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PubMed1977

Multifocal leukoencephalopathy in adult leukemia: histologic features and etiologic considerations.

A number of structural alteration in brains of leukemic children have been attributed to intrathecal administration of methotrexate and radiation therapy. We report an instance of asymptomatic encephalopathy in an adult who received thio-TEPA (by subarachnoid injection) as treatment for leukemic meningitis. The lesions were microscopic, confined to cerebral white matter and included: vacuolation, myelin destruction, axonal swelling, gliosis, deposition of mineral salts and aggregates of large foamy cells. The etiology of this condition remains undetermined.

Adult↗
PubMed1978

Histopathology and histochemistry of the insects treated with chemosterilants VI: brain damage including reduced neurosecretion caused by chemosterilants in Periplaneta americana (L).

The brain is damaged and neurosecretion is reduced in the P. americana treated with chemosterilants thio-tepa and bis (dimethylamino) dithiazolium chloride. The damage includes, separation of neurolemma, vacuolisation and chromatolysis in the nuclei of neurons and extensive damage to fibres. Reduced neurosecretion, vacuolisation in the cytoplasm and karyolysis in the nucleus of neurosecretory cells, are also observed. These changes in the brain are of considerable importance to understand the mode of action of the chemosterilants.

Animals↗
PubMed1992

Reductive metabolism of diaziquone (AZQ) in the S9 fraction of MCF-7 cells. II. Enhancement of the alkylating activity of AZQ by NAD(P)H: quinone-acceptor oxidoreductase (DT-diaphorase).

The alkylating activity of reduced diaziquone was studied by the nitrobenzylpyridine (NBP) assay and was compared to those of the parent compound and aziridine-containing N,N',N"-triethylenethiophosphoramide (Thio-TEPA). Diaziquone (AZQ) was reduced enzymatically by 2e- using S9 cell fraction from MCF-7 cells which is rich in NAA(P)H:quinone-acceptor oxidoreductase (DT-diaphorase) (QAO) activity. One electron enzymatic reduction was performed with NADPH-cytochrome c reductase. The alkylating activity of AZQ increased 3-fold when reduced by 2e-. This increase was inhibited by dicumarol, an inhibitor of QAO. In contrast, the alkylating activity of AZQ did not increase beyond that of the parent compound when reduced by 1e- using purified NADPH-cytochrome c reductase. Similar results were obtained when AZQ was reduced chemically with borohydride (2e-) and with NADPH (1e-). Anaerobic incubations of AZQ with the S9 fraction of MCF-7 cells (2e- reduction) resulted in an increase in NBP alkylation over its aerobic counterpart (1.8-fold) while maintaining the near 3-fold increase in alkylation over untreated AZQ. In contrast, AZQ incubations with NADPH-cytochrome c reductase (1e- reduction) under the same conditions did not result in an NBP alkylation increase over untreated AZQ. These results indicate that AZQ hydroquinone is most likely the responsible species for the observed alkylation of this antitumor agent to DNA and other nucleophiles. The results also suggest that NAD(P)H:quinone-acceptor oxidoreductase is a very important enzyme in the bioactivation of AZQ.

Alkylation↗
PubMed1979

Mutagenicity tests with griseofulvin.

Griseofulvin was studied for its ability to induce structural chromosomal aberrations in germ and somatic cells of the male mouse. It was also tested for its capacity to produce his+ revertants in Salmonella typhimurium. All tests yielded negative results, whereas highly significant effects were recorded in control assays with thio-TEPA.

Animals↗
PubMed1979

Effects of cancer chemotherapeutic agents on testicular DNA synthesis in the rat. Evaluation of a short-term test for studies of the genetic toxicity of chemicals and drugs in vivo.

Changes in the rate of testicular DNA synthesis in the rat were studied at various times after single doses of 12 cancer chemotherapeutic agents. The animals were given intravenous injections of [14C]thymidine and [3H]thymidine 24 and 3 h, resp., before they were killed. By combining measurements of the free serum radioactivity and the testicular incorporation of the differentially labelled precursor, different response patterns were obtained for agents with different modes of action. The DNA-damaging agents cyclophosphamide, chlorambucil, thio-TEPA, busulphan, CCNU and procarbacine, after some delay, caused a decrease of testicular thymidine incorporation and a corresponding increase of free serum radioactivity. The non-DNA-damaging agents 5-fluorouracil, methotrexate, hydroxyurea and cytosine arabinoside had a rapid effect on testicular thymidine incorporation and produced diverse response patterns different from that of the DNA-damaging agents. Actinomycin D and also vinblastine caused changes in testicular thymidine incorporation and showed response patterns different from those of the other agents. These results show that simple measurements of testicular DNA synthesis may provide useful information for the evaluation of genotoxic effects of chemical compounds and may help one to distinguish between DNA-damaging agents and metabolic inhibitors of DNA synthesis.

