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Pharmaceuticals -> Antineoplastic and immunomodulating agents -> Antineoplastic agents

Pharmaceuticals -> Listed in ZINC15

Warning

H302 (90.9%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 33 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In large clinical trials of rucaparib, abnormalities in routine liver tests were common; serum ALT elevations arising in 74% with values above 5 times the upper limit of normal (ULN) in 13%. Despite the frequency of serum enzyme elevations during therapy in clinical trials, there were no reports of hepatitis with jaundice or liver failure. Subsequent to its approval and more wide scale use, there have been no published reports of clinically apparent liver injury attributed to rucaparib. Thus, rucaparib is a frequent cause of serum enzyme elevations, but has not been linked to significant hepatotoxicity.

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Rucaparib is an anticancer agent that exerts cytotoxic effects against cancer cells. It works by inhibiting poly (ADP-ribose) polymerase (PARP), an enzyme that plays a role in DNA repair. Rucaparib inhibits PARP-1, PARP-2, and PARP-3. It also interacts with PARP-4, PARP-10, PARP-12, PARP-15, and PARP-16, but to a lesser extent. In mice, rucaparib accumulated and was retained in tumours, inhibiting PARP enzymes for seven days. Rucaparib decreases tumour growth in tumour cell lines with deficiencies in BRCA1/2 and other DNA repair genes. In addition to PARP inhibition, rucaparib demonstrated PARP-independent cytotoxic mechanisms in cancer cells. When co-administered with other chemotherapeutic agents, rucaparib contributed to synergistic or additive effects _in vitro_ and _in vivo_. There is evidence that rucaparib can sensitize cancer cells to chemotherapy. Rucaparib can also cause vasodilation, which may increase tumour perfusion and enhance the accumulation of cytotoxic drugs in cancer cells.

PARPs play a role in DNA repair by activating DNA damage response pathways, such as base excision repair, and facilitating DNA repair. PARPs were evaluated as novel anticancer therapeutic targets after discovering that PARP-1 inhibitors reduce tumour growth in BRCA-deficient cancers. BRCA1 and BRCA2 are tumour suppressor genes involved in various cellular processes related to cell growth and death, including DNA repair. More specifically, BRCA1 and BRCA2 are involved in homologous recombination (HR) DNA repair. Cancer cells with a deleterious BRCA mutation are HR-deficient, resulting in unregulated and aberrant cell repair and growth. Rucaparib inhibits PARP1, PARP2, and PARP3. Inhibiting PARP traps the enzyme on damaged DNA, halting the repair process and forming toxic PARP–DNA complexes. Alternatively, other DNA repair processes such as error-prone nonhomologous end joining (NHEJ) or alternative end-joining pathways can be initiated, leading to mutations or chromosomal change. Further DNA damage can trigger cancer cell apoptosis and cell death. Typically, inhibition of PARP converts single-strand breaks in DNA to double-strand breaks at replication forks. HR DNA repair pathways repair double-strand breaks; however, HR-deficient cancer cells lack this repair mechanism. Because HR-deficient cancer cells are more vulnerable to unsalvageable DNA damage, rucaparib-induced PARP inhibition leads to synthetic lethality. In this phenomenon, two non-lethal defects (HR deficiency and PARP inhibition) combine and cause cell death.