Novel n- and c-terminal substituted antagonistic analogs of gh-rh

Abstract

There is provided a novel series of synthetic analogs of hGH-RH(1-29)NH 2 (SEQ ID NO: 1) and hGH-RH(1-30)NH 2 . Of particular interest are those carrying PhAc, N-Me-Aib, Dca, Ac-Ada, Fer, Ac-Amc, Me-NH-Sub, PhAc-Ada, Ac-Ada-D-Phe, Ac-Ada-Phe, Dca-Ada, Dca-Amc, Nac-Ada, Ada-Ada, or CH 3 —(CH 2 ) 10 —CO-Ada, at the N-Terminus and β-Ala, Amc, Apa, Ada, AE 2 A, AE 4 P, ε-Lys(α-NH 2 ), Agm, Lys(Oct) or Ahx, at the C-terminus. These analogs inhibit the release of growth hormone from the pituitary in mammals as well as inhibit the proliferation of human cancers, and inhibit the hyperplastic and benign proliferative disorders of various organs, through a direct effect on the cancerous and non-malignant cells. The stronger inhibitory potencies of the new analogs, as compared to previously described ones, result from replacement of various amino acids.

What is claimed is: 
     
         1 . A method of treating a subject with cancer comprising administering a therapeutically effective amount of at least one GHRH antagonist peptide of the formula:
   [A 0 -Tyr 1 ,D-Arg 2 ,A 4 ,A 6 ,A 8 ,Har 9 ,Tyr(Me) 10 ,A 11 ,A 12 ,Abu 15 ,A 17 ,A 20 ,A 21 ,Nle 27 ,D-Arg 28 ,A 29 -A 30 -A 31 ]hGH-RH(1-29)NH 2      
       wherein
 A 0  is PhAc, N-Me-Aib, Dca, Ac-Ada, Fer, Ac-Amc, Me-NH-Sub, PhAc-Ada, Ac-Ada-D-Phe, Ac-Ada-Phe, Dca-Ada, Dca-Amc, Nac-Ada, Ada-Ada, or CH 3 —(CH 2 ) 10 —CO-Ada, 
 A 4  is Ala or Me-Ala, 
 A 6  is Cpa or Phe(F) 5 , 
 A 8  is Ala, Pal, or Me-Ala, 
 A 11  is His or Arg, 
 A 12  is Lys, Lys(0-11), Lys(Me) 2  or Orn, 
 A 17  is Leu or Glu, 
 A 20  is Har or His, 
 A 21  is -Lys, Lys(Me) 2  or Orn, 
 A 29  is Har, Arg or Agm, 
 A 30  is absent, β-Ala, Amc, Apa, Ada, AE 2 A, AE 4 P, ε-Lys(α-NH 2 ) or Agm, 
 A 31  is absent, Lys(Oct) or Ahx, 
 provided that where A 0  is PhAc, A 12  and A 21  are both other than Orn and A 30  is not absent and is not Agm, and 
 pharmaceutically acceptable salts thereof. 
 
     
     