Animals↗
PubMed1975

Chemical induction of sperm abnormalities in mice.

The sperm of (C57BL X C3H)F1 mice were examined 1, 4, and 10 weeks after a subacute treatment with one of 25 chemicals at two or more dose levels. The fraction of sperm that were abnormal in shape was elevated above control values of 1.2-3.4% for methyl methanesulfonate, ethyl methanesulfonate, griseofulvin, benzo[a]pyrene, METEPA [tris(2-methyl-l-aziridinyl)phosphine oxide], THIO-TEPA [tris(l-aziridinyl)phosphine sulfide], mitomycin C, myleran, vinblastine sulphate, hydroxyurea, 3-methylcholanthrene, colchicine, actinomycin D, imuran, cyclophosphamide, 5-iododeoxyuridine, dichlorvos, aminopterin, and trimethylphosphate. Dimethylnitrosamine, urethane, DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane], 1,1-dimethylhydrazine, caffeine, and calcium cyclamate did not induce elevated levels of sperm abnormalities. The results suggest that sperm abnormalities might provide a rapid inexpensive mammalian screen for agents that lead to errors in the differentiation of spermatogenic stem cells in vivo and thus indicate agents which might prove to be mutagenic, teratogenic, or carcinogenic.

Animals↗
PubMed1977

Cidal and subcidal effect of triethylene thiophosphoramide on cell kinetics of human bladder carcinoma cells in vitro.

In view of increasing topical use of various chemotherapeutic agents for bladder carcinoma, an experimental study concerning the effect of triethylene thiophosphoramide (Thio-Tepa) on cell kinetics of bladder carcinoma cells was performed, working on an established cell line of human bladder carcinoma. This polyfunctional alkylating agent, which is most widely used for instillation chemotherapy of bladder carcinoma, revealed a concentration dependent cytotoxicity against the cells. DNA precursor incorporation suggested that repair mechanism occurred following subcidal dose of this compound and faulty repair took place following cidal dose. The cell cycle was prolonged after subcidal treatment, the main effect being seen in DNA synthetic phase, and the changes in the cell cycle parameters returned to the normal within 2 cell cycle time. Repeated treatment with subcidal dose at an interval of 48 hr led to more extensive changes in the cell cycle as compared with that of single dose. Repeated exposures to subcidal dose, however, did not show any differences in the growth curves from those of the controls.

Cell Division↗
PubMed1978

Postoperative irradiation and chemotherapy in patients with advanced ovarian cancer.

Two groups of patients with stage III ovarian carcinoma were selected for a randomized clinical trial. The first group consisted of 157 patients who had radical surgery at their first laparotomy, the second group consisted of 145 patients with inoperable disease. The aim of the trial was to compare the results of maximum external megavoltage irradiation, 5 000 rads, to a large abdominal field, with the results of a reduced dose, 3 000 rads, immediately followed by chemotherapy with an alkylating agent (Thio-tepa). In none of the groups, did maximum radiotherapy prove superior to the schedule of a reduced dose combined with chemotherapy. The less costly and time saving combined treatment was better tolerated than irradiation alone. Histological tumour type did not influence the prognosis in these advanced cases where spread was found outside the true pelvis.

Clinical Trials as Topic↗
PubMed1975

Mesonephric carcinoma of the female urethra.

Mesonephric carcinoma of the female urethra is rare arising from vestiges of the Wolffian duct and is particularly of gynaecological or urological interest. It has been treated once successfully by radical anterior pelvic exenteration. By more conservative methods of treatment such as transurethral resections, radiation or topical application of thio-tepa it is poorly controlled. The diagnosis is established by a histological pattern reminiscent of the mesonephros.

Female↗
PubMed1978

[Effect of age on the sensitivity of mouse spermatogonia to mutagenic action].

Male BALB/c mice were whole body exposed to 0, 100, 200 or 300 R of X-rays or were given an i.p. injection of 5 mg/kg of thio-TEPA at 3 months or at 12 months of age. One hundred days after treatment the testes were examined for the presence of reciprocal translocations induced in spermatogonia and detectable in the dividing spermatocytes. Our results show that ages does not influence the yield of scorable chromosome rearrangements.

Aging↗
PubMed1977

Mutagenicity of cancer chemotherapeutic agents in the Salmonella/microsome test.

