PEPTIDES AND PEPTIDOMIMETICS IN COMBINATION USES AND TREATMENTS FOR CANCER PATIENT SUBPOPULATIONS

• US 20150056301A1
• Filed: 06/24/2014
• Published: 02/26/2015
• Est. Priority Date: 06/24/2013
• Status: Active Grant

• Current Assignee: CanBas Co., Ltd.
• Original Assignee: CanBas Co., Ltd.
• Inventors: Kawabe, Takumi, Sato, Takuji, Mine, Naoki, Saito, Naoya, Sakakibara, Keiichi
• Granted Patent: US 9,221,872 B2
• Time in Patent Office: Days
• US Class Current: 424/649
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids

Abstract

This invention provides compounds including peptides and peptidomimetics that can be used to treat cell proliferative disorders, such as those associated with benign and malignant tumor cells. While the invention is not limited to any particular mechanism, the compounds of the invention appear to function at least in part by inhibiting G2 cell cycle checkpoint. Thus, invention compounds can be used to inhibit cell growth alone or be used in combination with a nucleic acid damaging treatment to inhibit cell growth.

Claims

1. A method for increasing nucleic acid damage of a hyperproliferating cell or for the prophylaxis or treatment of a cell proliferative disorder in a mammal having a white blood cell count within a normal range, comprising administering a peptide compound, wherein the peptide compound comprises any of the following sequences:

A) a peptide comprising residues denoted P1-P6, with the structure, P1, P2, P3, P4, P5, P6 or P6, P5, P4, P3, P2, P1;

wherein P1 is Cha, Nal(2), (Phe-2,3,4,5,6-F), (Phe-3,4,5F), (Phe-4CF3), an amino acid that occupies a similar side chain space, or any amino acid with one or two aromatic, piperidine, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group(s), or one indole, pentalene, indene, naphthalene, benzofuran, benzothiophene, quinoline, indoline, chroman, quinoxaline, quinazoline group in the side chain;

wherein P2 is Cha, Nal(2), (Phe-2,3,4,5,6-F), (Phe-3,4,5F), (Phe-4CF3), Bpa, Phe4NO2, an amino acid that occupies a similar side chain space, or any amino acid with one or two aromatic, piperidine, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group(s), or one indole, pentalene, indene, naphthalene, benzofuran, benzothiophene, quinoline, indoline, chroman, quinoxaline, or quinazoline group in the side chain;

wherein P3, P4, P5 are any amino acid, or wherein one or more of P3, P4, P5 is a simple carbon chain such that the distance between P2 and P6 is about the same as the distance when each of P3, P4, P5 are amino acids;

wherein P6 is Bpa, Phe4NO2, any one amino acid and Tyr, any one amino acid and Phe, any amino acid, or nothing;

or

B) the peptide of A), wherein the amino acid having a simple carbon chain is 11-aminoundecanoic acid, 10-aminodecanoic acid, 9-aminononanoic acid, 8-aminocaprylic acid, 7-aminoheptanoic acid, 6-aminocaproic acid, or a similar structure with one or more unsaturated carbon bonds, and/or

wherein the any one amino acid is Ser, and/or

wherein P4 is Trp, and/or

wherein the amino acid that occupies a similar side chain space is Tyr or Phe;

or

C) a peptide comprising residues denoted P1-P12, with any the following structures;

P1, P2, P3, P4, P5, P6;

P6, P5, P4, P3, P2, P1;

P1, P2, P3, P4, P5, P6, P7, P8, P9, P10, P11, P12;

P1, P2, P3, P4, P5, P6, P12, P11, P10, P9, P8, P7;

P6, P5, P4, P3, P2, P1, P7, P8, P9, P10, P11, P12;

P6, P5, P4, P3, P2, P1, P12, P11, P10, P9, P8, P7;

P7, P8, P9, P10, P11, P12, P1, P2, P3, P4, P5, P6;

P7, P8, P9, P10, P11, P12, P6, P5, P4, P3, P2, P1;