         2 . The method of  claim 1 , wherein the GHRH antagonist peptide is selected from the group consisting of:
 P-11107 [(N-Me-Aib) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11109 [Dca 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11111 [(Ac-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11113 [Fer 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11115 [(Ac-Amc) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11117 [(PhAc-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11119 [(Ac-Ada-D-Phe) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11121 [(Ac-Ada-Phe) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11123 [(Dca-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11125 [(CH 3 —(CH 2 ) 10 —CO-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ,   P-11207 [PhAc 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 -Amc 30 ]hGH-RH(1-29)NH 2 ;   P-11209 [PhAc 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 -Apa 30 ]hGH-RH(1-29)NH 2 ;   P-11211 [PhAc 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 ]hGH-RH(1-29)NH 2 ;   P-11215 [PhAc 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Arg 29 -Ada 30 ]hGH-RH(1-29)NH 2 ;   P-11307 [(Ac-Amc) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 -Amc 30 ]hGH-RH(1-29)NH 2 ;   P-11309 [(Me-NH-Sub) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 -Amc 30 ]hGH-RH(1-29)NH 2 ;   P-11311 [(Ac-Amc) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Agm 29 ]hGH-RH(1-29);   P-11313 [(Ac-Amc) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 -Agm 30 ]hGH-RH(1-29);   P-11315 [(Ac-Amc) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 ]hGH-RH(1-29)NH 2 ;   P-11317 [(Ac-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 ]hGH-RH(1-29)NH 2 ;   P-11321 [(Ac-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Arg 29 -Ada 30 ]hGH-RH(1-29)NH 2 ;   P-11407 [(Ac-Amc) 0 -Tyr 1 , D-Arg 2 , (Me-Ala) 4 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11408 [(Ac-Amc) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , (Me-Ala) 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11409 [(Ac-Amc) 0 -Tyr 1 , D-Arg 2 , (Me-Ala) 4 , Cpa 6 , (Me-Ala) 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11411 [PhAc 0 -Tyr 1 , D-Arg 2 , Cpa 6 , (Me-Ala) 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 -Amc 30 ]hGH-RH(1-29)NH 2 ;   P-11415 [(Ac-Amco) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , (Me-Ala) 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 -Agm 30 ]hGH-RH(1-29);   P-11417 [(Ac-Amc) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , (Me-Ala) 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 -Amc 30 ]hGH-RH(1-29)NH 2 ;   P-11421 [(N-Me-Aibo) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -AE 2 A 30 ]hGH-RH(1-29)NH 2 ;   P-11427 [(N-Me-Aib) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Lys(0-11) 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2  wherein (0-11) is N-Me-Aib-Tyr-D-Arg-Asp-Ala-Ile-Cpa-Thr-Ala-Har-Tyr(Me)-His- and the C-terminal carbonyl group of the (0-11) peptide sequence forms an amide bond with the epsilon amino group of Lys 12 ;   P-11431 [(N-Me-Aib) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -Ala 30 -Lys(Oct) 31 ]hGH-RH(1-29)NH 2 ;   P-11435 [(Ac-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11437 [(Dca-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11439 [(Ac-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , (Lys(Me) 2 ) 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11441 [(Ac-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , (Lys(Me) 2 ) 12 , Abu 15 , His 20 , (Lys(Me) 2 ) 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11443 [(Dca-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , (Lys(Me) 2 ) 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11445 [(Dca-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , (Lys(Me) 2 ) 12 , Abu 15 , His 20 , (Lys(Me) 2 ) 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11449 [(Ac-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , Har 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11451 [(Nac-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , D-Arg 28 , Har 29 -AE 2 A 30 ]hGH-RH(1-29)NH 2 ;   P-11453 [(Dca-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , D-Arg 28 , Har 29 -AE 2 A 30 ]hGH-RH(1-29)NH 2 ;   P-11455 [(Ac-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -AE 2 A 30 ]hGH-RH(1-29)NH 2 ;   P-11459 [(PhAc-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11461 [(Ac-Ada-Phe) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11463 [PhAc 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 -Amc 30 ]hGH-RH(1-29)NH 2 ;   P-11465 [PhAc 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 ]hGH-RH(1-29)NH 2 ;   P-11467 [(Ada-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 ]hGH-RH(1-29)NH 2 ;   P-11469 [(Ac-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 ]hGH-RH(1-29)NH 2 ;   P-11471 [(Ac-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Lys(0-11) 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2  wherein (0-11) is PhAc-Tyr-D-Arg-Asp-Ala-Ile-Cpa-Thr-Ala-Har-Tyr(Me)-His- and the C-terminal carbonyl group of the (0-11) peptide sequence forms an amide bond with the epsilon amino group of Lys 12 ;   P-11473 [(PhAc-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 ]hGH-RH(1-29)NH 2 ;   P-11475 [(Ac-Ada-D-Phe) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 ]hGH-RH(1-29)NH 2 ;   P-11477 [(Ac-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , Glu 17 , His 20 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11479 [(Ac-Ada) 0 -Tyr 1 , D-Arg 2 , (Phe(F) 5 ) 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11481 [(Ac-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -ε-Lys(α-NH 2 ) 30 -Ahx 31 ]hGH-RH(1-29)NH 2 ;   P-11483 [(Ac-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -AE 4 P 30 ]hGH-RH(1-29)NH 2 ;   P-11485 [(CH 3 —(CH 2 ) 10 CO-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 ]hGH-RH(1-29)NH 2 ;   P-11487 [(CH 3 —(CH 2 ) 10 CO-Ada) 0 -Tyr, D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Omr 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11491 [(Dca-Ada) 0 -Tyr 1 , D-Arg 2 , (Phe(F) 5 ) 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11497 [(Ac-Amc) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 hGH-RH(1-29)NH 2 ;   P-11501 [(Ac-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -β-Ala 30 -Lys(Oct) 31 ]hGH-RH(1-29)NH 2 ;   P-11503 [(Dca-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -β-Ala 30 -Lys(Oct) 31 ]hGH-RH(1-29)NH 2 ;   P-11513 [Dca 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , Har 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11515 [(Dca-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Lys(0-11) 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2  wherein (0-11) is PhAc-Tyr-D-Arg-Asp-Ala-Ile-Cpa-Thr-Ala-Har-Tyr(Me)-His- and the C-terminal carbonyl group of the (0-11) peptide sequence forms an amide bond with the epsilon amino group of Lys 12 ;   P-11601 [(CH 3 —(CH 2 ) 10 —CO-Ada) 0 -Tyr 1 , D-Arg 2 , (Phe(F) 5 ) 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11602 [(PhAc-Ada) 0 -Tyr 1 , D-Arg 2 , (Phe(F) 5 ) 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11603 [(Dca-Ada) 0 -Tyr 1 , D-Arg 2 , (Phe(F) 5 ) 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11604 [(PhAc-Ada) 0 -Tyr 1 , D-Arg 2 , (Phe(F) 5 ) 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 , Agm 30 ]hGH-RH(1-29);   P-11606 [(PhAc-Ada) 0 -Tyr 1 , D-Arg 2 , (Phe(F) 5 ) 6 , (Me-Ala) 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 , Agm 30 ]hGH-RH(1-29);   P-11611 [(Ac-Amc) 0 -Tyr 1 , D-Arg 2 , (Phe(F) 5 ) 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 ]hGH-RH(1-29)NH 2 ;   P-11612 [(Ac-Ada) 0 -Tyr 1 , D-Arg 2 , (Phe(F) 5 ) 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 ]hGH-RH(1-29)NH 2 ;   P-11620 [(Ac-Amc) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Arg 29 -Ada 30 ]hGH-RH(1-29)NH 2 ;   P-11621 [(Me-NH-Sub) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 ]hGH-RH(1-29)NH 2 ;   P-11629 [(Ac-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , (Me-Ala) 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 -Amc 30 ]hGH-RH(1-29)NH 2 ;   P-11701 [(Dca-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , Glu 17 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -AE 4 P 30 ]hGH-RH(1-29)NH 2 ;   P-11702 [(Dca-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , Glu 17 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -AE 4 P 30 ]hGH-RH(1-29)NH 2 ;   P-11703 [(Dca-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , Glu 17 , Har 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -AE 4 P 30 ]hGH-RH(1-29)NH 2 ;   P-11704 [(CH 3 —(CH 2 ) 10 —CO-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -AE 4 P 30 ]hGH-RH(1-29)NH 2 , and combination thereof.   
     
