Influence of tetrachlorodecaoxide (Ryoxon) on the development of leukemia after total-body gamma-irradiation.

The effect of tetrachlorodecaoxide (TCDO) treatment after total-body irradiation (TBI) with gamma-rays (single dose, about LD 50) on the development of radiation-induced leukemia was tested in rats. TCDO was applied intravenously from day 4 through day 11. The control group was exposed to the same dosage of X-rays (TBI), but received physiological saline solution instead of TCDO. Compared to the control group, TCDO therapy initially markedly increased the survival rate: 72 versus 44% (6 months after TBI) and 36 versus 20% (1-year survival rate). The overall survival, however, was not significantly prolonged. TBI caused leukemia in 36% of the rats in the irradiation control group without TCDO treatment, however, none of 24 rats treated with TCDO after X-ray exposure developed leukemia. Since in this study TCDO was only administered for 8 days during the acute phase of radiation syndrome, we suppose that additional TCDO treatment at various times later on would lead to even better results.

Anticarcinogenic effect of tetrachlorodecaoxide after total-body gamma irradiation in rats.

Tetrachlorodecaoxygen (TCDO) therapy of acute radiation syndrome was tested for a possible influence on the development of X-ray-induced malignancies. BD IX rats were exposed to total-body irradiation (TBI, gamma rays, 9 or 11 Gy) and received daily intravenous injections of either TCDO or physiological saline solution from days 4 through 11 after TBI. The short-term TCDO therapy reduced the acute death rate markedly, but survival rates after 4 months were similar with and without TCDO. The first malignancy after TBI occurred on day 103, and over the lifetime of the animals the tumor incidence in the group given TBI (11 Gy) without TCDO treatment was 73% vs 20% in animals with short-term TCDO therapy after TBI. In particular, there was a highly significant prevention of radiation-induced leukemia [P (one-sided) < 0.001] by TCDO, and a significantly reduced incidence of malignant epithelial tumors [P (one-sided) < 0.05]. The development of sarcomas was not affected by TCDO. Long-term survival was not enhanced by TCDO due to the occurrence of bronchopneumonial infections about 1 year after TBI. In conclusion, TCDO is not only a potent therapeutic agent in acute radiation syndrome, but it also significantly reduced the carcinogenic risk in rats after exposure to ionizing radiation.

Comparative study on the effects of chlorite oxygen reaction product TCDO (tetrachlorodecaoxygen) and sodium chlorite solution (NaClO2) with equimolar chlorite content on bone marrow and peripheral blood of BDIX rats.

The effects of the chlorite-oxygen reaction product TCDO (tetrachlorodecaoxygen, active ingredient of the systemic application form of WF 10) were investigated on bone marrow and peripheral blood of BDIX rats in comparison to a sodium chlorite solution with a chlorite content identical to that of WF 10. Despite difficulties in determining the chemical differences between TCDO and a sodium chlorite solution, their differing effects on cells, tissue and organism were striking. The following characteristics have been observed: Stimulation of the bone marrow, evidenced by the pronounced increase in mature granulocytes, pronormo- and normoblasts, or increased cell proliferation rate, determined by means of the BrdUrd method, was achieved only with WF 10 (TCDO). Stimulation of the bone marrow led in turn to increased numbers of leucocytes and monocytes in the peripheral blood. In addition, WF 10 induced the production of large granular lymphocytes (LGLs), referred to as natural killer cells (NK-cells). In contrast, NaClO2 solution suppressed bone marrow function, exhibiting a toxic effect when given on a long-term basis. At the same time the number of mature granulocytes as well as pronormo- and normoblasts decreased, while the presence of LGLs was not observed. The results showed that TCDO is a potent stimulator of the bone marrow function and an effective modulator of the entire immune system. The toxic effect of chlorite, derived from the TCDO matrix, is not noticeable, being completely compensated by the favourable effects of TCDO.

[Prevention of extravasation necroses as a complication following intravenous cytostatic drug therapy. Results of an open pilot study]. / Verhinderung von Extravasatnekrosen als Komplikation nach intravenöser Zytostatikatherapie. Ergebnisse einer offenen Pilotstudie.