P12, P11, P10, P9, P8, P7, P1, P2, P3, P4, P5, P6;

P12, P11, P10, P9, P8, P7, P6, P5, P4, P3, P2, P1;

P12, P11, P6, P9, P8, P7, P2, P1;

P12, P11, P10, P6, P9, P4, P7, P2, P1;

P1, P2, P7, P8, P9, P6, P11, P12;

or P1, P2, P7, P4, P9, P6, P10, P11, P12;

wherein P1 is Cha, Nal(2), (Phe-2,3,4,5,6-F), (Phe-3,4,5F), (Phe-4CF3), Bpa, Phe4NO2, an amino acid that occupies a similar side chain space (e.g. d- or 1-Tyr, d- or 1-Phe), or any amino acid with one or two aromatic, piperidine, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group(s), or one indole, pentalene, indene, naphthalene, benzofuran, benzothiophene, quinoline, indoline, chroman, quinoxaline, or quinazoline group in the side chain;

wherein P2 is Cha, Nal(2), (Phe-2,3,4,5,6-F), (Phe-3,4,5F), (Phe-4CF3), or an amino acid that occupies a similar side chain space, or any amino acid with one or two aromatic, piperidine, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group(s), or one indole, pentalene, indene, naphthalene, benzofuran, benzothiophene, quinoline, indoline, chroman, quinoxaline, quinazoline group in the side chain;

wherein P3, P4, P5 are any amino acid, or wherein one or more of P3, P4, P5 is a simple carbon chain such that the distance between P2 and P6 is about the same as the distance when each of P3, P4, P5 are amino acids;

wherein P6 is Bpa, Phe4NO2, any one amino acid and Tyr, any one amino acid and Phe; and

wherein at least three of P7, P8, P9, P10, P11, P12 are basic amino acids with the rest being any amino acid or absent;

or

D) the peptide of C), wherein the amino acid having a simple carbon chain is 11-aminoundecanoic acid, 10-aminodecanoic acid, 9-aminononanoic acid, 8-aminocaprylic acid, 7-aminoheptanoic acid, 6-aminocaproic acid, or a similar structure with one or more unsaturated carbon bonds, and/or,

wherein the any one amino acid is Ser, and/or,

wherein P4 is Trp and/or,

wherein the amino acid that occupies a similar side chain space is Tyr or Phe;

or

E) a peptide comprising residues denoted P1-P12, with any the following structures;

P1, P2, P3, P4, P5, P6, P7, P8, P9, P10, P11, P12;

P12, P11, P10, P9, P8, P7, P6, P5, P4, P3, P2, P1;

P12, P11, P10, P6, P9, P4, P7, P2, P1;

or P1, P2, P7, P4, P9, P6, P10, P11, P12;

wherein P1 is Cha, Nal(2), (Phe-2,3,4,5,6-F), (Phe-3,4,5F), (Phe-4CF3), Bpa, Phe4NO2, an amino acid that occupies a similar side chain space, or any amino acid with one or two aromatic, piperidine, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group(s), or one indole, pentalene, indene, naphthalene, benzofuran, benzothiophene, quinoline, indoline, chroman, quinoxaline, or quinazoline group in the side chain;

wherein P2 is Cha, Nal(2), (Phe-2,3,4,5,6-F), (Phe-3,4,5F), (Phe-4CF3), an amino acid that occupies a similar side chain space, or any amino acid with one or two aromatic, piperidine, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group(s), or one indole, pentalene, indene, naphthalene, benzofuran, benzothiophene, quinoline, indoline, chroman, quinoxaline, quinazoline group in the side chain;

wherein P3, P4, P5 are any amino acid, or wherein one or more of P3, P4, P5 is a simple carbon chain such that the distance between P2 and P6 is about the same as the distance when each of P3, P4, P5 are amino acids;

wherein P6 is Bpa, Phe4NO2, any one amino acid and Tyr, any one amino acid and Phe, any amino acid, or nothing; and

wherein at least three of P7, P8, P9, P10, P11, P12 are basic amino acids with the rest being any amino acid or absent;

or

F) the peptide of E), wherein the amino acid having a simple carbon chain is aminoundecanoic acid or 8-aminocaprylic acid, and/or,

wherein the any one amino acid is Ser, and/or,

wherein the amino acid that occupies a similar side chain space is Tyr or Phe;

or

G) a peptide comprising residues denoted P1-P12, with any the following structures;