     
         3 . The method of  claim 1 , wherein the cancer is selected from lung cancer, prostate cancer, breast cancer, ovarian cancer, endometrial cancer, gastric cancer, intestinal cancer, pancreatic cancer, kidney cancer, bone cancer, liver cancer, glioblastomas, pheochromocytomas, melanomas, and lymphomas. 
     
     
         4 . The method of  claim 1 , wherein the administration of the at least one GHRH antagonist peptide is selected from the group consisting of subcutaneous, intramuscular, transdermal and intravenous injection. 
     
     
         5 . The method of  claim 1 , wherein the at least one GHRH antagonist peptide is administered at a dose in the range of 2 to 20 milligrams/day/subject. 
     
     
         6 . The method of  claim 1 , wherein the at least one GHRH antagonist peptide is selected from:
 P-11602 [(PhAc-Ada) 0 -Tyr 1 , D-Arg 2 , (Phe(F) 5 ) 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ;   P-11604 [(PhAc-Ada) 0 -Tyr 1 , D-Arg 2 , (Phe(F) 5 ) 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 , Agm 30 ]hGH-RH(1-29);   P-11606 [(PhAc-Ada) 0 -Tyr 1 , D-Arg 2 , (Phe(F) 5 ) 6 , (Me-Ala) 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 , Agm 30 ]hGH-RH(1-29), and combination thereof.   
     
