Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Lutenizing hormone releasing factor ; related peptides
Reexamination Certificate
1993-01-25
2001-04-10
Wessendorf, T. D. (Department: 1627)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Lutenizing hormone releasing factor ; related peptides
C530S328000, C530S816000, C530S810000, C514S015800, C514S800000, C424S195110, C424S193100, C424S198100, C930S110000
Reexamination Certificate
active
06214969
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to novel peptides which contain cytotoxic moieties, have influence on the release of gonadotropins from the pituitary in mammals and possess antineoplastic effect. More specifically, the present invention relates to analogs of luteinizing hormone-releasing hormone (LHRH) with the structure of
pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH
2
salts thereof and to pharmaceutical compositions and methods of using these analogs.
DISCUSSION OF THE PRIOR ART
Hypothalamic luteinizing hormone-releasing hormone (LHRH) controls the pituitary release of gonadotropins (LH and FSH) that stimulate the synthesis of sex steroids in the gonads.
A new approach in the treatment of hormone-sensitive tumors has been developed directed to the use of agonists and antagonists of LHRH (A. V. Schally and A. M. Comaru-Schally, Sem. Endocrinol., 5 389-398, 1987). Some LHRH agonists, when substituted in position 6, 10, or both are much more active than LHRH and also possess prolonged activity. The following superagonists are used in the clinical practice:
[D-Leu
6
, NH-Et
10
]LHRH (Leuprolide; J. A. Vilchez-Martinez et al., Biochem. Biophys. Res. Commun., 59 1226-1232, 1974)
[D-Trp
6
]LHRH (Decapeptyl, D. H. Coy et al., J.Med.Chem., 19 423-425, 1976).
[D-Ser(tBu)
6
,NH-Et
10
]LHRH (Buserelin, W. Koenig et al., In: R. Walter and J. Meienhofer (eds.),
Peptides: Chemistry, Structure and Biology. Proceedings of the Fourth American Peptide Symposium. Ann Arbor Science, Ann Arbor, Mich., 1975, pp. 883-888.
[D-Ser(tBu)
6
,NH—NH—CO—NH
2
10
]LHRH (Zoladex, A. S. Dutta et al., J. Med. Chem., 21 1018-1024, 1978).
[D-Nal(2)
6
]LHRH (Nafarelin, J. J. Nestor et al., J. Med. Chem., 25 795-801, 1982).
Changes in position 1, 2, 3, 6 and optionally in positions 5 and 10 of the LHRH molecule led to the creation of powerful antagonists (M. J. Karten and J. E. Rivier, Endocrine Review, 7 44-66, 1986; S. Bajusz et al., Int. J. Pept. Prot. Res., 32 425-435, 1988) which inhibit the LH and FSH release from the pituitary and have potential as therapeutic agents in the treatment of hormone dependent cancers (prostate, breast and pancreatic) (A. V. Schally, in General Gynecology, Vol 6., Parthenon Press, Carnforth, England, 1989, pp. 1-20).
Ideal anticancer drugs would theoretically be those that eradicate cancer cells without harming normal cells. Hormones carrying antineoplastic agents would solve the problem by achieving more efficiently targeted chemotherapy of receptor-containing tumors. An ideal mechanism of action of hormone-drug conjugates would be their binding to a cell membrane receptor, followed by internalization of the hybrid molecules and release of the drugs or their biologically active derivatives from the carrier hormone in the endosomes or secondary lysosomes. The released substances then pass across the membrane of the vesicles into the cytosol and reach their final target sites. For the conjugates to be effective by this mechanism, the bond between the drug and hormone must be stable before internalization of conjugates into the target tumor cells but should be effectively cleaved after this internalization.