Extravasation of some cytostatics applied i.v. can often cause local edema with skin redness, thrombophlebitis and not infrequently skin necrosis with chronic ulcera. Local treatment is usually ineffective, and so far surgical excision of ulcera is the only curative approach. Tetrachlorodecaoxygen anion complex (TCDO) has shown high activity in healing chronic leg ulcera, by increasing pO2 in hypoxic wound tissue and stimulating phagocytosis as one of anti-inflammatory processes To study the local activity of TCDO in tissue necrosis and chronic ulcera caused by cytostatic extravasation, 23 patients with local skin complications underwent local treatment with TCDO, made as isotonic water solution. Seventeen patients experienced only local edema with redness, while 6 patients showed deep chronic ulcera. All the skin changes were complications after i.v. doxorubicin, cisplatinum, dactinomycin or vinblastine application. The treatments with TCDO followed 1-3 months after ulcera appeared, while skin inflammations were treated 1-8 days after they occurred. TCDO was applied locally twice a day by impregnated cotton tissue for 4-6 weeks. Evaluable were only measurable lesions. From 17 patients with only skin inflammation 3 patients obtained complete resolution, 8 partial resolution and 6 had stable lesions. Thus, overall response was recorded in 65% of patients (11/17). In 6 patients with deep chronic ulcera a longer treatment (6 weeks) was needed, and in 5 of them the complete epithelization and resolution occurred. One patient had a partial wound healing. No side effects of treatment were observed. The effect of locally applied TCDO in chronic ulcera seems to be preferable to surgical treatment. A controlled study will show the exact therapeutic value of this new anti-inflammatory compound.

Regenerative effects of tetrachlorodecaoxide in BD IX rats after total-body gamma irradiation.

Tetrachlorodecaoxide (TCDO) was tested for its effects in BD IX rats when combined with a single dose nearing LD50 of total-body irradiation (gamma rays, 60Co). In pilot tests we found that TCDO administrations prior to or immediately after irradiation led to a very high mortality rate (up to 90%), whereas the initiation of TCDO treatment on Day 2, 3, or 4 after irradiation lowered the death rate noticeably, with optimum results when TCDO application was started on Day 4. In our major experiment on 100 BD IX rats, it was demonstrated that the following treatment schedule considerably decreased the death rate (from 44 to 4%): 15.5 mumol TCDO/kg body wt/day on Days 4-6 after irradiation and 7.75 mumol/kg body wt/day on Days 7-11. The animals treated with TCDO showed only mild anemia in the peripheral blood, accompanied by reticulocytosis and low-grade leukocytopenia. Examination of the bone marrow on Day 12 after irradiation revealed X-ray-induced agranulocytosis in the animals that had received only physiological saline solution, whereas in the bone marrow of the animals treated with TCDO there was erythropoiesis as well as myelopoiesis. In addition, the degree of hair loss and depigmentation occurring about 1 month after irradiation was considerably reduced by TCDO. From these results it can be postulated that TCDO has two different effects: as an oxygen donator it causes radiosensitization in the tissue when given before or immediately after irradiation; as an agent stimulating phagocytes and tissue regeneration, it promotes regeneration very effectively when damage is already evident in the tissue.

Carcinogenic effect of cisplatin (cis-diammine-dichloroplatinum (II), CDDP) in BD IX rats.

The potent antitumor agent cis-diammine-dichloroplatinum(II) (CDDP) also has carcinogenic properties. CDDP was administered i.p. to 50 BD IX rats for 3 weeks, 3 X 1 mg/kg body weight per week. All animals were pretreated by hydration before each CDDP application, but only half the animals additionally received mannitol together with the CDDP solution, as a nephroprotective measure. To date, 455 days after the first application, 33 animals have died, 13 of them of malignancies: 12 leukemias and 1 renal fibrosarcoma. So far, no significant differences in the frequency and type of malignancies have been observed between animals which additionally received mannitol and the others which did not. In the control group of 25 animals, which received NaCl solution 0.9% i.p. (3 X 1 ml/kg per week, for 3 weeks) malignancies have not yet occurred. The high tumor incidence determined in this study reveals that the risk of secondary tumor development in patients treated with CDDP should not be disregarded.

Chemotherapy-induced malignancies in rats after treatment with cisplatin as single agent and in combination: preliminary results.

6 groups of 24-50 BD IX rats, each, were treated with cis-diamminedichloroplatinum (CDDP)-(II) alone or in combination chemotherapy. The animals were either bearing transplanted adenocarcinomas of the stomach or large bowel, or were treated without having any tumors, to study the long-term consequences of the chemotherapy. CDDP was given within 3 weeks either as 9 X 1 mg/kg body weight, or 9 X 2 mg/kg. Autopsy findings revealed fibrosarcomas of the kidneys and/or leukemias in each of the six groups, while the 77 animals of the control group, which did not receive chemotherapeutic agents, did not show any malignancies in postmortem examinations. In one group of rats, which received CDDP in combination with 1-methyl-1-nitroso-urea (MNU), 50% of the animals that survived chemotherapy for more than 100 days died of malignancies, mainly of fibrosarcomas of the kidneys and leukemias. In another group, 24% of the animals, which survived more than 100 days after chemotherapy with CDDP alone, had developed myeloic leukemias. We therefore may presume that a carcinogenic risk in cancer chemotherapy with CDDP is also present in humans.