P1, P2, P3, P4, P5, P6 or P6, P5, P4, P3, P2, P1,

wherein P1 is Cha, Nal(2), (Phe-2,3,4,5,6-F), (Phe-3,4,5F), (Phe-4CF3), Bpa, Phe4NO2, Tyr, or Phe;

wherein P2 is Cha, Nal(2), (Phe-2,3,4,5,6-F), (Phe-3,4,5F), (Phe-4CF3), Bpa, Phe4NO2, Tyr, or Phe;

wherein P3 is Ser, Arg, Cys, Pro, or Asn;

wherein P4 is Trp;

wherein P5 is Ser, Arg, or Asn;

or

wherein P3, P4, P5 is a single aminoundecanoic acid or a single 8-aminocaprylic acid; and

wherein P6 is Bpa, Phe4NO2, (Ser-Tyr), or (Ser-Phe);

or

H) a peptide comprising residues denoted P1-P12, with any the following structures;

P1, P2, P3, P4, P5, P6, P7, P8, P9, P10, P11, P12;

P1, P2, P3, P4, P5, P6, P12, P11, P10, P9, P8, P7;

P6, P5, P4, P3, P2, P1, P7, P8, P9, P10, P11, P12;

P6, P5, P4, P3, P2, P1, P12, P11, P10, P9, P8, P7;

P7, P8, P9, P10, P11, P12, P1, P2, P3, P4, P5, P6;

P7, P8, P9, P10, P11, P12, P6, P5, P4, P3, P2, P1;

P12, P11, P10, P9, P8, P7, P1, P2, P3, P4, P5, P6;

P12, P11, P10, P9, P8, P7, P6, P5, P4, P3, P2, P1;

P12, P11, P6, P9, P8, P7, P2, P1;

P12, P11, P10, P6, P9, P4, P7, P2, P1;

P1, P2, P7, P8, P9, P6, P11, P12;

or P1, P2, P7, P4, P9, P6, P10, P11, P12;

wherein P1 is Cha, Nal(2), (Phe-2,3,4,5,6-F), (Phe-3,4,5F), (Phe-4CF3), Bpa, Phe4NO2, Tyr, or Phe;

wherein P2 is Cha, Nal(2), (Phe-2,3,4,5,6-F), (Phe-3,4,5F), (Phe-4CF3), Bpa, Phe4NO2, Tyr, or Phe;

wherein P3 is Ser, Arg, Cys, Pro, or Asn;

wherein P4 is Trp;

wherein P5 is Ser, Arg, or Asn;

or

wherein P3, P4, P5 is a single aminoundecanoic acid or a single 8-aminocaprylic acid;

wherein P6 is Bpa, Phe4NO2, (d-Ser-d-Tyr), or (d-Ser-d-Phe); and

wherein at least three of P7, P8, P9, P10, P11, P12 are Arg or Lys with the rest being any amino acid or absent;

or

I) a peptide comprising residues denoted P1-P12, with any the following structures;

P1, P2, P3, P4, P5, P6, P7, P8, P9, P10, P11, P12;

P12, P11, P10, P9, P8, P7, P6, P5, P4, P3, P2, P1;

P12, P11, P10, P6, P9, P4, P7, P2, P1;

or P1, P2, P7, P4, P9, P6, P10, P11, P12;

wherein P1 is Cha, or Nal(2);

wherein P2 is (Phe-2,3,4,5,6-F), (Phe-3,4,5F), (Phe-4CF3);

wherein P3 is Ser;

wherein P4 is Trp;

wherein P5 is Ser or Asn;

wherein P6 is Bpa, Phe4NO2, (Ser-Tyr), or (Ser-Phe); and

wherein at least three of P7, P8, P9, P10, P11, P12 are Arg with the rest being any amino acid or absent;

or

J) a peptide comprising residues denoted P1-P12, with any the following structures;

