A Critical Review of Chloroquine and Hydroxychloroquine as Potential Adjuvant Agents for Treating People with Cancer
Abstract
:1. Introduction
2. Pharmacokinetics
3. Preclinical Studies of Anticancer Activity of CQ and HCQ
4. Dose and Schedule
5. Safety Profile
6. Clinical Trials
7. Drug-Drug and Drug-Disease Interactions
8. Conclusions and Future Perspectives
- Despite their preclinical anticancer and safety profile, there are currently no sensitive and reliable predictive biomarkers for the rational selection of cancer patients who could benefit from the use of CQ/HCQ and avoid the exposure of non-responders to their adverse effects.
- Consideration of the risk and benefit for CQ/HCQ in cancer patients must be individualized.
- Some anticancer drugs and HCQ/CQ are associated with a prolonged QT interval. Given the multifactorial developmental nature of TdP, careful cardiac monitoring and correction of electrolyte imbalance are critical and treatment withdrawal is needed if cardiac manifestations arise.
- Given the homeostatic role of autophagy, which is inhibited by HCQ/CQ, monitoring of vital organs is essential.
- Long-term follow-up of treated patients for potential cardiovascular, renal and retinal toxicities is warranted.
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Drug | Cancer Type | Treatment Schedule of CQ or HCQ (n = Sample Size) | Clinical Outcome | Ref |
---|---|---|---|---|
CQ | Glioblastoma multiforme | CQ (150 mg dose/day) was administered 24 h post-surgery and continued with radiotherapy and chemotherapy throughout the observation period (24–50 months) (n = 9/control cohort and n = 9/CQ cohort). | CQ prolonged the survival compared to the controls. | [64] |
Glioblastoma multiforme | CQ (n = 6: 200 mg, n = 3: 300 mg and n = 4: 400 mg) was started 1 week before chemoradiation (temozolomide + radiotherapy). |
| [76] | |
Brain metastases from solid tumours | Whole brain irradiation (30 Gy in 10 fractions over two weeks) together with CQ (150 mg/day were administered 1 h before whole brain irradiation and continued for 4 weeks) (n = 34/placebo cohort and n = 39/CQ cohort). |
| [65] | |
Breast cancer | 500 mg/day as monotherapy for 2–6 weeks before surgery (n = 24/placebo cohort and n = 46/CQ cohort). |
| [60] | |
Metastatic or unresectable pancreatic cancer | 3+3 dose escalation study in which patients received single weekly dose of gemcitabine followed by single weekly doses of CQ (100, 200 or 300 mg) (n = 9). |
| [74] | |
HCQ | Pancreatic adenocarcinoma | Pre-operative gemcitabine + HCQ (1200 mg/kg/day) for 31 days until surgery (n = 35). |
| [69] |
Metastatic pancreatic cancer | Patients received (n = 10: 400 mg or n = 10: 600 mg) HCQ BID. |
| [70] | |
Resectable pancreatic adenocarcinoma | Preoperative HCQ (600 mg BID) (n = 30/nab-paclitaxel and gemcitabine (PG) cohort and n = 34/HCQ + PG cohort). |
| [61] | |
Advanced or metastatic pancreatic adenocarcinoma | HCQ (600 mg BID) (n = 57/PG cohort and n = 55/PG + HCQ cohort). |
| [72] | |
Non-small cell lung cancer |
|
| [77] | |
Advanced solid tumours and melanoma | HCQ (200–1200 mg/day) + temozolomide for 7/14 days (n = 37). |
| [67] | |
Glioblastoma multiforme | Phase I: HCQ (200 to 800 mg/day) with radiotherapy and temozolomide (n = 16). Phase II: HCQ (200 to 800 mg/day) with radiotherapy and temozolomide (n = 76). |
| [78] | |
Advanced metastatic colorectal cancer | HCQ (600 mg/day) + vorinostat in a 3-week cycle (n = 20). |
| [63] | |
Refractory/ relapsed myeloma | Two week run-in of HCQ as a monotherapy (100, 200, 400, 800 or 1200 mg/day) followed by combination therapy with bortezomib (n = 25). |
| [66] | |
