TREATMENT OF RESISTANT OR REFRACTORY CANCERS WITH MULTI-ARM POLYMERIC CONJUGATES OF 7-ETHYL-10-HYDROXYCAMPTOTHECIN

1 . A method of treating a resistant or refractory cancer in a mammal, comprising: administering an effective amount of a compound of formula (I):

wherein

R 1 , R 2 , R 3 and R 4 are independently OH or

wherein

L is a bifunctional linker;

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;

or a pharmaceutically acceptable salt thereof to said mammal.

2 . The method of claim 1 , wherein the resistant or refractory cancer is selected from the group consisting of solid tumors, lymphomas, lung cancer, small cell lung cancer, acute lymphocytic leukemia (ALL), breast cancer, pancreatic cancer, glioblastoma, ovarian cancer and gastric cancer.

3 . The method of claim 1 , wherein the cancer is resistant or refractory to camptothecin or camptothecin analog therapy.

4 . The method of claim 1 , wherein the cancer is resistant or refractory to CPT-11 therapy.

5 . The method of claim 1 , wherein the cancer is resistant or refractory to camptothecin therapy.

6 . The method of claim 1 , wherein L is a residue of an amino acid or amino acid derivative, and 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, isodemosine, allo-isoleucine, N-methylglycine, sarcosine, N-methyl-isoleucine, 6-N-methyl-lysine, N-methylvaline, norvaline, norleucine, and ornithine.

7 . 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 21 (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 O) 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 (CR 24 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 substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 1-6 heteroalkyl, substituted C 3-6 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, substituted and arylcarbonyloxy;

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

(v) is 0 or 1.

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

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

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

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

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

13 . The method of claim 1 , wherein the compound of formula (I) is part of a pharmaceutical composition and the compound of formula (I) included therein has about 3.9 units of

14 . A method of claim 1 , wherein the compound of formula (I) is selected from the group consisting of

15 . The method of claim 1 , wherein the compound of formula (I) is

16 . The method of claim 1 , wherein the compound is administered in amounts of from about 0.1 to about 45 mg/m 2 /dose.

17 . The method of claim 1 , wherein the compound is administered in amounts of from about 1.25 to about 16.5 mg/m 2 /dose.

18 . The method of claim 1 , wherein the compound is administered in combination with a second chemotherapeutic agent simultaneously or sequentially.

19 . A method of treating a resistant or refractory cancer in a mammal, comprising:

administering an effective amount of a compound of

in amounts from about 1.25 to about 16.5 mg/m 2 /dose,

wherein n is from about 28 to about 341

to said mammal.