P1, P2, P3, P4, P5, P6 or P6, P5, P4, P3, P2, P1;

wherein P1 is Cha, or Nal(2);

wherein P2 is (Phe-2,3,4,5,6-F), (Phe-3,4,5F) or (Phe-4CF3);

wherein P3 is Ser;

wherein P4 is Trp;

wherein P5 is Ser; and

wherein P6 is Bpa, or (Ser-Tyr);

or

K) a peptide comprising residues denoted P1-P12, with any the following structures;

P1, P2, P3, P4, P5, P6;

P6, P5, P4, P3, P2, P1;

P1, P2, P3, P4, P5, P6, P7, P8, P9, P10, P11, P12;

P1, P2, P3, P4, P5, P6, P12, P11, P10, P9, P8, P7;

P6, P5, P4, P3, P2, P1, P7, P8, P9, P10, P11, P12;

P6, P5, P4, P3, P2, P1, P12, P11, P10, P9, P8, P7;

P7, P8, P9, P10, P11, P12, P1, P2, P3, P4, P5, P6;

P7, P8, P9, P10, P11, P12, P6, P5, P4, P3, P2, P1;

P12, P11, P10, P9, P8, P7, P1, P2, P3, P4, P5, P6;

P12, P11, P10, P9, P8, P7, P6, P5, P4, P3, P2, P1;

P12, P11, P6, P9, P8, P7, P2, P1;

P12, P11, P10, P6, P9, P4, P7, P2, P1;

P1, P2, P7, P8, P9, P6, P11, P12;

or P1, P2, P7, P4, P9, P6, P10, P11, P12;

wherein P1 is Cha, or Nal(2);

wherein P2 is (Phe-2,3,4,5,6-F), (Phe-3,4,5F) or (Phe-4CF3);

wherein P3 is any amino acid;

wherein P4 is d- or 1-Trp;

wherein P5 is any amino acid;

wherein P6 is Bpa or (Ser-Tyr);

wherein P7 is Arg;

wherein P8 is Arg;

wherein P9 is Arg;

wherein P10 is Gln or Arg;

wherein P11 is Arg; and

wherein P12 is d- or 1-Arg, or

L) the peptide of K), wherein the any amino acid is Ser, or Pro;

or

M) a peptide comprising residues denoted P1-P12, with any the following structures;

P1, P2, P3, P4, P5, P6, P7, P8, P9, P10, P11, P12;

P12, P11, P10, P9, P8, P7, P6, P5, P4, P3, P2, P1;

P12, P11, P10, P6, P9, P4, P7, P2, P1;

or P1, P2, P7, P4, P9, P6, P10, P11, P12;

wherein P1 is Cha or Nal(2);

wherein P2 is (Phe-2,3,4,5,6-F);

wherein P3 is Ser;

wherein P4 is Trp;

wherein P5 is Ser;

wherein P6 is Bpa or (Ser-Tyr);

wherein P7 is Arg;

wherein P8 is Arg;

wherein P9 is Arg;

wherein P10 is Gln or Arg;

wherein P11 is Arg; and

wherein P12 is Arg;

or

a prodrug thereof or a pharmaceutically acceptable salt thereof to the mammal, thereby increasing nucleic acid damage of the hyperproliferating cell or prophylaxis or treatment of the cell proliferative disorder.

