g, are used as recipients. Congenic C57BL/6J-Gpi-1a/Gpi-1a (B6-Gpi-1a) and BALB.B10LiLa (Gpi-1a) mice are used as a source of syngeneic and allogeneic donor bone marrow, respectively. The latter combination is H-2-compatible (both H-2b), but mismatched on a number of minor histocompatibility loci. Thio-TEPA is dissolved in PBS and injected i.p. at a single bolus of 20 mg/kg. Preliminary pilot experiments have established that this approximated to the maximal tolerated dose when higher doses result in lethal gastrointestinal toxicity. Cyclophosphamide (CY) is dissolved in PBS and administered i.p. at a single dose of 200 mg/kg. Total body irradiation is delivered using a 137Cs γ-irradiation unit at a dose rate of 87 cGy/min to a dose of 5 Gy. After Thio-TEPA treatment the mice are maintained on neomycin (3.5 g/L sterile drinking water) for 2 weeks to minimize the possible problems of endotoxemia via gut toxicity[2].

[1]. Hagen B, et al. Metabolism and alkylating activity of thio-TEPA in rat liver slice incubation. Cancer Chemother Pharmacol. 1991;28(6):441-7.

[2]. Down JD, et al. Thiotepa improves allogeneic bone marrow engraftment without enhancing stem cell depletion in irradiated mice. Bone Marrow Transplant. 1998 Feb;21(4):327-30.

Calicheamicin | Carmustine | RITA (NSC 652287) | Lomustine | SJG-136 | Fotemustine | Procarbazine hydrochloride | VAL-083 | Miriplatin | Altretamine | Treosulfan | Uramustine | Satraplatin

DATA ITEMS CITED :

116

MOLECULAR FORMULA :

C6-H12-N3-P-S

MOLECULAR WEIGHT :

189.24

WISWESSER LINE NOTATION :

T3NTJ APS&- AT3NTJ&- AT3NTJ

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

Standard Draize test

ROUTE OF EXPOSURE :

Administration onto the skin

SPECIES OBSERVED :

Human

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Parenteral

SPECIES OBSERVED :

Human - man

DOSE/DURATION :

631 ug/kg

TOXIC EFFECTS :

Peripheral Nerve and Sensation - paresthesis Blood - changes in bone marrow (not otherwise specified)

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

8 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

9400 ug/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraarterial

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

8750 ug/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

38 mg/kg

TOXIC EFFECTS :

Peripheral Nerve and Sensation - flaccid paralysis without anesthesia (usually neuromuscular blockage) Behavioral - somnolence (general depressed activity) Behavioral - ataxia

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

11 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

16500 ug/kg

TOXIC EFFECTS :

Liver - hepatitis (hepatocellular necrosis), zonal Kidney, Ureter, Bladder - changes in tubules (including acute renal failure, acute tubular necrosis) Blood - changes in spleen

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

14500 ug/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intramuscular

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

11500 ug/kg

TOXIC EFFECTS :

Tumorigenic - active as anti-cancer agent

TYPE OF TEST :

LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

760 ug/kg

TOXIC EFFECTS :

Blood - leukopenia Blood - agranulocytosis Blood - other changes

TYPE OF TEST :

LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Primate - monkey

DOSE/DURATION :

1500 ug/kg

TOXIC EFFECTS :

Blood - leukopenia Blood - agranulocytosis Blood - other changes

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rabbit

DOSE/DURATION :

5500 ug/kg

TOXIC EFFECTS :

Liver - hepatitis (hepatocellular necrosis), zonal Kidney, Ureter, Bladder - changes in tubules (including acute renal failure, acute tubular necrosis) Blood - changes in spleen

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Bird - quail

DOSE/DURATION :

237 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Bird - wild bird species

DOSE/DURATION :

5620 ug/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Parenteral

SPECIES OBSERVED :

Human - man

DOSE/DURATION :

33 mg/kg/3Y-I

TOXIC EFFECTS :

Tumorigenic - Carcinogenic by RTECS criteria Blood - leukemia

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Unreported

SPECIES OBSERVED :

Human - woman

DOSE/DURATION :

17 mg/kg/56W-I

TOXIC EFFECTS :

Tumorigenic - Carcinogenic by RTECS criteria Blood - leukemia

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

218 mg/kg/1Y-I

TOXIC EFFECTS :

Tumorigenic - Carcinogenic by RTECS criteria Sense Organs and Special Senses (Ear) - effect, not otherwise specified Skin and Appendages - tumors

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

52 mg/kg/1Y-I

TOXIC EFFECTS :

Tumorigenic - Carcinogenic by RTECS criteria Gastrointestinal - tumors Blood - lymphoma, including Hodgkin's disease

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Administration onto the skin

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

10 gm/kg/17W-I

TOXIC EFFECTS :

Tumorigenic - equivocal tumorigenic agent by RTECS criteria Skin and Appendages - tumors

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

47 mg/kg/8W-I

TOXIC EFFECTS :

Tumorigenic - neoplastic by RTECS criteria Lungs, Thorax, or Respiration - tumors

TYPE OF TEST :

TD - Toxic dose (other than lowest)

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

360 mg/kg/1Y-I

TOXIC EFFECTS :

Tumorigenic - Carcinogenic by RTECS criteria Blood - leukemia Blood - lymphoma, including Hodgkin's disease

TYPE OF TEST :

TD - Toxic dose (other than lowest)

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

218 mg/kg/1Y-I

TOXIC EFFECTS :

Tumorigenic - Carcinogenic by RTECS criteria Sense Organs and Special Senses (Ear) - effect, not otherwise specified Skin and Appendages - tumors

