Research/Patent on Chloroquine treatment against DNA damage

.

"...exposure to chloroquine prior to irradiation increased cell Survival by 30%." 

  US 2005/0014785 A1 

 Authors: 

Michael B. Kastan, Cordova, TN (US); 

Christopher Bakkenist, Cordova, TN (US);

Mark McCamish, Cupertino, CA (US) 

 Pub. Date: Jan. 20, 2005 

 Note: a Patent is not a proof that the invention works! 

 Quotes:

ABSTRACT The present invention provides methods and compositions for the treatment of DNA damage related disorders. One embodiment is a method for the inhibition of Side effects asSociated with chemotherapeutic and radiotherapeutic agents using chloroquine compounds. Another embodiment is a method for treatment and/or prevention of lethal or Sub-lethal radiation toxicities associated with terrorist acts or war.

BRIEF DESCRIPTION OF THE FIGURES 0007 FIG. 1 shows a Kaplan-Meier survival curve of C57/BL6 mice after exposure to 8 Gy total body irradiation (TBI). Half of the cohort received a dose of chloroquine (dashed line) by either i.p. injection (1.75 mg/kg or 3.5 mg/kg) or in their drinking water (3.5 mg/kg or 7 mg/kg) the day before the TBI. The one mouse which died in the chloroquine-treated group received 1.75 mg/kg by i.p. injection.

0008 FIG. 2 shows that chloroquine treatment enhances survival after TBI by enhancing recovery of hematopoietic progenitor cells. Five mice received 3.5 mg/kg chloroquine (C) by i.p. injection 24 and 4 hours prior to TBI (bars with diagonal Stripes). Five mice received no chloroquine (stippled bars). Fourteen days after irradiation, the cellular ity (open bars) of hematopoietic tissues (spleen, thymus, bone marrow) was assessed by a blinded observer on a scale of 0-3 with 3 being normal cellularity. The bars represent the average cellularity of the tissues from the 5 mice in each group.

0009 FIG.3 shows a Kaplan-Meier survival curve of AT mice after exposure to 8 GyTBI. Half of the cohort received a dose of 3.5 mg/kg chloroquine (CHL; dashed line) by i.p. injection 24 and 4 hours prior to the TBI.

0010 FIG. 4 demonstrates that chloroquine treatment prevents the development of tumors in Eul-myc mice. After weaning, a cohort of transgenic mice expressing the c-myc oncogene were started on chloroquine (CHL) at 7.0 mg/kg in the drinking water ((+), solid line). Within 100 days, all of the mice with no drug in the water had died of leukemia, while none of the cohort of mice on drug had Succumbed. The latter group of mice was then divided into two groups (timing of this event depicted by heavy arrow), one group of which was taken off of chloroquine ((-), dashed line) and the other group of which was started on i.p. injections of 3.5 mg/kg of chloroquine once a week. Within a month, all of the mice taken off of chloroquine had developed malignan cies and all of the mice on the weekly i.p. injections remained tumor-free for months.

0011 FIG. 5 illustrates that chloroquine treatment reduces the development of tumors in mice injected with the potent chemical carcinogen, 3-methylcholanthrene (3-MC). Chloroquine (CHL, 3.5 mg/kg) was given by i.p. injection 24 and 4 hours prior to 3-MC injection in 30 mice and 30 mice received the carcinogen with no chloroquine pretreat ment. The percentage of animals remaining tumor-free is plotted. Statistical significance, log rank test P-0.0001.

0012 FIG. 6 demonstrates that chloroquine treatment reduces the development of tumors in mice exposed to ionizing radiation in a protocol that induces thymic lym phomas. Chloroquine (CHL, 3.5 mg/kg) was given by i.p. injection 24 and 4 hours prior to irradiation in four Successive weeks and animals were subsequently observed for the development of tumors. Statistical Significance, log rank test P=0.0012.

0013 FIG. 7 shows tumor incidence in wildtype mice receiving either placebo or CHQ before 3-MC injection. CHQ markedly protects from tumor development.

0014 FIG. 8 shows tumor incidence in ATM-null mice receiving either placebo or CHQ before 3 MC injection. CHQ does not protect from tumor development.

0015 FIG. 9 shows tumor incidence in p53-null mice receiving either placebo or CHQ before 3 MC injection. CHQ does not protect from tumor development.

0016 FIG. 10 demonstrates the efficacy of two chloroquine compounds in preventing, in Varying degree, the change in coat color in mice treated with 8 GY radiation.

------------ Update 14-Aug-2020 -----------------

"Hydroxychloroquine-loaded hollow mesoporous silica nanoparticles for enhanced autophagy inhibition and radiation therapy",by Yan Li et al., 25-June-2020