2. The method of claim 1, wherein the peptide compound comprises any the following sequences:

(d-Bpa) (d-Ser)(d-Trp)(d-Ser) (d-Phe-2,3,4,5,6-F)(d-Cha)(d-Arg) (d-Arg) (d-Arg) (d-Gln)(d-Arg) (d-Arg);

(d-Arg) (d-Arg) (d-Arg) (d-Gln)(d-Arg) (d-Arg) (d-Bpa)(d-Ser)(d-Trp)(d-Ser)(d-Phe-2,3,4,5,6-F) (d-Cha);

(d-Bpa) (d-Ser)(d-Trp)(d-Ser) (d-Phe-2,3,4,5,6-F)(d-Cha)(d-Arg) (d-Arg) (d-Gln) (d-Arg) (d-Arg) (d-Arg) (SEQ ID NO;

59);

(d-Arg) (d-Arg) (d-Gln) (d-Arg) (d-Arg) (d-Arg) (d-Bpa) (d-Ser)(d-Trp)(d-Ser) (d-Phe-2,3,4,5,6-F) (d-Cha);

(d-Cha) (d-Phe-2,3,4,5,6-F) (d-Ser)(d-Trp)(d-Ser) (d-Bpa) (d-Arg) (d-Arg) (d-Arg) (d-Gln)(d-Arg) (d-Arg);

(d-Arg) (d-Arg) (d-Arg) (d-Gln) (d-Arg)(d-Arg)(d-Cha)(d-Phe-2,3,4,5,6-F)(d-Ser)(d-Trp)(d-Ser)(d-Bpa);

(d-Cha)(d-Phe-2,3,4,5,6-F)(d-Ser)(d-Trp)(d-Ser)(d-Bpa)(d-Arg)(d-Arg) (d-Gln) (d-Arg) (d-Arg) (d-Arg);

(d-Arg) (d-Arg) (d-Gln) (d-Arg) (d-Arg) (d-Arg) (d-Cha) (d-Phe-2,3,4,5,6-F) (d-Ser)(d-Trp)(d-Ser) (d-Bpa) (SEQ ID NO;

64);

(d-Arg) (d-Arg) (d-Arg) (d-Arg) (d-Arg) (d-Arg) (d-Cha) (d-Phe-2,3,4,5,6-F) (d-Ser) (d-Trp)(d-Ser)(d-Bpa);

(d-Cha)(d-Phe-2,3,4,5,6-F) (d-Ser) (d-Trp)(d-Ser)(d-Bpa)(d-Arg)(d-Arg) (d-Arg) (d-Arg) (d-Arg) (d-Arg);

(d-Arg) (d-Arg) (d-Arg) (d-Arg) (d-Arg) (d-Arg) (d-Bpa) (d-Ser)(d-Trp)(d-Ser) (d-Phe-2,3,4,5,6-F)(d-Cha);

(d-Bpa) (d-Ser) (d-Trp)(d-Ser) (d-Phe-2,3,4,5,6-F)(d-Cha) (d-Arg) (d-Arg) (d-Arg) (d-Arg) (d-Arg) (d-Arg);

(d-Arg)(d-Arg)(d-Bpa) (d-Arg) (d-Arg) (d-Arg) (d-Phe-2,3,4,5,6-F)(d-Cha) (SEQ ID NO;

69);

(d-Cha) (d-Phe-2,3,4,5,6-F) (d-Arg) (d-Arg) (d-Arg) (d-Bpa) (d-Arg)(d-Arg);

(d-Arg) (d-Arg) (d-Arg) (d-Bpa) (d-Arg)(d-Trp) (d-Arg) (d-Phe-2,3,4,5,6-F)(d-Cha);

(d-Cha) (d-Phe-2,3,4,5,6-F) (d-Arg)(d-Trp) (d-Arg) (d-Bpa) (d-Arg) (d-Arg) (d-Arg);

(d-Arg)(d-Arg)(d-Arg)(d-Arg)(d-Bpa) (d-Arg)(d-Trp)(d-Arg) (d-Phe-2,3,4,5,6-F) (d-Cha);

(d-Cha) (d-Phe-2,3,4,5,6-F) (d-Arg) (d-Trp)(d-Arg) (d-Bpa) (d-Arg) (d-Arg) (d-Arg) (d-Arg);

(d-Arg) (d-Arg)(d-Arg)(d-Bpa)(d-Arg)(d-Arg) (d-Arg) (d-Phe-2,3,4,5,6-F)(d-Cha);

or (d-Cha) (d-Phe-2,3,4,5,6-F) (d-Arg) (d-Arg) (d-Arg) (d-Bpa) (d-Arg) (d-Arg) (d-Arg).

