HYDRALAZINE

Hydralazine is a well established blood pressure drug used in a limited number of older trials together with valproic acid used to manage epilepsy. The combination is proposed for their respective actions on processes widely seen upregulated in cancer progression : DNA methylation and histone deacetylases (HDACs). Again, a variety of positive lab studies have not easily developed into clinical trial results.

Evidence on the benefits of this sometimes named epigenetic therapy is presently limited to studies in late stage patients including chronic myeloid leukemia, liver and cervical cancers. The majority of patients in these various trials saw some trends towards longer disease stabilty and slowed progression. However, the concentration of these trials to only a couple of research teams, and the lack of more recent results in larger clincial trials limits the evidence for these drugs in cancer.

This combination of drugs may develop further, within oncology, if it can be well targeted.

This phase II study suggests that DNA methylation and HDAC inhibitors overcome resistance to chemotherapy because clinical benefit (PR + SD) was observed in 80% of patients. This study design is unique in that the majority of patients were actively progressing to chemotherapy; this is best illustrated by the fact that seven patients deteriorated clinically during the week of hydralazine and valproate administration and prior to the first chemotherapy cycle. Therefore, the achievement of response and disease stabilization can only be attributed to...

Our results suggest that the epigenetic drugs hydralazine and valproate revert the resistance to imatinib in patients with CML [chronic myeloid leukemia]…Two [of 8] (25%) patients had a complete hematologic response, one (12.5%) had an major cytogenetic response, and one (12.5%) had a complete cytogenetic response. Three (37.5%) patients had stable disease, At a median follow-up time of 18 months (range, 3-18 months), the median survival had not been reached, and the projected overall survival was 63%…. No grade 3 or 4 toxicity was ob...

Thirty-seven [liver cancer] patients with 16 sorafenib-experienced, underwent GCGG treatment, and 30 of them underwent the following Dox-DTIC treatment. The median OS [overall survival] was 14.6 months [the study quotes typical OS as 5 to 12 months]. The median PFSs for patients treated with VA- and HZ-combined GCGG and Dox-DTIC were 3.7 and 4.2 months, respectively; the RRs were 10/37 (27.0%) and 7/30 (23.3%); and grade 3/4 neutropenia were 54% and 51%. However, there were no chemotherapy-related deaths

We conducted a phase I trial combining valproic acid and hydralazine to determine the maximally tolerated dose (MTD) of hydralazine in combination with a therapeutic dose of valproic acid in patients with advanced, unresectable, and previously treated solid cancers….One partial response by Response Evaluation Criteria In Solid Tumors criteria was observed, and five subjects experienced stable disease for 3 to 6 months. The combination of hydralazine and valproic acid is simple, nontoxic, and might be appropriate for chemoprevention or combi...

TABLE OF REFERENCES

Help grow the evidence. JOIN us for online forms or try Feedback and Ideas below.

