Treatment of non-hodgkin's lymphomas with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamtothecin

1. A method of treating a mammal having a non-Hodgkin's lymphoma, comprising administering an effective amount of a compound of the formula

wherein

R 1 , R 2 , R 3 and R 4 are independently OH or (L) m -D;

L is a bifunctional linker;

D is

m is 0 or a positive integer; and

n is a positive integer;

provided that R 1 , R 2 , R 3 and R 4 are not all OH;

to a mammal in need thereof; wherein the non-Hodgkin's lymphoma is a Burkitt's lymphoma or a follicular lymphoma.

2. The method of claim 1 , wherein the amount administered is from about 0.3 mg/m 2 body surface/dose to about 90 mg/m 2 body surface/dose.

3. The method of claim 2 , wherein the amount administered is from about 0.9 mg/m 2 body surface/dose to about 30 mg/m 2 body surface/dose.

4. The method of claim 1 , wherein the amount is administered according to a protocol of from about 1 mg/m 2 body surface/dose to about 16 mg/m 2 body surface/dose given weekly for three weeks, followed by 1 week without treatment and repeating for about 3 cycles.

5. The method of claim 4 , wherein the amount administered per every three weeks is from about 1.25 mg/m 2 body surface/dose to about 45 mg/m 2 body surface/dose.

6. The method of claim 1 , wherein L is an amino acid or amino acid derivative, wherein the amino acid derivative is selected from the group consisting of 2-aminoadipic acid, 3-aminoadipic acid, beta-alanine, beta-aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, piperidinic acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, 2,4-aminobutyric acid, desmosine, 2,2-diaminopimelic acid, 2,3-diaminopropionic acid, n-ethylglycine, N-ethylasparagine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylglycine, sarcosine, N-methyl-isoleucine, 6-N-methyl-lysine, N-methylvaline, norvaline, norleucine, and ornithine.