3. The method of claim 1, wherein the peptide compound comprises:

4. The method of claim 1, wherein the mammal has a white blood cell count of less than about 11,000 white blood cells per microliter (wbc/μ

l) of blood.

5. The method of claim 1, wherein the mammal has a white blood cell count between about 4,000 to about 11,000 white blood cells per microliter (wbc/1) of blood.

6. The method of claim 1, wherein the mammal has a white blood cell count of less than about 10,000 white blood cells per microliter (wbc/μ

l) of blood.

7. The method of claim 1, wherein the mammal has a white blood cell count of less than about 9,000 white blood cells per microliter (wbc/μ

l) of blood.

8. The method of claim 1, wherein the mammal has a white blood cell count between about 4,000 to about 9,000 white blood cells per microliter (wbc/μ

l) of blood.

9. The method of claim 1, wherein the mammal has a white blood cell count of less than about 8,000 white blood cells per microliter (wbc/μ

l) of blood.

10. The method of claim 1, wherein the mammal has a white blood cell count of less than about 7,000 white blood cells per microliter (wbc/μ

l) of blood.

11. The method of claim 1, wherein the mammal has a white blood cell count of less than upper normal limit by each clinical laboratories white blood cells per microliter (wbc/μ

l) of blood.

12. The method of claim 1, wherein the peptide compound comprises a pharmaceutical formulation.

13. The method of claim 1, wherein the pharmaceutically acceptable salt thereof is selected from acetate, sulfonate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen-phosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methyl benzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, -hydroxybutyrate, glycolate, tartrate, methane-sulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

14. The method of any of claims 1 to 3, wherein the peptide compound has a length from 6 to 10, 10 to 15, 15 to 20, 20 to 25, 25 to 30, 30 to 40, 40 to 50, 50 to 75, 75 to 100, 100 to 150, 150 to 200, or 200 to 300 amino acid residues.

15. The method of any of claims 1 to 3, wherein the peptide compound further comprises a cell penetrating molecule attached or conjugated thereto.

16. The method of claim 15, wherein the cell penetrating molecule is joined to the peptide compound by a covalent bond, or a peptide or a non-peptide linker.

17. The method of claim 15, wherein the cell penetrating peptide comprises an alternating pattern of polar/charged amino acids and non-polar, hydrophobic amino acids.

18. The method of claim 15, wherein the cell penetrating peptide comprises a polycationic or amphipathic alpha-helix structure.

19. The method of claim 1 or 15, wherein the peptide compound and/or the cell penetrating peptide comprises L- or D-isomer amino acids, or a mixture of L- and D-isomer amino acids.

20. The method of claim 15, wherein the cell penetrating peptide comprises a poly-Arginine (Arg) sequence.

21. The method of claim 15, wherein the cell penetrating peptide comprises or consists of (d-Arg)(d-Arg)(d-Arg)(d-Gln)(d-Arg)(d-Arg).

22. The method of any of claims 1 to 3, further comprising administering a nucleic acid damaging agent, a nucleic acid damaging treatment, an anti-proliferative agent, or an anti-proliferative treatment.

23. The method of claim 22, wherein the nucleic acid damaging agent, a nucleic acid damaging treatment, an anti-proliferative agent, or anti-proliferative treatment comprises surgical resection, radiotherapy, ionizing or chemical radiation therapy, chemotherapy, immunotherapy, local or regional thermal (hyperthermia) therapy, vaccination, an alkylating agent, an anti-metabolite, a plant extract, a plant alkaloid, nitrosourea, a hormone, or a nucleoside or nucleotide analogue.

