Merck + Co., Inc.

Sloan-kettering Institute for Cancer Research

Allen I Oliff

Victor M Garsky

Raymond E Jones

David C Heimbrook

Deborah DeFeo-Jones

Dong-Mei Feng

Walfred S Saari

Mark W Riemen

Samuel L Graham

George C Prendergast

Joel R Huff

Neal Rosen

Laura Sepp-Lorenzino

Edward M Scolnick

Jackson B Gibbs

Steven M Stirdivant

Jenny M Wai

Nancy Kohl

Mona Ivey-Hoyle

Janet Ahern

Deborah D Jones

Gwynneth M Edwards

Mark M Moasser

The present invention relates to methods of treating cancer using a combination of a compound which is an antineoplastic agent and a compound which is a inhibitor of prenyl-protein transferase, which methods comprise administering to said mammal, either sequentially in any order or simultaneously, amounts of at lest two therapeutic agents selected from a group consisting of a compound which is an antineoplastic agent and a compound which is an inhibitor or prenyl-protein transferase. The invention also relates to methods of preparing such compositions.

Method of treating cancer

Chemical conjugates which comprise oligopeptides, having amino acid sequences that are selectively proteolytically cleaved by free prostate specific antigen (PSA), hydrophilic oligopeptide blocking groups and known cytotoxic agents are disclosed. Such conjugates are useful in the treatment of prostatic cancer and benign prostatic hypertrophy (BPH).

Conjugates useful in the treatment of prostate cancer

We have modified PE,toxin by removing at least two of its four cysteine amino acid residues and have formed hybrid molecules containing modified PE,linked to a cell recognition protein that can be an antibody, a growth factor, a hormone, a lymphokine, or another polypeptide cell recognition protein for which a specific cellular receptor exists whereby the modified PE,toxin is directed to cell types having receptors for the cell recognition protein linked to the modified PE,.

Modified PE40 toxin fusion proteins

Novel pharmaceutical compositions useful for the treatment of benign prostatic hyperplasia which comprises novel oligopeptides, which are selectively cleaved by enzymatically active PSA, in conjugation with a cytotoxic agent are described. Methods of treating benign prostate hypertrophy are also disclosed.

Conjugates useful in the treatment of benign prostatic hyperplasia

Oligopeptides which comprise amino acid sequences that are recognized and proteolytically cleaved by free prostate specific antigen (PSA) are described. Also described are assays which comprise such oligopeptides useful for determining free PSA protease activity in vitro and in vivo. Therapeutic agents which comprise conjugates of such oligopeptides and known cytotoxic agents are also described.

Peptides

Methods and compositions for treating bladder cancer using TGF-alpha or EGF fused to PE.sub.40 or cysteine modified derivatives are taught. Also, a method of producing TGF-alpha-PE.sub.40 derivatives of enhanced potency is described.

Method of treating bladder cancer cells

Assays which comprise oligopeptides and which are useful for determining free PSA protease activity in vitro and in vivo are described. Such oligopeptides comprise amino acid sequences that are recognized and proteolytically cleaved by free prostrate specific antigen (PSA). Also described are assays useful in identifying inhibitors of free PSA.

The present invention is directed to a novel protein with E2F-like properties and the cDNA that encodes for that protein. The purified protein exhibits biological activity which is deemed important to medical science in the study of cell cycle regulation in general and the specific study of the Rb rumor suppressor protein and certain viral oncogenes. The protein may be employed in a complex with pRb or other cellular proteins to study inhibitors of biochemical transformations of those proteins, such as for example the phosphorylation of the pRb portion of the complex, therefore aiding in the study of potential pharmaceutical agents useful against certain oncoproteins encoded by DNA tumor viruses.

E2F-2, a novel mammalian transcription factor

Small cell lung carcinoma cells (SCLC) contain gastrin releasing peptide (GRP) receptors. The response of the cells to GRP is rapid growth. We have found a group of heptapeptides that act as GRP antagonists by blocking the binding of GRP to its receptor thereby inhibiting the growth of cells that are sensitive to the growth promoting acitivity of GRP.

Gastrin releasing peptide antagonist

Small cell lung carcinoma cells (SCLC) contain gastrin releasing peptide (GRP) receptors. The response of the cells to GRP is rapid growth. We have found a group of peptide derivatives that act as GRP antagonists by blocking the binding of GRP to its receptor thereby inhibiting the growth of cells that are sensitive to the growth promoting activity of GRP.

Small cell lung carcinoma (SCLC) cells contain gastrin releasing peptide (GRP) receptors. The response of the cells to GRP is rapid growth. We have found a group of peptide derivatives that act as GRP antagonists by blocking the binding of GRP to its receptor thereby inhibiting the growth of cells that are sensitive to the growth promoting activity of GRP.

Compounds of formula I and its pharmaceutically acceptable salts are formulated with a pharmaceutical carrier for the treatment or prevention of neoplastic diesase states sensitive to such treatment in animals including humans ##STR1## wherein: A is an alkyl group having 1-6 carbons;

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Gwynedd Valley, PA, United States of America

Allen I Oliff