Anaerobe targeted enzyme-mediated prodrug therapy
View Patent ↗Recombinant anaerobic bacterial compositions that under anaerobic conditions present in a solid tumor and produce an enzyme capable of catalyzing the conversion of a prodrug to its cytotoxic product in situ are described. Methods of treating tumors using the composition are also described.
1. A composition comprising an obligately anaerobic bacteria of the genus Clostridium transformed with a recombinant expression vector including the coding sequence for an enzyme capable of catalyzing the conversion of a prodrug into a chemotherapeutic agent, wherein said bacteria have the ability to germinate in a tumor.
2. An obligately anaerobic Clostridium bacterial composition, comprising a coding sequence for an enzyme capable of catalyzing the conversion of a prodrug into a chemotherapeutic agent, wherein said bacteria have the ability to germinate in a tumor.
3. The composition according to claim 1 , wherein the enzyme is selected from the group consisting of cytosine deaminase, nitroreductase, β-glucuronidase, and alkaline phosphatase.
4. The composition according to claim 1 , wherein the prodrug is selected from the group consisting of a glucuronide, a glucuronide of epirubicin, 5-fluorocytosine, CB1954, 4-hydroxycyclophosphamide, hydroxyanaline mustard, and 5-fluorouracil.
5. The composition according to claim 1 , wherein the prodrug is 5-fluorocytosine.
6. The composition according to claim 1 , wherein the enzyme is cytosine deaminase.
7. The composition according to claim 2 , wherein the enzyme is selected from the group consisting of cytosine deaminase, nitroreductase, β-glucuronidase, and alkaline phosphatase.
8. The composition according to claim 2 , wherein the prodrug is selected from the group consisting of a glucuronide, a glucuronide of epirubicin, 5-fluorocytosine, CB1954, 4-hydroxycyclophosphamide, hydroxyanaline mustard, and 5-fluorouracil.
9. The composition according to claim 2 , wherein the prodrug is 5-fluorocytosine.
10. The composition according to claim 2 , wherein the enzyme is cytosine deaminase.
11. A composition comprising Clostridium bacteria genetically engineered to express an enzyme capable of converting a prodrug into a chemotherapeutic agent, wherein said bacteria have the ability to germinate in a tumor.
12. The composition according to claim 11 , wherein the enzyme is selected from the group consisting of cytosine deaminase, nitroreductase, β-glucuronidase, and alkaline phosphatase.
13. The composition according to claim 11 , wherein the prodrug is selected from the group consisting of a glucuronide, a glucuronide of epirubicin, 5-fluorocytosine, CB1954, 4-hydroxycyclophosphamide, hydroxyanaline mustard, and 5-fluorouracil.
14. The composition according to claim 11 , wherein the prodrug is 5-fluorocytosine.
15. The composition according to claim 11 , wherein the enzyme is cytosine deaminase.
16. The composition according to claim 11 , wherein the bacteria is Clostridium sporogenes.
17. The composition according to claim 1 , wherein the bacteria is Clostridium sporogenes.
18. The composition according to claim 17 , wherein the enzyme is selected from the group consisting of cytosine deaminase, nitroreductase, β-glucuronidase, β-galactosidase, carboxypeptidase, alkaline phosphatase and β-lactamase.
19. The composition according to claim 17 , wherein the prodrug is selected from the group consisting of a glucuronide conjugate of epirubicin, a glucuronide conjugate of doxorubicin, 5-fluorocytosine, CB1954, 4-hydroxycyclophosphamide, hydroxyanaline mustard, etoposide phosphate, doxorubicin phosphate, mitomycin C phosphate, and 5-fluorocytosine.
20. The composition according to claim 19 , wherein the prodrug is 5-fluorocytosine.
21. The composition according to claim 17 , wherein the enzyme is cytosine deaminase.
22. The obligately anaerobic bacterial composition according to claim 2 , wherein the bacteria is Clostridium sporogenes.
23. The obligately anaerobic bacterial composition according to claim 2 , wherein the enzyme is selected from the group consisting of cytosine deaminase, nitroreductase, β-glucuronidase, β-galactosidase, carboxypeptidase, alkaline phosphatase, and β-lactamase.
24. The anaerobic bacterial composition according to claim 2 , wherein the prodrug is selected from the group consisting of a glucuronide conjugate of epirubicin, a glucuronide conjugate of doxorubicin, 5-fluorocytosine, CB1954, 4-hydroxycyclophosphamide, hydroxyanaline mustard, etoposide phosphate, doxorubicin phosphate, mitomycin C phosphate, and 5-fluorocytosine.
25. The anaerobic bacterial composition according to claim 24 , wherein the prodrug is 5-fluorocytosine.
26. The anaerobic bacterial composition according to claim 24 , wherein the enzyme is cytosine deaminase.