Methods and compositions for treating metastatic cancer
Methods and compositions for producing targeted delivery vectors are provided. Such vectors are useful for treating neoplastic disorders. Also provided are protocols for administering targeted delivery vectors in a clinical setting such that a therapeutic effect is achieved.
1. A method of inhibiting tumor metastasis in a human patient having a tumor that has metastasized, said method comprising:
intravenously administering to the patient a therapeutically effective amount of retroviral particles at a cumulative dose of at least 1.8×10 11 colony forming units (cfu), wherein each of the retroviral particles comprises:
i) a modified retroviral envelope protein wherein the retroviral envelope protein includes a receptor binding region which has been modified to contain a collagen binding domain comprising a peptide comprising the amino acid sequence Gly-His-Val-Gly-Trp-Arg-Glu-Pro-Ser-Phe-Met-Ala-Leu-Ser-Ala-Ala (SEQ ID NO:1), and
ii) encodes a heterologous therapeutic polypeptide.
2. The method of claim 1 , wherein the retroviral particles accumulate in the patient in areas of exposed collagen.
3. The method of claim 2 , wherein the areas of exposed collagen include neoplastic lesions, areas of active angiogenesis, metastatic tumor invasion lesions, cancerous lesions, areas of vascular injury, surgical sites, inflammatory sites or areas of tissue destruction.
4. The method of claim 1 , wherein the therapeutic polypeptide is an N-terminal deletion mutant of cyclin G1 consisting of amino acid 41 to 249 of human cyclin G1.
5. The method of claim 1 , wherein the therapeutic polypeptide is interleukin-2 (IL-2).
6. The method of claim 1 , wherein the therapeutic polypeptide is granulocyte macrophage-colony stimulating factor (GM-CSF).
7. The method of claim 1 , wherein the therapeutic polypeptide is thymidine kinase.
8. The method of claim 1 , wherein the retroviral envelope protein is a modified 4070A amphotropic envelope protein.
9. The method of claim 1 , wherein the receptor binding region is modified by inserting the peptide comprising the amino acid sequence Gly-His-Val-Gly-Trp-Arg-Glu-Pro-Ser-Phe-Met-Ala-Leu-Ser-Ala-Ala (SEQ ID NO:1) between two consecutively numbered amino acid residues of the native gp70 portion of the 4070A amphotropic envelope protein.
10. The method of claim 9 , wherein the peptide is inserted between amino acids 6 and 7 of the native gp70 portion of the 4070A amphotropic envelope protein.
11. The method of claim 8 , wherein the peptide is contained in the gp70 portion of the modified 4070A amphotropic envelope protein.