     
         7 . A method of treating a subject with cancer comprising administering a therapeutically effective amount of at least one GHRH antagonist peptide selected from the group consisting of:
 P-11419 [PhAc 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -AE 2 A 30 ]hGH-RH(1-29)NH 2 ;   P-11429 [PhAc 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -(β-Ala 30 -Lys(Oct) 31 ]hGH-RH(1-29)NH 2 ;   P-11457 [PhAc 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala, Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 ]hGH-RH(1-29)NH 2 ;   P-11499 [PhAc 0 -Tyr 1 , D-Arg 2 , (Phe(F) 5 ) 6 , Ala, Har 9 , Tyr(Me) 10 , His, Orn 12 , Abu 5 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 ]hGH-RH(1-29)NH 2 ;   P-1109 [PhAc 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , Glu 17 , His 20 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ,   P-1111 [PhAc 0 -Tyr 1 , D-Arg 2 , (Me-Ala) 4 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ,   P-1113 [PhAc 0 -Tyr 1 , D-Arg 2 , Cpa 6 , (Me-Ala) 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ,   P-1115 [PhAc 0 -Tyr 1 , Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , (Lys(Me) 2 ) 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ,   P-1117 [PhAc 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , (Lys(Me) 2 ) 12 , Abu 15 , His 20 , (Lys(Me) 2 ) 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ,   P-11213 [Oct 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , His 9 , Tyr(Et) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 ]hGH-RH(1-29)NH 2 ,   P-11319 [(Ac-Ada) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , His 9 , Tyr(Et) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 ]hGH-RH(1-29)NH 2 ,   P-11423 [PhAc 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Dip 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -AE 2 A 30 ]hGH-RH(1-29)NH 2 ,   P-11425 [PhAc 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Lys(0-11) 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2  wherein (0-11) is PhAc-Tyr-D-Arg-Asp-Ala-Ilelle-Cpa-Thr-Ala-Har-Tyr(Me)-His- and the C-terminal carbonyl group of the (0-11) peptide sequence forms an amide bond with the epsilon amino group of Lys 12 ,   P-11433 [Nac 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -AE 2 A 30 ]hGH-RH(1-29)NH 2 ,   P-11447 [PhAc 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Abu 15 , Har 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2 ,   P-11521 [(Dca-Amc) 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Orn 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 ]hGH-RH(1-29)NH 2 ,   P-11523 [PhAc 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His, Orn 12 , Orn 15 , Glu 17 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 ]hGH-RH(1-29)NH 2 ,   P-11525 [PhAc 0 -Tyr 1 , D-Arg 2 , Cpa 6 , Ala 8 , Har 9 , Tyr(Me) 10 , His 11 , Orn 12 , Orn 15 , His 20 , Orn 21 , Nle 27 , D-Arg 28 , Har 29 -Ada 30 ]hGH-RH(1-29)NH 2 ;   P-11413 [PhAc 0 -Tyr 1 , D-Arg 2 , Cpa 6 , 3-Pal 8 , Har 9 , Tyr(Me) 10 , His 11 , Abu 15 , His 20 , Nle 27 , D-Arg 28 , Har 29 -Amc 30 ]hGH-RH(1-29)NH 2 , and combinations thereof.   
     
     
         8 . The method of  claim 7 , wherein the cancer is selected from lung cancer, prostate cancer, breast cancer, ovarian cancer, endometrial cancer, gastric cancer, intestinal cancer, pancreatic cancer, kidney cancer, bone cancer, liver cancer, glioblastomas, pheochromocytomas, melanomas, and lymphomas. 
     
     
         9 . The method of  claim 7 , wherein the administration of the at least one GHRH antagonist peptide is selected from the group consisting of subcutaneous, intramuscular, transdermal and intravenous injection. 
     
     
         10 . The method of  claim 7 , wherein the at least one GHRH antagonist peptide is administered at a dose in the range of 2 to 20 milligrams/day/subject.