Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-02
2003-02-11
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S492000
Reexamination Certificate
active
06518278
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process of compatibly administrating carcinostatic substances and compatibly administrative carcinostatic substances, and especially to a process of compatibly administrating carcinostatic substances in which the synergistic effect appears by compatible administration, compatibly administrative carcinostatic substances employable in the practice of the above process and a mixed carcinostatic substance prepared by mixing these carcinostatic substances. The present invention further relates to a process of rapidly inspecting the carcinostatic substances.
A carcinostatic substance is generally administrated compatibly with another carcinostatic substance for elevating its effectiveness and for preventing tumor cells from obtaining a resistance against a medicine. However, no special method has existed for suitably selecting the administrative substance. The administrative substance has been selected depending on the experience of a clinician under the general considerations on {circle around (1)} an administrative substance is also effective when employed by itself and {circle around (2)} a side effect is not overlapped with that of the administrative substance.
A reaction for restoring from the damage induced by a medicine (carcinostatic substance) is derived in the tumor cell, and if the recovering mechanism is not sufficiently realized, the tumor cell becomes extinct. However, a certain period of time is required for achieving the extinction (necessity of additional administration). When two or more kinds of carcinostatic substances are compatibly employed, a cell biological reaction (synergistic effect) may take place which cannot be recognized in single administration, and in this case the distinct actions of the respective carcinostatic substances (not completely elucidated) may competitively appear. Various administrations conducted under the different conditions such as a dosage of the compatible agents and a dosage time are necessary for elucidating the above mechanism.
The present inventor has developed a reasonable technique in connection with the compatible administration of carcinostatic substances (CANCER CHEMOTHERAPY; Challenge for the Future, vol. 4, 1989; Molecular Biology of DNA Topoisomerases. Proceedings of the International Symposium on DNA Topoisomerases in Chemotherapy, 1991), and proved the effect of the compatible administration of the various carcinostatic substances. However, the combination of the carcinostatic substance which produces the synergistic effect is scarce so that the satisfactorily compatible effect of the carcinostatic substances cannot be easily obtained.
Medicines are roughly divided in accordance with an administration means into two groups one of which is directed to the administration through an intravenous injection and the other is directed to the pororal administration. Most of conventional platinum carcinostatic substances are perorally administrated so that a large burden is applied to a patient.
In the meantime, a cell exists from its birth to its death performing various morphological changes especially a nucleic change. It is interesting to monitor the morphological changes in view of molecular biology. In order to conduct this monitoring, a microscope is generally employed so that the condition of the cell is visually observed. However, in this commonly employed microscope observation, the morphological changes inside of the cell cannot be monitored so that the employment of fluorescence dye has been proposed.
However, the fluorescence dye destroys the cell after it is bonded to the cell so that the continuous observation of the morphological changes of the living cell can be impossible even though the morphosis of the cell at the time of employing the fluorescence dye may be observed.
In order to overcome this drawback, the present inventor had investigated various kinds of the fluorescence dye so as to propose 4′,6-diamidino-2-phenylindole•2HCl (hereinafter referred to as “DAPI”) as fluorescence dye which may be employed for continuously observing the morphological changes of living cells without extinguishing the cells even if it is bonded to the cell [Article in General Meeting of Japan Cancer Institute (July 1990) page 390, 1946).
On the other hand, cell division is an especially interesting phenomenon among the morphological changes, and the the process of the cell division is classified and divided into a division prophase, a division metaphase, a division anaphase and a division telophase.
FIGS. 1
to
9
show the conditions of the cell division from the division prophase at the time of initiation of the cell division to the cell division telophase in turn. The left sides of the respective figures are microphotographs of 1500 magnifications of the cell division taken without employing fluorescence dye. Among these,
FIGS. 1
to
3
show the cells of the division prophase,
FIGS. 4
to
6
show the cells of the division metaphase.
FIG. 7
shows the cells of the division anaphase and
FIGS. 8 and 9
show the cells of the division telophase.
The cells of
FIGS. 1
to
9
are under the conditions of the cell division, but only the cells of
FIGS. 6
to
9
can be recognized to be in the cell division through the ordinary microscope observation employing specimens fixed by means of a fixative. The cells of
FIGS. 1
to
6
cannot be recognized only through the ordinary microscope observation.
The easy recognition whether the cell is in the condition of the cell division or not is important not only for the scientific purpose but also for the confirmation purpose of the effectiveness of the various medicines.
However, as mentioned, among the several phases of the cell division, the division conditions of the cells in the division prophase and in the period from the first half to the beginning of the second half of the division metaphase cannot be recognized through the ordinary microscope observation so that the detailed study thereof is impossible.
Frequent occurrence of the various organ cancers invites vital developments of anti-tumor substances or carcinostatic substances, and in these developments, it is essential to rapidly conduct the inspection of the effectiveness of the carcinostatic substances (sensibility test) for reducing the development expenses.
The above inspection test is roughly divided into two methods. A first method essentially consists of cultivating tumor cells, cultivating the tumor cells in a test tube with carcinostatic substances and judging the degree of the extinction after the extinction of the cells, and a second method essentially consists of injecting or perorally administrating carcinostatic substances to an animal transplanted with tumor cells and comparing the numbers of survival days of the animals for judging the effectiveness of the carcinostatic substances.
The judgment of the effectiveness of the carcinostatic substances cannot be performed before the extinction of the cells of the death of the animals in each of the above methods and between one and four weeks are ordinarily required for the judgment so that not only the rapid judgment is impossible but also the expenses for continuing the test increase.
Although the present inventor has proposed a method of more rapidly inspecting the effectiveness of medicines (Japanese patent laid open gazette No. 58-184547), not less than four days and between seven days and four weeks are required in the test tube method and in the animal method, respectively, for the judgment.
Further in these methods, only the effectiveness of medicines or the extinction effect is made clear and how the carcinostatic substance functions to extinct the cancer cells (mechanism) cannot be specified.
Although the above method employing DAPI as fluorescence dye has enabled the visual observation of the process of cell extinction by means of the carcinostatic substance while keeping the cells alive, the effectiveness of the carcinostatic substance cannot be confirmed without the obs
Oguro Masao
Ohnishi Junji
Debio Pharm S.A.
Goldberg Jerome D.
Klauber & Jackson
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