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

2 mg/kg

SEX/DURATION :

male 5 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Fertility - male fertility index (e.g. # males impregnating females per # males exposed to fertile nonpregnant females)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

5 mg/kg

SEX/DURATION :

female 12 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) Reproductive - Specific Developmental Abnormalities - musculoskeletal system Reproductive - Specific Developmental Abnormalities - Central Nervous System

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

7500 ug/kg

SEX/DURATION :

male 1 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Paternal Effects - spermatogenesis (incl. genetic material, sperm morphology, motility, and count)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

2500 ug/kg

SEX/DURATION :

female 12 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) Reproductive - Specific Developmental Abnormalities - musculoskeletal system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

500 ug/kg

SEX/DURATION :

female 13 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetal death Reproductive - Specific Developmental Abnormalities - musculoskeletal system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intratesticular

DOSE :

8 mg/kg

SEX/DURATION :

male 1 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Fertility - male fertility index (e.g. # males impregnating females per # males exposed to fertile nonpregnant females) Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured before birth)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

25 mg/kg

SEX/DURATION :

male 5 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Fertility - pre-implantation mortality (e.g. reduction in number of implants per female; total number of implants per corpora lutea)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

625 ug/kg

SEX/DURATION :

female 12 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Newborn - behavioral

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

1 mg/kg

SEX/DURATION :

female 10 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - musculoskeletal system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

1250 ug/kg

SEX/DURATION :

male 1 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Paternal Effects - spermatogenesis (incl. genetic material, sperm morphology, motility, and count) Reproductive - Fertility - pre-implantation mortality (e.g. reduction in number of implants per female; total number of implants per corpora lutea)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

5 mg/kg

SEX/DURATION :

female 10 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - craniofacial (including nose and tongue)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

7500 ug/kg

SEX/DURATION :

female 7 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - Central Nervous System Reproductive - Specific Developmental Abnormalities - body wall

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

3 mg/kg

SEX/DURATION :

female 10 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

5 mg/kg

SEX/DURATION :

male 5 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Paternal Effects - spermatogenesis (incl. genetic material, sperm morphology, motility, and count)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

1 mg/kg

SEX/DURATION :

male 5 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Paternal Effects - testes, epididymis, sperm duct

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intratesticular

DOSE :

16 mg/kg

SEX/DURATION :

male 1 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Fertility - male fertility index (e.g. # males impregnating females per # males exposed to fertile nonpregnant females) Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured before birth)

TYPE OF TEST :

Specific locus test

TYPE OF TEST :

Sex chromosome loss and nondisjunction

TYPE OF TEST :

Micronucleus test

TYPE OF TEST :

DNA inhibition

TYPE OF TEST :

Mutation test systems - not otherwise specified

TYPE OF TEST :

Micronucleus test

TYPE OF TEST :

DNA damage

TYPE OF TEST :

Cytogenetic analysis

TYPE OF TEST :

Cytogenetic analysis

TYPE OF TEST :

Sister chromatid exchange

TYPE OF TEST :

Dominant lethal test

TYPE OF TEST :

Dominant lethal test

TYPE OF TEST :

Sperm Morphology

TYPE OF TEST :

Heritable translocation test

TYPE OF TEST :

Cytogenetic analysis

TYPE OF TEST :

Sister chromatid exchange

TYPE OF TEST :

Sister chromatid exchange

TYPE OF TEST :

Cytogenetic analysis

TYPE OF TEST :

Cytogenetic analysis

TYPE OF TEST :

Sister chromatid exchange

MUTATION DATA

TYPE OF TEST :

DNA inhibition

TEST SYSTEM :

Rodent - rabbit Kidney

DOSE/DURATION :

15 mg/L

REFERENCE :

ECREAL Experimental Cell Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.10- 1950- Volume(issue)/page/year: 36,92,1964 *** REVIEWS *** IARC Cancer Review:Animal Sufficient Evidence IMEMDT IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- Volume(issue)/page/year: 9,85,1975 IARC Cancer Review:Animal Sufficient Evidence IMEMDT IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- Volume(issue)/page/year: 50,123,1990 IARC Cancer Review:Human Sufficient Evidence IMEMDT IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- Volume(issue)/page/year: 50,123,1990 IARC Cancer Review:Human Inadequate Evidence IMEMDT IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- Volume(issue)/page/year: 9,85,1975 IARC Cancer Review:Group 1 IMEMDT IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- Volume(issue)/page/year: 50,123,1990 TOXICOLOGY REVIEW 32XPAD "Teratology," Berry, C.L., and D.E. Poswillo, eds., New York, Springer, 1975 Volume(issue)/page/year: -,49,1975 TOXICOLOGY REVIEW ANPIAM Arquivos de Neuro-Psiquiatria. (Caixa Postal 30.657, 01051 Sao Paulo, Brazil) V.1- 1943- Volume(issue)/page/year: 5,447,1965 TOXICOLOGY REVIEW CRTXB2 CRC Critical Reviews in Toxicology. (CRC Press, Inc., 2000 Corporate Blvd., NW, Boca Raton, FL 33431) V.1- 1971- Volume(issue)/page/year: 2,159,1973 *** NIOSH STANDARDS DEVELOPMENT AND SURVEILLANCE DATA *** NIOSH OCCUPATIONAL EXPOSURE SURVEY DATA : NOES - National Occupational Exposure Survey (1983) NOES Hazard Code - X4618 No. of Facilities: 142 (estimated) No. of Industries: 1 No. of Occupations: 6 No. of Employees: 11452 (estimated) No. of Female Employees: 8724 (estimated)