Renal cell carcinoma | Everolimus + HCQ (400 or 600 mg BID) (n = 38). First Cycle (35 days): 1-week everolimus alone. Subsequent cycles (28 days/cycle): everolimus +HCQ. |
| [68] | |
Early-stage solid tumors | 200 or 400 mg BID for 14 days before surgery (n = 9). |
| [75] | |
Chronic phase chronic myeloid leukemia | Imatinib (n = 30) or imatinib + HCQ (400 mg BID) (n = 32) for 12 months. | Imatinib + HCQ was tolerated with modest improvement in BCR-ABL1 qPCR levels at 12 and 24 months. | [59] | |
Advanced BRAFV600-mutant melanoma | Patients (n = 38) were treated with dabrafenib and trametinib for one week and then HCQ (starting Phase I dose = 400 mg BID) was co-administered. Treatment continued until PD, and after PD in the case of isolated progression, which could be locally treated. |
| [79] |
Drug | Interacting Drug | Type of Interaction/Recommendations | Ref |
---|---|---|---|
CQ | Some antacids | Some antacids decreases CQ bioavailability and time spacing >4 h is recommended. | [83] |
CQ | Ampicillin | CQ decreases the bioavailability of ampicillin | [84] |
CQ/HCQ | QT Prolongation inducing drugs | Co-administration of >1 QT prolonging drugs can increase the risk of developing prolonged QT associated-arrthymia. | [51,52,58] |
CQ/HCQ | Tamoxifen | Increased risk for retinopathy. | [56,85] |
CQ | Ciclosporin(cyclosporin) | Three-day CQ administration was associated with elevated serum ciclosporin and creatinine levels which was reversed one week after CQ discontinuation. | [86] |
CQ | Methotrexate | CQ decreases the area plasma under the curve of methotrexate. | [87] |
CQ | Cimetidine | Cimetidine impairs CQ elimination. | [88] |
CQ | Acetaminophen (Paracetamol) | CQ increases the peak plasma levels and AUC of paracetamol. | [89] |
CQ | Primaquine | CQ increases the plasma levels of primaquine and carboxyprimaquine and its use is associated with slight corrected QT (QTc) interval prolongation. | [90] |
CQ | Digoxin | CQ increases the serum levels of digoxin which warrants careful monitoring. | [91] |
CQ | Cisplatin | CQ exacerbates acute cisplatin-induced nephrotoxicity. | [55] |
HCQ | Insulin and hypoglycaemic drugs | HCQ induces hypoglycaemia and dose re-adjustment of insulin or hypoglycaemic drugs is necessary. | [92] |
HCQ | Metoprolol | HCQ increases the bioavailability of metoprolol. | [80] |
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Abdel-Aziz, A.K.; Saadeldin, M.K.; Salem, A.H.; Ibrahim, S.A.; Shouman, S.; Abdel-Naim, A.B.; Orecchia, R. A Critical Review of Chloroquine and Hydroxychloroquine as Potential Adjuvant Agents for Treating People with Cancer. Future Pharmacol. 2022, 2, 431-443. https://doi.org/10.3390/futurepharmacol2040028
Abdel-Aziz AK, Saadeldin MK, Salem AH, Ibrahim SA, Shouman S, Abdel-Naim AB, Orecchia R. A Critical Review of Chloroquine and Hydroxychloroquine as Potential Adjuvant Agents for Treating People with Cancer. Future Pharmacology. 2022; 2(4):431-443. https://doi.org/10.3390/futurepharmacol2040028
Chicago/Turabian StyleAbdel-Aziz, Amal Kamal, Mona Kamal Saadeldin, Ahmed Hamed Salem, Safaa A. Ibrahim, Samia Shouman, Ashraf B. Abdel-Naim, and Roberto Orecchia. 2022. "A Critical Review of Chloroquine and Hydroxychloroquine as Potential Adjuvant Agents for Treating People with Cancer" Future Pharmacology 2, no. 4: 431-443. https://doi.org/10.3390/futurepharmacol2040028
APA StyleAbdel-Aziz, A. K., Saadeldin, M. K., Salem, A. H., Ibrahim, S. A., Shouman, S., Abdel-Naim, A. B., & Orecchia, R. (2022). A Critical Review of Chloroquine and Hydroxychloroquine as Potential Adjuvant Agents for Treating People with Cancer. Future Pharmacology, 2(4), 431-443. https://doi.org/10.3390/futurepharmacol2040028