Seventeen cancer chemotherapeutic agents were tested for their ability to mutate Salmonella typhimurium tester strains in the Salmonella/microsome mutagenicity test. There was a high correlation between the mutagenicity and carcinogenicity of a given agent. Carcinogens positive in the test were Adriamycin, daunomycin, 1-propanol-3,3'-iminodimethanesulfonate, cyclophosphamide, isophosphamide, hycanthone, chlornaphazin, nitrogen mustard, uracil mustard, melphalan, and thio-tepa. Two carcinogesn, actinomycin D and bleomycin, were not detected as mutagens. The presumptive noncarcinogen, methotrexate, was negative in the test. Tilorone and 6-mercaptopurine, tentatively classified as noncarcinogens, were mutagenic. The carcinogenicity of cis-dichlorodiammineplatinum(II), which was positive in the test, has not been determined.

2-Naphthylamine↗
PubMed1978

[Metastasis to the lymph nodes as an index of the effectiveness of preoperative endolymphatic polychemotherapy of cervix cancer].

Ninety eight patients with cervical cancer were subjected to endolymphatic chemotherapy with multiple cytostatic drugs to affect metastatic lymph nodes. A comcentrated mixture of chemotherapeutic drugs (total amount about 20 ml) was injected into plantar lymph vessels, an interval being 10-14 days. The combinations and dosage of the drugs were as follows: thio-TEPA (100-150 mg) or cyclophosphamid (1000-2000 mg)+methotrexate (100 mg)+5-fluorouracil (1000-1500 mg). Subsequently, 76 patients underwent an extended extirpation of the uterus with adnexa, and their lymph-nodes were studied morphologically. It was found that the number of metastases into the lymphnodes was considerably less than it had been expected. Of 45 patients with the disease stage II metastases have been found only in 3 cases (7%). Of 24 patients with cancer stage III the lymphnodes were involved in 4 cases (16.6%). According to the literature data metastatic involvement of the lymphnodes is on an average encountered in 36% for stage II and in 51% - for stage III.

Clinical Trials as Topic↗
PubMed1975

[Chemotherapy of patients with recurring malignant tumors of the ovaries].

The results of treatment in 59 patients with recurrent malignant ovarian tumors, using three chemotherapeutic drugs: thio-TEPA, cyclophosphane and a drug from the sym.-triazine (No31) group are analysed. The effect of these substances was estimated comparatively. The frequency of remissions proved to be practically similar. However, there was noted a tendency toward greater duration of remissions with the drug No 31 chemotherapy.

Adult↗
PubMedDate not supplied

[Study of the cytogenetic activity of radioprotectors in a human lymphocyte culture. II].

Action of certain radioprotectors: 2-mercaptoethylamine HCl (MEA), cysteine HCl, 2-aminoethylsothiouronium (AET), dithiol 2,3-dimercaptopropansulphate Na (unithiol), aminopropylaminoethylthiophosphoric acid (gammaphos), cystaphos and 5-metoxytriptamine (mexamine) was studied as applied to human chromosome aberrations induced with thio-TEPA. It was shown that with an increase in thioTEPA and protectors concentrations their effect grows.

5-Methoxytryptamine↗
PubMed1975

[The mutagenic effect of thioTEPA in laboratory mice. IV. The influence of genotype and sex on the frequency of induced chromosome aberrations in bone marrow cells].

In bone marrow cells of eleven genotypes of mice strain and sex variations in sensitivity to cytogenetic effect of thio-TEPA were studied. Strains 101/H, C57BL/6 and A/Sn were the more sensitive and F1 (CBAXC57BL/6) and F1 (C3HX101) were the more resistant to induction of chromosome damages. The rate of induced chromosome aberrations was correlated with the level of spontaneous chromosome damages in bone marrow cells (r=+/-0,893+/-0,02). From all strains males were more mutable than females. It is recommended to use C57BL/6 strain of mice male for genetic tests of chemicals by cytogenetic methods in vivo.

Animals↗
PubMed1975

[The mutagenic effect of thioTEPA in laboratory mice. V. The influence of female genotype on the realization of dominant lethal mutations induced in male spermatids].

Hybrid male mice (F1 males derived from the cross DBA/2 X AKR) were injected intraperitoneally with thio-TEPA at a 2 mg/kg dose. The mutagenic effect was determined from the frequency of dominant lethal mutations induced in spermatids of males. The malles were mated during the second and the third week after the injection to females of the strains C57BL/6, CBA/lac and to the F1 hybrid females derived from the cross CBA X C57BL/6 differing in the frequency of spontaneous and induced aberrations in bone marrow cells. In the course of investigation of pregnant C57BL/6 females, F1 (CBA X C57BL/6) and CBA/Lac females the frequency of dominant lethals induced in late spermatidis was established to be 63.4, 54.0and 37.9% respectively. The differences were interpreted as the evidence of different rates of recovery of a certain proportion of premutational lesions of the chromosomes of sperms in fertilized eggcells of female mice. No significant differences between the groups of females were observed in case of the treatment of early spermatids. It is established that the F1 hybrids derived from the cross DBA/2X XAKR are characterized by a high mutability.

Animals↗