24. The method of any of claims 1 to 3, wherein the peptide compound is administered prior to, with or after a nucleic acid damaging agent, a nucleic acid damaging treatment, an anti-proliferative agent, or an anti-proliferative treatment is administered.

25. The method of any of claims 1 to 3, wherein the peptide compound is administered less than 48 hours prior to or after a nucleic acid damaging agent, a nucleic acid damaging treatment, an anti-proliferative agent, or an anti-proliferative treatment is administered.

26. The method of any of claims 1 to 3, wherein the peptide compound is administered less than 24 hours prior to or after a nucleic acid damaging agent, a nucleic acid damaging treatment, an anti-proliferative agent, or an anti-proliferative treatment is administered.

27. The method of any of claims 1 to 3, wherein the peptide compound is administered less than 12 hours prior to or after a nucleic acid damaging agent, a nucleic acid damaging treatment, an anti-proliferative agent, or an anti-proliferative treatment is administered.

28. The method of any of claims 1 to 3, wherein the peptide compound is administered less than 6 hours prior to or after a nucleic acid damaging agent, a nucleic acid damaging treatment, an anti-proliferative agent, or an anti-proliferative treatment is administered.

29. The method of any of claims 1 to 3, wherein the peptide compound is administered less than 4 hours prior to or after a nucleic acid damaging agent, a nucleic acid damaging treatment, an anti-proliferative agent, or an anti-proliferative treatment is administered.

30. The method of any of claims 1 to 3, wherein the peptide compound is administered less than 2 hours prior to or after a nucleic acid damaging agent, a nucleic acid damaging treatment, an anti-proliferative agent, or an anti-proliferative treatment is administered.

31. The method of any of claims 1 to 3, wherein the peptide compound is administered less than 1 hour prior to or after a nucleic acid damaging agent, a nucleic acid damaging treatment, an anti-proliferative agent, or an anti-proliferative treatment is administered.

32. The method of any of claims 22 to 31, wherein the nucleic acid damaging agent or anti-proliferative agent comprises a drug.

33. The method of any of claims 22 to 31, wherein the nucleic acid damaging agent or anti-proliferative agent comprises a platinum containing drug.

34. The method of any of claims 22 to 31, wherein the nucleic acid damaging agent or anti-proliferative agent comprises cis-platin, carboplatin, nedaplatin, mitaplatin, satraplatin, picoplatin, triplatin, miriplatin, or oxaliplatin.

35. The method of any of claims 1 to 3, further comprising administering a platinum containing drug, cis-platin, carboplatin, oxaliplatin, pemetrexed, gemcitabine, 5-fiuorouracil (5-FU), rebeccamycin, adriamycin (ADR), bleomycin (Bleo), pepleomycin, cisplatin, cisplatinum, or cis-diamminedichloroplatinum(II) (CDDP), oxaliplatin, or camptotecin (CPT), cyclophosphamide, azathioprine, cyclosporin A, prednisolone, melphalan, chlorambucil, mechlorethamine, busulphan, methotrexate, 6-mercaptopurine, thioguanine, 5-fluorouracil, cytosine arabinoside, AZT, 5-azacytidine (5-AZC) or a 5-azacytidine related compound, actinomycin D, mithramycin, mitomycin C, carmustine, lomustine, semustine, streptozotocin, hydroxyurea, cisplatin, mitotane, procarbazine, dacarbazine, a taxane, vinblastine, vincristine, doxorubicin, dibromomannitol, radiation or a radioisotope.

36. The method of claim 35, wherein the radiation comprises UV radiation, IR radiation, Xray, or alpha-, beta- or gamma-radiation.

37. The method of claim 35, wherein the radioisotope comprises I¹³¹, I¹²⁵, Sr⁸⁹, Sm¹⁵³, Y⁹⁰, or Lu¹⁷⁷.

38. The method of claim 1, wherein the cell proliferative disorder comprises a tumor or cancer.

39. The method of claim 38, wherein the cell proliferative disorder comprises a metastatic tumor or cancer.

40. The method of claim 38 or 39, wherein the tumor or cancer comprises a lung tumor or cancer.

41. The method of claim 38 or 39, wherein the lung tumor or cancer comprises a small cell or non-small cell lung cancer.

42. The method of claim 38 or 39, wherein the lung tumor or cancer comprises an adenocarcinoma, squamous cell carcinoma or a large cell carcinoma.

