|
|||||||||||
|
|||||||||||
|
|||||||||||||||
 |
|
|
PRECLINICAL ANTI-TUMOR STUDIES
THE EFFECT OF AMYGDALIN IN THE DEVELOPMENT OF BREAST TUMORS
Translation from the original performed by Dr. Kanematsu Sugiura
We received 60 female mice CD8F1 from Dr. Daniel S. Martin of the Catholic Medical Center of Brooklyn and Oueens, New York, on the fourth of May, 1973, for our experiments with AMYGDALIN. These mice were born in December of 1972. We separated the mice into two groups: 30 control mice which were given daily (except Sundays) intraperitoneal injections of saline solution for eight weeks or more and another 30 mice which were given AMYGDALIN in daily dosages of 2,000 mg/kg per mouse during the same period of time. The animals were weighed weekly and the development of the tumors was recorded. Approximately 30% of the mice were found to be pregnant. The purpose of this study is to document the effect of AMYGDALIN in the development of spon taneous breast cancer and its metastasis to the lung. The experiment was initiated May 8, 1973. From May 8 to July 9 (62 days), the control group as well as the experimental ones maintained ade quate body weight. The general state of health and the appearance of the animals treated with AMYG DALIN and those of the control group was good. Nevertheless, five of the 30 mice in the experimental group died during this period because the dosage was reduced to 1,000 mg/kg per day. The sudden death of these animals was probably due to the insertion of the needle into the intestine or the uterus of the pregnant mice, because the No. 23 1/2-inch (Becton-Dickinson and Co.) needles were changed to 14-inch needles. During the course of the experiment the effect of AMYGDALIN administered orally in the mice was determined. Each experiment consisted of two BaIb C57-C1 mice and they received a daily solution of AMYGDALIN. It was observed that dosages of 2,000 and 1,000 mg/kg per day caused the death of the animals in one hour. With dosages of 500 mg/kg per day, the animals lived more than one hour but died within two to three hours after the administration. All animals experienced bleeding in the lungs. With dosages of 250,100 and 50 mg/kg per day, they lived on indefinitely. The daily examination of the animals treated with AMYGDALIN and those of the control group (until August 2,1973, or 86 days from the beginning of the experiment) did not show evidence of the development of spontaneous breast tumors in the animals. In August the mice were eight months old and I am still waiting for the appearance of spontaneous tumors in the control group. The histological studies of the breat tumors from the first experiment (September 12, 1972), reported in every case adenocarcinomas with very active neoplastic cells and with abundant.mitosis in the control group, but in the tumors of the animals treated with AMYGDALIN, the neoplastic cells are not so active, they have less mitosis and the tissues are hemorrhogic with degenerative signs. The histological studies of the lungs of the control animals and those treated with AMYGDALIN. revealed that the discovery of pulmonary metastasis, was correlated adequately with the macroscopic discoveries. Shortly, I will prepare my observations concerning the effect of AMYGBALIN in spontaenous breast tumors in Swiss Albino mice.
KANEMATSU
SUGIURA
August 3,1973 Translation from the original performed by Br. Kanematsu Sugiura of the Sloan-Kettering Institute for Cancer Research, New York USA, 1974
Breast Tumors CD8F1 (AdenocarcinomaS)
Control Animals
The injections of CMC were begun September 12, 1972, and were completed December 13, 1972, or when the animals died.
Breast Tumors CD8F1 (Adenocarcinomas). Animals Treated with AMYGDALIN in Dosages of 1,000 Mg/Kg Per Day
The injections of AMYGDALIN were begun on September 12, 1972, and were completed December 13. 1972, or when the animals died
THE EFFECT OF AMYGDALIN IN SPONTANEOUS BREAST TUMORS IN MICE CD8F1
On April 13, 1973, we received 20 female mice CD8F1, with spontaneous breast tumors, from Dr. B.S.Martin of the Catholic Medical Center of Brooklyn and Queens, New York. Fourteen of the 20, or 70%, had two or three spontaneous breast cancers, which indicates that these mice were older than those used in the two previous experiments (September 12, 1972 and February 20, 1973). The primary tumors were also definitely larger than those in the mice of the previous experiments. Ten control mice with 19 tumors (between 2.6 x 2.4 cm the largest, and 0.6 x 0.5 cm the smallest) received CMC in daily intraperitoneal injections, and 10 experimental mice with 18 initial tumors (be tween 3.4 x 2.7 cm the largest, and 1.1 x 0.8 cm the smallest) received AMYGDALIN daily by intraperitoneal injection, in dosages of 2,000 mg/kg per day, except Sundays, for four consecutive weeks
Four control and one experimental animals died within seven days after
the experiment was initiated and therefore were not included in the
results. The results obtained are summarized in Tables 1 and 2 (April 19, 1973). It shows that the repeated intraperitoneal injections of AMYGDALIN in dosages of 2,000 mg/kg per day for four weeks, were not able to destroy the spontaneous breast tumors in the mice. All the tumors grew normally in the control mice (see Table 1); nevertheless, there was a strong inhibitory effect in the development of pulmonary met stasis in the mice treated with AMYGDALIN (22%vs. 100%) and the general health and appearance of these animals was much better than that of the control animals.
