Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-12-01
2001-05-29
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C424S520000, C514S009100, C514S016700, C514S017400, C514S019300, C530S323000, C530S329000, C530S330000, C530S333000, C548S204000
Reexamination Certificate
active
06239104
ABSTRACT:
INTRODUCTION
The present invention relates to cytostatic linear and cyclo-depsipeptides herein denominated “Dolastatin 16,” “Dolastatin 17,” and “Dolastatin 18” which are obtained from the Indian Ocean shell-less mollusk
Dolabella auricularia;
and to methods of using such substances to inhibit malignant cell growth associated with neoplastic diseases in animals and humans afflicted therewith, including pharmaceutical preparations containing Dolastatin 16, Dolastatin 17 and Dolastatin 18 and their derivatives.
BACKGROUND OF THE INVENTION
The great Roman natural scientist Gaius Plinius Secundus (Pliny the Elder) first described Indian Ocean sea hare of the genus Dolabella around 60 A.D. (The Romans first designated Mollusca of the family Aplysidae as sea hares because of the similarity between the ears of a hare and the auriculate tentacles of these gastropods). However, a consideration of the potential of the Indian Ocean Dolabella with respect to modern medical problems is only of recent origin. For example, see the following patents which are hereby incorporated by reference: U.S. Pat. No. 4,414,205, Nov. 8, 1983, Dolastatins 1-3; U.S. Pat. No. 4,486,414, Dec. 4, 1984, Dolastatins A and B; U.S. Pat. No. 4,816,444, Mar. 28, 1989, Dolastatin 10; U.S. Pat. No. 4,879,278, Nov. 7, 1989, Dolastatin 15; U.S. Pat. No. 4,986,988, Jun. 22, 1991, Dolastatin 13 and Dehydrodolastatin 13; and U.S. Pat. No. 5,138,036, Aug. 11, 1992, Dolastatin 14. The aforementioned Dolastatins may correspond to
D. auricularia
constituents (See: 1969 Ph.D. dissertation of M. Watson. U. of Hawaii, “Some Aspects of the Pharmacology, Chemistry and Biology of the Midgut Gland Toxins of Some Hawaiian Sea Hares, especially
Dolabella auricularia
and
Aplysia pulmonica
”, University Microfilms Inc., Ann Arbor, Mich.)
The biological properties exhibited by the
Dolabella auricularia
have been pursued for centuries, but it was only in 1972 that this laboratory found Indian Ocean specimens of this sea hare which yielded extracts that proved effective (over 100% increase in life span) against the U.S. National Cancer Institute's (NCI) murine P388 lymphocytic leukemia (PS system). Subsequently, the Cancer Research Institute at Arizona State University, Tempe, Ariz., succeeded in isolating many new (and powerful) cell growth inhibitory and/or antineoplastic peptides from
Dolabella auricularia
by using solvent separation techniques to fractionate these peptides in combination with bioassaying the fractionated aliquots for antineoplastic activity. Because the sea hare yields only very small quantities of antineoplastic substances (about 1 mg each from 100 kg), isolating and elucidating the structure of these peptides is exceptionally challenging.
Of the early work, Dolastatin 1 was found to be the most active (lowest dose) antineoplastic substance (33% cure rate against the NCI murine B16 melanoma at 11 pg/kg) known in its time. Later another substance was isolated and determined to be a unique linear pentapeptide and was denominated “Dolastatin 10”.
Dolabella auricularia
antineoplastic constituent appeared to be the most active (lowest dose) antineoplastic substance found up to its time. In practice, Dolastatin 10 showed a 17-67% curative response at 3.25-26 &mgr;g/kg against the National Cancer Institute (“NCI”) human melanoma xenograph (nude mouse), 42-138% life extension at 1.44-11.1 &mgr;g/kg using the B16 melanoma and 69-102% life extension at 1-4 &mgr;g/kg against the PS leukemia (ED
50
=4.6×10
5
&mgr;g/ml). In contrast, Dolastatin 14 is strongly active against NCI's P388 lymphocytic leukemia (PS System) (See: Schmidt et al,
Experienta,
1978, 37, 659-660) cell line with ED
50
of 0.0018 &mgr;g/ml. The PS System is generally accepted as an excellent predictor of activity against various types of human cancer (See: Vendetti et al,
Lloydia,
30,332 et seq. (1967) and references cited therein).
SUMMARY OF THE INVENTION
The present invention relates to the discovery of new and potent cytostatic substances denominated Dolastatin 16, Dolastatin 17, and Dolastatin 18 which are extracted from the Indian Ocean shell-less mollusk
Dolabella auricularia
in the manner hereinafter described in detail. The substances and their pharmaceutically acceptable derivatives can be formulated into useful pharmaceutical preparations having demonstrable and confirmable levels of cell growth inhibitory activity when measured by the generally accepted protocols in use at the United States National Cancer Institute.
Accordingly, this invention provides a number of new agents useful in the retardation or remission of one or more types of malignant cells.
The present invention also provides methods and procedures for isolating a cell growth inhibitory substance from marine life in a form in which it may be readily and usefully employed in the therapeutic treatment and management of one or more types of neoplasms which occur in human or animal hosts.
Further, the present invention also provides the means and methods of creating useful pharmaceutical preparations for the treatment and management of neoplastic disease which preparations contain as their essential active ingredient a unique cytostatic factor obtained from the Indian Ocean shell-less mollusk
Dolabella auricularia,
its synthetic counterpart, or a pharmaceutically active derivative thereof.
These and still further objects as shall hereinafter appear are readily fulfilled by the present invention as will be readily discerned from the following detailed description of an exemplary embodiment thereof.
REFERENCES:
patent: 5410024 (1995-04-01), Pettit et al.
patent: 5504191 (1996-04-01), Pettit et al.
patent: 5521284 (1996-05-01), Pettit et al.
patent: 5530097 (1996-06-01), Pettit et al.
patent: 5554725 (1996-09-01), Pettit
patent: 5599902 (1997-02-01), Pettit et al.
patent: 5635483 (1997-06-01), Pettit et al.
patent: 5663149 (1997-09-01), Pettit et al.
patent: 5665860 (1997-09-01), Pettit et al.
Pettit George R.
Xu Jun-ping
Arizona Board of Regents
Low Christopher S. F.
Mybeck Richard R.
Tu Stephen
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