43. The method of claim 38 or 39, wherein the tumor or cancer comprises a carcinoma, sarcoma, lymphoma, leukemia, adenoma, adenocarcinoma, melanoma, glioma, glioblastoma, meningioma, neuroblastoma, retinoblastoma, astrocytoma, oligodendrocytoma, mesothelioma, reticuloendothelial, lymphatic or haematopoietic neoplasia, tumor, cancer or malignancy.

44. The method of claim 38 or 39, wherein the sarcoma comprises a lymphosarcoma, liposarcoma, osteosarcoma, chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma or fibrosarcoma.

45. The method of claim 43, wherein the haematopoietic neoplasia, tumor, cancer or malignancy comprises a myeloma, lymphoma or leukemia.

46. The method of claim 38 or 39, wherein the tumor or cancer comprises a lung, thyroid, head or neck, nasopharynx, throat, nose or sinuses, brain, spine, breast, adrenal gland, pituitary gland, thyroid, lymph, gastrointestinal (mouth, esophagus, stomach, duodenum, ileum, jejunum (small intestine), colon, rectum), genito-urinary tract (uterus, ovary, cervix, endometrial, bladder, testicle, penis, prostate), kidney, pancreas, liver, bone, bone marrow, lymph, blood, muscle, or skin neoplasia, tumor, or cancer.

47. The method of claim 38 or 39, wherein the tumor or cancer comprises a breast cancer, prostate cancer, pancreas cancer, gastric cancer, pleural mesothelioma, colon cancer, rectal cancer, large bowel cancer, small intestinal cancer, esophageal cancer, duodenal cancer, lingual cancer, pharyngeal cancer, salivary gland cancer, cerebral tumor, schwanoma, liver cancer, kidney cancer, bile duct cancer, endometrial cancer, cervical cancer, uterine body cancer, ovarian cancer, bladder cancer, urethral cancer, skin cancer, angioma, malignant lymphoma, malignant melanoma, thyroid cancer, parathyroid cancer, nasal cancer, paranasal cancer, auditory organ cancer, carcinoma of oral floor, laryngeal cancer, parotid cancer, submandibular cancer, bone tumor, angiofibroma, retinal sarcoma, penile cancer, testicular tumor, pediatric solid cancer, Kaposi'"'"'s sarcoma, tumor of maxillary sinus, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, lymphoma, multiple myeloma or leukemia.

48. The method of any of claims 1 to 3, wherein the mammal is a human.

49. The method of any of claims 1 to 3, wherein the peptide compound comprises:

50. The method of any of claims 1 to 3, wherein the amount of the peptide compound administered is effective to treat the tumor or cancer.

51. The method of any of claims 1 to 3, wherein the method inhibits or reduces relapse, growth, progression, worsening or metastasis of the tumor or cancer.

52. The method of any of claims 1 to 3, wherein the method results in partial or complete destruction of the neoplastic, tumor, cancer or malignant cell mass, volume, size or numbers of cells, stimulating, inducing or increasing neoplastic, tumor, cancer or malignant cell necrosis, lysis or apoptosis, reducing neoplasia, tumor, cancer or malignancy volume size, cell mass, inhibiting or preventing progression or an increase in neoplasia, tumor, cancer or malignancy volume, mass, size or cell numbers, or prolonging lifespan.

53. The method of any of claims 1 to 3, wherein the method results in reducing or decreasing severity, duration or frequency of an adverse symptom or complication associated with or caused by the neoplasia, tumor, cancer or malignancy.

54. The method of any of claims 1 to 3, wherein the method results in reducing or decreasing pain, discomfort, nausea, weakness or lethargy, or results in increased energy, appetite, improved mobility or psychological well being.