March 5,1974 Table 1. Breast Tumors CD8F1 (Adenocarcinomas) Control Animal
The injections of CMC were begun on April 19,1973 and finalized May 24, 1973, or when the animals died. Evaluation of Pulmonary Metastasis: +++
= more than 10 nodules in the lungs ++ = no metatsasis + = fewer
than five nodules in the lungs -- = no mtastasis () = date on which the tumor was detectecd (month/year)
Table 2.
Breast Tumors CD8F1 (Adenocarcinomas)
The injections of CMC were begun on April 19,1973 and finalized May 24, 1973, or when the animals died.
Evaluation of Pulmonary Metastasis:
Recently we carried out three separate experiments (Feb. 22, 1974, Mar. 4,1974 and Mar. 11, 1974) concerning the effects of the prolonged treatment with AMYGDALIN of Mexican and German origin (racemic compound), In the growth of spontaneous breast tumors (adenocarcinomas) in female mice CD8F1. Each group consisted of 10 control animals which received a saline solution of 0.5 cc by intraperitoneal injection, daily except Sundays, and 10 experimental animals which received AMYGDALIN (Mexican or German) in dosages of 2,000 mg/kg per day. The animals were kept on a normal diet (Purina Laboratory Chow) and water. When the primary tumors became large (generally more than four weeks after the beginning of the experiment and with tumoral dimensions or more than 2.5 cm in diameter), the animals were killed and the negative lungs were given a biological examination to show the presence or absence of metastasis. Nevertheless, if the animals died, the lungs were inspected macroscopically with the aid of a magnifying glass, and histopathologically in order to show metastasis. The results of the experiment of Feb. 22, 1974 in relation to pulmonary metastasis, are summarized in Table 1, 2, and 3. The results from the tables show that the intraperitoneal injections of AMYGDALIN in dosages of 2.000 mg/kg per day for four to nine weeks had a strong, inhibitory effect upon the development of pulmonary metastasis. Control mice: eight positive, two negative or 20% without metastasis. AMYGDALIN (Mexican): three positive, seven negative or 70% without metastasis. AMYGDALIN (German): two positive, eight negative or 80% without metastasis. This experiment (of Feb. 22, 1974) was repeated (Mar. 4,1974) 'using 30 female mice CD8F1 with spontaneous breast tumors. The control animals received saline solution daily except Sundays and the experimental animals received daily intraperitoneal injections of AMYGDALIN (Mexican or German) in dosages of 2.000 mg/kg per day. The results obtained in the experiment of March 4,1974, in relation to pulmonary metastasis, is summarized in Tables 4, 5, and 6. The results from the tables show that the repeated intraperitoneal injections of AMYGDALIN in dosages of 2.000 mg/kg per day for four to nine weeks had a strong, inhibitory effect upon the development of pulmonary metastasis. Control mice: eight positive, one negative or 11% without metastasis. AMYGDALIN (Mexican): two positive, seven negative or 78% without metastasis. AMYGDALIN (German): three positive, seven negative or 70% without metastasis. The results from the experiment of March 11, 1974, in relation to pulmonary metastasis are summarized in Tables 7, 8 and 9. The results of the tables show that the repeated intraperitoneal injections of AMYGDALIN in dosages of 2.000 mg/kg per day for four to nine weeks had a strong, inhibitory effect on the development of pulmonary metastasis. Control mice: nine positive, one negative or 10% without metastasis AMYGDALIN (Mexican): four positive, five negative or 56% without metastasis. AMYGDALIN (German) three positive, seven negative or 70% without metastasis. The three present experiments show that the pulmonary anti-metastasis activity of AMYGDALIN of Mexican and German origin seems to be equal - 68% and 73% respectively without metastasis, against l4% without metastasis for the control group. On May 31, 1974, one animal from the control group and two animals treated with Mexican AMYGDALIN, of the original 90 animals, were still alive.
KANEMATSU SUGIURA
Table 1.
First Experiment February 22, 1974
Breast Tumors CD8F1 (Adenocarcinomas) Control Group
Table 2.
First Experiment February 22, 1974
Breast Tumors CD8F1 (Adenocarcinomas)
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