7. The method of claim 6 , wherein L is glycine, alanine, methionine or sarcosine.

8. The method of claim 6 wherein L is glycine.

9. The method of claim 1 , wherein L is selected from the group consisting of

—[C(═O)] v (CR 22 R 23 ) t —,

—[C(═O)] v (CR 22 R 23 ) t —O—,

—[C(═O)] v (CR 22 R 23 ) t —NR 26 —,

—[C(═O)] v O(CR 22 R 23 ) t —,

—[C(═O)] v O(CR 22 R 23 ) t O—,

—[C(═O)] v O(CR 22 R 23 ) t NR 26 —,

—[C(═O)] v NR 21 (CR 22 R 23 ) t —,

—[C(═O)] v NR 21 (CR 22 R 23 ) t O—,

—[C(═O)] v NR 21 (CR 22 R 23 ) t NR 26 —,

—[C(═O)] v (CR 22 R 23 O) t —,

—[C(═O)] v O(CR 22 R 23 O) t —,

—[C(═O)] v NR 21 (CR 22 R 23 O) t —,

—[C(═O)] v (CR 22 R 23 O) t (CR 24 R 25 ) y —,

—[C(═O)] v O(CR 22 R 23 O) t (CR 24 R 25 ) y —,

—[C(═O)] v NR 2 l(CR 22 R 23 O) t (CR 24 R 25 ) y —,

—[C(═O)] v (CR 22 R 23 O) t (CR 24 R 25 ) y O—,

—[C(═O)] v (CR 22 R 23 ) t (CR 24 R 25 O) y —,

—[C(═O)] v O(CR 22 R 23 O) t (CR 24 R 25 ) y O—,

—[C(═O)] v O(CR 22 R 23 ) t (CR 24 R 25 O) y —,

—[C(═O)] v NR 21 (CR 22 R 23 O) t (CR 24 R 25 ) y O—,

—[C(═O)] v NR 21 (CR 22 R 23 ) t (CR 24 R 25 O) y —,

—[C(═O)] v (CR 22 R 23 ) t O—(CR 28 R 29 ) t′ —,

—[C(═O)] v (CR 22 R 23 ) t NR 26 —(CR 28 R 29 ) t′ —,

—[C(═O)] v (CR 22 R 23 ) t S—(CR 28 R 29 ) t′ —,

—[C(═O)] v O(CR 22 R 23 ) t O—(CR 28 R 29 ) t′ —,

—[C(═O)] v O(CR 22 R 23 ) t NR 26 —(CR 28 R 29 ) t′ —,

—[C(═O)] v O(CR 22 R 23 ) t S—(CR 28 R 29 ) t′ —,

—[C(═O)] v NR 21 (CR 22 R 23 ) t O—(CR 28 R 29 ) t′ —,

—[C(═O)] v NR 21 (CR 22 R 23 ) t NR 26 —(CR 28 R 29 ) t′ —,

—[C(═O)] v NR 21 (CR 22 R 23 ) t S—(CR 28 R 29 ) t′ —,

—[C(═O)] v (CR 22 R 23 CR 28 R 29 O) t NR 26 —,

—[C(═O)] v (CR 22 R 23 CR 28 R 29 O) t —,

—[C(═O)] v O(CR 22 R 23 CR 28 R 29 O) t NR 26 —,

—[C(═O)] v O(CR 22 R 23 CR 28 R 29 O) t —,

—[C(═O)] v NR 21 (CR 22 R 23 CR 28 R 29 O) t NR 26 —,

—[C(═O)] v NR 21 (CR 22 R 23 CR 28 R 29 O) t —,

—[C(═O)] v (CR 22 R 23 CR 28 R 29 O) t (CR 24 R 25 ) y —,

—[C(═O)] v O(CR 22 R 23 CR 28 R 29 ) t (CR 24 R 25 ) y —,

—[C(═O)] v NR 21 (CR 22 R 23 CR 28 R 29 O) t (CR 24 R 25 ) y —,

—[C(═O)] v (CR 22 R 23 CR 28 R 29 O) t (CR2 4 R 25 ) y O—,

—[C(═O)] v (CR 22 R 23 ) t (CR 24 R 25 CR 28 R 29 O) y —,

—[C(═O)] v (CR 22 R 23 ) t (CR 24 R 25 CR 28 R 29 O) y NR 26 —,

—[C(═O)] v O(CR 22 R 23 CR 28 R 29 O) t (CR 24 R 25 ) y O—,

—[C(═O)] v O(CR 22 R 23 ) t (CR 24 R 25 CR 28 R 29 O) y —,

—[C(═O)] v O(CR 22 R 23 ) t (CR 24 CR 25 CR 28 R 29 O) y NR 26 —,

—[C(═O)] v NR 21 (CR 22 R 23 CR 28 R 29 O) t (CR 24 R 25 ) y O—,

—[C(═O)] v NR 21 (CR 22 R 23 ) t (CR 24 R 25 CR 28 R 29 O) y —,

—[C(═O)] v NR 21 (CR 22 R 23 ) t (CR 24 R 25 CR 28 R 29 O) y NR 26 —,

wherein:

R 21 -R 29 are independently selected from the group consisting of hydrogen, amino, substituted amino, azido, carboxy, cyano, halo, hydroxyl, nitro, silyl ether, sulfonyl, mercapto, C 1-6 alkylmercapto, arylmercapto, substituted arylmercapto, substituted C 1-6 alkylthio, C 1-6 alkyls, C 2-6 alkenyl, C 2-6 alkynyl, C 3-19 branched alkyl, C 3-8 cycloalkyl, C 1-6 substituted alkyl, C 2-6 substituted alkenyl, C 2-6 substituted alkynyl, C 3-8 substitute cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 1-6 heteroalkyl, substituted C 1-6 heteroalkyl, C 1-6 alkoxy, aryloxy, C 1-6 heteroalkoxy, heteroaryloxy, C 2-6 alkanoyl, arylcarbonyl, C 2-6 alkoxycarbonyl, aryloxycarbonyl, C 2-6 alkanoyloxy, arylcarbonyloxy, C 2-6 substituted alkanoyl, substituted arylcarbonyl, C 2-6 substituted alkanoyloxy, substituted aryloxycarbonyl, C 2-6 substituted alkanoyloxy, and substituted arylcarbonyloxy;

(t), (t′) and (y) are independently selected from zero or a positive integer; and

(v) is 0 or 1.

10. The method of claim 1 , wherein m is from about 1 to about 10.

11. The method of claim 1 , wherein m is about 1.

12. The method of claim 1 , wherein n is from about 28 to about 341.

13. The method of claim 1 , wherein n is from about 114 to about 227.

14. The method of claim 1 , wherein n is about 227.

15. The method of claim 1 , wherein the compound is selected from the group consisting of

16. The method of claim 1 , wherein the compound is

17. A method of treating a mammal having a non-Hodgkin's lymphoma, comprising administering an effective amount of a compound having the formula

to a mammal in need thereof,

wherein

the effective amount administered is from about 0.3 mg/m 2 body surface/dose to about 90 mg/m 2 body surface/dose; and

n is about 227; wherein the non-Hodgkin's lymphoma is a Burkitt's lymphoma or a follicular non-Hodginkin's lymphoma.

18. The method of claim 17 wherein the effective amount administered is from about 0.9 mg/m 2 body surface/dose to about 30 mg/m 2 body surface/dose.

19. The method of claim 17 , wherein the amount is administered according to a protocol of from about 1 mg/m 2 body surface/dose to about 16 mg/m 2 body surface/dose given weekly for three weeks, followed by 1 week without treatment and repeating for about 3 cycles.

20. The method of claim 19 , wherein the amount administered per every three weeks is from about 1.25 mg/m 2 body surface/dose to about 45 mg/m 2 body surface/dose.