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Antimutagenic radioprotective compounds have been reported to decrease the yield of chemically induced chromosome aberrations even when administered long before the chemical mutagen thio-TEPA. Because thio-TEPA can induce aberrations in all parts of the cell cycle, it seemed likely that the apparent decrease in aberrations was the result of an effect of the antimutagen on the progression of cells through the cell cycle so that cells treated in the more sensitive stage would be scored. To test this possibility human lymphocytes were treated with the protective compound WR2721 and then thio-TEPA. The cells were grown in the presence of 5-bromodeoxyuridine, which allows the definitive determination of metaphases from cells that divided once, twice, or three times after treatment. The yield of aberrations observed in first division cells was the same whether or not the protector was present. A decrease in aberration yields appeared only in rapidly cycling cells that were in the second division at the time of fixation. Labeling experiments showed that in this rapidly dividing population fewer of the metaphase cells had been in G2 when thio-TEPA was added. The results indicate that part of the decrease in aberration yields obtained by treatment with an antimutagen several hours before the addition of a mutagen is an artifact of cell selection.
Combination effect of antitumor agents, including doxorubicin and daunorubicin, was evaluated on the concept of pharmacological synergism in ascites sarcoma-180 system. In alternate adminsitration, combinations of doxorubicin plus cyclophosphamide, thio-TEPA, carboquone, actinomycin-D, vinblastine, vincristine, methotrexate, cytarabine, 6-mercaptopurine, or L-asparaginase showed synergism, but in simultaneous one, only three agents, cyclophosphamide, carboquone, and cytarabine, were synergistic. On the other hand, combination of daunorubicin plus one of 8 agents (thio-TEPA, mitomycin-C, bleomycin, actinomycin-D, vinblastine, ancytabine, 6-mercaptopurine, and L-asparaginase) and 6 agents (cyclophosphamide, thio-TEPA, mitomycin-C, bleomycin, actinomycin-D, and vinblastine) provided synergism in alternate and simultaneous administration. Combination effect of agents was affected by the schedule of drug administration for doxorubicin, but weak for daunorubicin. Toxicity of doxorubicin or daunorubicin in combination with other drugs was also affected by the schedule of administration. Combination of a larger number of agents in simultaneous administration provided antagonism compared with an alternate administration.
This report is based on 903 patients with resections for gastric carcinoma between October 1957, and July 1969, entered in controlled trials of adjuvant therapy with Thio-TEPA and FUDR. Neither Thio-TEPA nor FUDR, as administered, prolonged survival. The extent of disease at the time of curative surgery is related to survival for the first 36 months postoperatively. Involvement of lymph nodes, resection of the esophagus, and serosal penetration are predictive of recurrence up to 36 months. There appear to be three groups of patients: 1) Cured (26%); 2) Slowly growing tumor--23% (median survival, 25 months); and 3) Rapidly growing tumor--51% (median survival, eight months). The absence of blood-vessel invasion, lymphatic invasion, lymph-node involvement, and serosal penetration characterize those patients in Group A.
Twenty-one anti-cancer drugs have been tested for their ability to cause mutations in Salmonella typhimurium test strains in the Salmonella/microsome mutagenicity test. Nine of the 21 anticancer drugs showed this ability: cyclophosphmide, nitromin, thio-tepa, busulfan, 6-mercaptopurine, neocarzinostatin, daunomycin, adriamycin and estramustine phosphate. Seven of these 9 mutagenic drugs were injected continuously into the jugular veins of rats. Urine was collected through a cystostomy tube and tested for mutagenicity. The urine from rats treated with 6 of these 7 drugs was mutagenic. These were cyclophosphamide, nitromin, thio-tepa, neocarzinostatin, adriamycin and daunomycin.
A comparison was made of 14C-leucine incorporation and cell viability of T24 human bladder carcinoma cells after treatment with Thio-Tepa, a potent alkylating agent. It was found that Thio-Tepa produced concentration-dependent damage in these cells and also that 14C-leucine incorporation correlated well with cell viability. 14C-leucine incorporation can be used as a reliable and rapid screening test for the assessment of the relative potencies of anticancer drugs.
In vitro sensitivity of an established cell line from human urinary bladder cancer to various chemotherapeutic agents was determined by 14C-leucine incorporation into the target cells. Of 12 drugs tested, Carboquone, Neocarzinostatin, Actinomycin D, Adriamycin, Mitomycin C and Chromomycin A3 produced intensive cytotoxic effects, while Thio-Tepa, Bleomycin, 5-Fluorouracil and Vincirstine were less cytotoxic, Intravesical instillation of Carboquone, one of the most toxic agents in vitro, resulted in complete or partial tumor remission in 6 of 9 patients with bladder cancer. Prophylactic effects of periodic intravesical Carboquone were also indicated in 7 of 8 patients who had experienced recurring superficial bladder tumors.
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.
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.
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.
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.
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.
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.
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.
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.
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.