URL	Rating	Highlight	Highlight 2
https://www.annalsofoncology.org/article/S0923-7534(19)42189-3/fulltext	3.5	This phase II study suggests that DNA methylation and HDAC inhibitors overcome resistance to chemotherapy because clinical benefit (PR + SD) was observed in 80% of patients. This study design is unique in that the majority of patients were actively progressing to chemotherapy; this is best illustrated by the fact that seven patients deteriorated clinically during the week of hydralazine and valproate administration and prior to the first chemotherapy cycle. Therefore, the achievement of response and disease stabilization can only be attributed to the use of the epigenetic agents because this was the only difference between pre-study and protocol regimens. Further, chemotherapy-regimen dose intensity during hydralazine and valproate administration was actually lower, which strengthens the results.	In conclusion, the response and disease stabilization rates observed suggest that hydralazine and valproate overcome epigenetic changes, mediating chemotherapy resistance regardless of chemotherapy drug and tumor type. In addition, despite the fact that this epigenetic therapy increased the myelotoxicity of chemotherapy the toxicity is manageable. Nevertheless, this is a single-arm study; therefore, the possibility that patients would have responded to or stabilized with subsequent cycles of chemotherapy cannot be ruled out. To confirm the benefit of epigenetic therapy, placebo-controlled randomized phase III trials of hydralazine and valproate added to chemotherapy are ongoing
https://pubmed.ncbi.nlm.nih.gov/22420986/	3.5	Our results suggest that the epigenetic drugs hydralazine and valproate revert the resistance to imatinib in patients with CML [chronic myeloid leukemia]...Two [of 8] (25%) patients had a complete hematologic response, one (12.5%) had an major cytogenetic response, and one (12.5%) had a complete cytogenetic response. Three (37.5%) patients had stable disease,	At a median follow-up time of 18 months (range, 3-18 months), the median survival had not been reached, and the projected overall survival was 63%. All the patients had mild neurologic toxicity, including distal tremor and somnolence. No grade 3 or 4 toxicity was observed.
https://onlinelibrary.wiley.com/doi/abs/10.1111/ajco.13443	3	Thirty-seven [liver cancer] patients with 16 sorafenib-experienced, underwent GCGG treatment, and 30 of them underwent the following Dox-DTIC treatment. The median OS [overall survival] was 14.6 months [the study quotes typical OS as 5 to 12 months]. The median PFSs for patients treated with VA- and HZ-combined GCGG and Dox-DTIC were 3.7 and 4.2 months, respectively; the RRs were 10/37 (27.0%) and 7/30 (23.3%); and grade 3/4 neutropenia were 54% and 51%.	VA- and HZ-combined sequential chemotherapy was effective in advanced HCC with manageable toxicities...Chemotherapy modulated with valproic acid (VA) as a deacetylation inhibitor of histone and DNA damage response proteins, and hydralazine (HZ) as a DNA hypomethylating agent, hypothetically suppressing DNA repair, were used in phase II trial here for advanced HCC
https://link.springer.com/article/10.1007/s12032-010-9700-3	3	At a median follow-up time of 7 months (1–22), the median PFS is 6 months for CT + PLA and 10 months for CT + HV (P = 0.0384, two tailed). Although preliminary, this study represents the first randomized clinical trial to demonstrate a significant advantage in progression-free survival for epigenetic therapy over one of the current standard combination chemotherapy in cervical cancer	The reversing of epigenetic aberrations using the inhibitors of DNA methylation and histone deacetylases may have therapeutic value in cervical cancer. This is a randomized phase III, placebo-controlled study of hydralazine and valproate (HV) added to cisplatin topotecan in advanced cervical cancer. Patients received hydralazine at 182 mg for rapid, or 83 mg for slow acetylators, and valproate at 30 mg/kg, beginning a week before chemotherapy and continued until disease progression
https://pmc.ncbi.nlm.nih.gov/articles/PMC4792814/	3	We conducted a phase I trial combining valproic acid and hydralazine to determine the maximally tolerated dose (MTD) of hydralazine in combination with a therapeutic dose of valproic acid in patients with advanced, unresectable, and previously treated solid cancers....One partial response by Response Evaluation Criteria In Solid Tumors criteria was observed, and five subjects experienced stable disease for 3 to 6 months. The combination of hydralazine and valproic acid is simple, nontoxic, and might be appropriate for chemoprevention or combination with other cancer treatments	Although the dose of 400 mg per day of hydralazine did not exceed DLT as defined, the rates of mild, symptomatic hypotension and edema were considered unacceptable for the purpose of prolonged administration. This study demonstrates that pharmacological doses of hydralazine and valproic acid may be delivered to patients with heavily pretreated malignancies, with evidence of potential clinical activity in melanoma, soft-tissue sarcoma, and carcinomas of the breast, ovary, and head and neck
https://www.spandidos-publications.com/or/25/2/399	1	Ten pairs of pre- and post-treatment cervical tumor samples were analyzed by microarray analysis. Treatment for seven days with hydralazine and valproate (HV) in patients up-regulated 964 genes. The two pathways possessing the highest number of up-regulated genes comprised the ribosome protein and the oxidative phosphorylation pathways, followed by MAPK signaling, tight junction, adherens junction, actin cytoskeleton, cell cycle, focal adhesion, apoptosis, proteasome, Wnt signaling, and antigen processing and presentation pathways	Up-regulated genes by HV, clustered with down-regulated genes in untreated primary cervical carcinomas and were more alike as compared with up-regulated genes from untreated patients in terms of gene ontology. Increased acetylated p53 was also observed. Epigenetic therapy with HV leads to gene reactivation in primary tumors of cervical cancer patients as well as protein acetylation. A number of these reactivated genes have a definitive role as a tumor suppressors. The global expression pattern induced by HV suggests this therapy has an impact on pathways related to energy production which may promote apoptosis.

HYDRALAZINE

TABLE OF REFERENCES

Help grow the community