Many human tumors are hormone dependent or hormone-responsive and contain hormone receptors. Certain of these tumors are dependent on or responsive to sex hormones or growth factors or have components which are so dependent or responsive. The remaining tumors or tumor components are not so dependent. Mammary carcinomas contain estrogen, progesterone, glucocorticoid, LHRH, EGF, IGF-I. and somatostatin receptors. Peptide hormone receptors have also been detected in acute leukaemia, prostate-, breast-, pancreatic, ovarian-, endometrial cancer, colon cancer and brain tumors (M. N. Pollak, et al., Cancer Lett. 38 223-230, 1987; F. Pekonen, et al., Cancer Res., 48 1343-1347, 1988; M. Fekete, et al., J. Clin.Lab. Anal. 3 137-147, 1989; G. Emons, et al., Eur. J. Cancer Oncol., 25 215-221, 1989). It has been found (M. Fekete, et al., Endocrinology, 124 946-955, 1989; M. Fekete, et al.Pancreas 4 521-528, 1989) that both agonistic and antagonistic analogs of LHRH bind to human breast cancer cell membranes, and also to the cell membranes of pancreatic cancer, although the latter tumor thought to be hormone-independent. It has been demonstrated that biologically active peptides such as melanotropin (MSH), epidermal growth factor, insulin and agonistic and antagonistic analogs of LHRH (L. Jennes, et. al., Peptides 5 215-220, 1984) are internalized by their target cells by endocytosis.
Alkylating agents used in the treatment of cancer have a basically nonselective mechanism of action. They act by exerting the cytotoxic effect via transfer of their alkyl groups to various cell constituents. Alkylation of DNA within the nucleus probably represents the major interaction that leads to cell death. However, under physiologic conditions, one can alkylate all cellular nucleophiles such as ionized carboxylic and phosphoric acid groups, hydroxyl groups, thiols and uncharged nitrogen moieties. Nitrogen mustards (chlorambucil, cyclophosphamide and melphalan) are among the oldest anticancer drugs in clinical use. They spontaneously form cyclic aziridinium (ethylenimonium) cation derivatives by intramolecular cyclization, which may directly or through formation of a carbonium ion, transfer an alkyl group to a cellular nucleophile. Aziridine moiety containing drugs like thio-TEPA act by the same mechanism.
Cyclopropane is another alkylating agent. The highly strained ring is prone to cleavage by nucleophiles. It can be cleaved to singlet biradical transition and zwitterion transition state in epimerization reactions and thus might act as an alkylating species for interaction with nucleophilic bases of DNA. Incorporation of cyclopropyl group into distamycin (natural antiviral antitumor agent) resulted in four fold increase in cytostatic activity (K. Krowicki, et al., J. Med. Chem. 31 341-345, 1988).
Almost all clinically used alkylating agents are bifunctional and have ability to cross-link two separate molecules, or alkylate one molecule at two separate nucleophilic sites. The cross-links with DNA may be within a single strand, between two complementary strands or between DNA and other molecules, such as proteins. It is thought that the cytotoxicity of alkylating agents is correlated with their cross-linking efficiency (J. J. Roberts et al., Adv. Radiat. Biol. 7 211-435, 1978).
Cisplatin (cis-diaminedichloroplatinum) has been used in the cancer therapy for a long time. LHRH analogs with cisplatin related structure in the side-chain have high affinities for membrane receptors of rat pituitary and human breast cancer cells (S. Bajusz et al. Proc. Natl. Acad. Sci. USA 86 6313-6317, 1989). Incorporation of cytotoxic copper(II) and nickel(II) complexes into suitably modified LHRH analogs resulted in compounds with high hormonal activity and affinity for LHRH receptors on human breast cancer cell membrane. Several of these metallopeptides have cytotoxic activity against human breast and prostate cell lines in vitro. For example pGlu-His-Trp-Ser-Tyr-D-Lys[Ahx-A
2
bu(SAL)
2
(Cu)]-Leu-Arg-Pro-Gly-NH
2
inhibits the [
3
H]thymidine incorporation into DNA of the human mammary cell line MDA-MB-231 by 87% at 10 &mgr;g dose.
Many drugs used in cancer chemotherapy contain the quinone group in their structure. Anthracycline antitumor antibiotics such as adriamycin, daunorubicin, mitomycin C and mitoxantrone bind to DNA through intercalation between specific bases and block the synthesis of new RNA or DNA (or both), cause DNA strand scission, and interfere with cell replication. Bioreductive reactions of the quinone group can lead to formation of free radicals (superoxide and hydroxyl radicals) that can induce DNA strand breaks (Bachur et al. Cancer Res. 38 1745-1750, 1978). An alternative pathway is the reduction of quinone to hydroquinone followed by conversion into the alkylating intermediate, the quinonemethide (Moore et al., D
Bajusz Sandor
Janaky Tamas
Juhasz Attila
Schally Andrew V.
Selitto & Associates, P.C.
The Administrators of the Tulane Educational Fund
Wessendorf T. D.
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