Re:스타틴의 항암용량 사용법

[문형철]

beyond reason

예를들어 심바스타틴

1정 20mg(황갈색 MSD740), 40mg(붉은 벽돌색 MSD 749) 두종류 있음.

최초 개시용량은 심바스타틴 1일 20mg 1일 1회 저녁에 투여

이후 아침저녁으로 20mg씩 2회 투여 총 40 mg

베라파민, 딜티아젬, 드로네다론(항부정맥약물, 칼슘블록커)을 투여하는 환자는 1일 10mg이상투여 안됨. 

아미오다론(항부정맥), 암로디핀(칼슘블록커), 라놀라진(협심증)을 투여하는 환자에게는 1일 20mg이상 투여 안됨.

다른 지질저하제와 병용투여시 1일 10mg초과하면 안됨

신장기능 장애환자는 하루 5mg으로 시작해야... 심바스타틴이 신장으로 배설되기 때문

80mg사용환자에게서 근육병증(횡문근융해) 발생할 우려가 있음.

이 약물 과민반응 환자

간질환 환자

임신부

cyp3a4 억제제(자몽주스, 이트라코나졸, 보세프레비르, 크라리트로마이신 등)

갈락토스 불내성 유전문제가 있는 환자는 사용하면 안됨.

주의

알콜중독자, 간기능 장애 환자

신장기능 장애

갑상선기능저하증

고령자

여성 등

고지혈증약물 스타틴의 항암기전

1) 암세포의 증식을 억제

2) Proapoptotic effects 자극 암세포 사멸

3) 암세포 전이를 억제

Statins are potential anticancerous agents (Review)

• Authors: 
  • Abdullah K. Altwairgi

• View Affiliations

• Published online on: January 20, 2015     https://doi.org/10.3892/or.2015.3741
• Pages: 1019-1039

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Abstract

Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), which is a rate-limiting enzyme in the meval‎‎onate pathway. The pleiotropic effects of statins may be mediated by the inhibition of downstream products such as small GTP-binding proteins, Rho, Ras and Rac whose localization and function are dependent on isoprenylation. Preclinical studies of statins in different cancer cell lines and animal models showed antiproliferative, pro‑apoptotic and anti-invasive effects. Notably, statins showed targeted action in cancerous cell lines compared to normal cells. Previous studies have also shown the synergistic effects of statins with chemotherapeutic agents and radiotherapy. This effect of statins was also observed in chemotherapeutic-resistant tumors. Statins were reported to sensitize the cells to radiation by arresting them in the late G1 phase of the cell cycle. Similarly, population-based studies also demonstrated a chemopreventive and survival benefit of statins in various types of cancers. However, this benefit has yet to be proven in clinical trials. The inter-individual variation in response to statins may be contributed to many genetic and non-genetic factors, including single-nucleotide polymorphisms in HMGCR gene and the overexpression‎‎ of heterogeneous nuclear ribonucleoprotein A1, which was reported to reduce HMGCR enzyme activity. However, more studies with large phase III randomized controlled trials in cancer patients should be conducted to establish the effect of statins in cancer prevention and treatment.

1. Introduction

The global burden due to cancer increased to 14.1 million new cases and 8.2 million cancer-associated mortalities in 2012 (1). The outcome of cancer patients remains poor, despite recent advances in the understanding of the molecular mechanism of tumorigenesis. Thus, more effective initial treatments for this intractable disease are required. Recent therapies under investigation include immunotherapy, chemotherapy, targeted molecular, antiangiogenic and gene therapy, radiation enhancement and drugs for overcoming resistance (2). Statins are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), commonly used as cholesterol-lowering agents (3), that have proven their effectiveness in the treatment of cardiovascular diseases. Preclinical evidence has indicated their antiproliferative, pro-apoptotic, anti-invasive and radio-sensitizing properties (4), and there are emerging interests in the use of statins as anticancer agents. In the present study, we reviewed the current data of statins in cancer.

2. Mechanism of action of statins

Inhibition of HMGCR by statins is a rate-limiting step in the meval‎‎onate pathway. The products of the meval‎‎onate pathway include isoprene units incorporated into sterol and non-sterol compounds. This inhibition by a statin may result in decreased levels of meval‎‎onate and its downstream products, which affects critical cell functions such as membrane integrity, cell signaling, protein synthesis and cell cycle progression. The effect of statins on these processes and consequently on tumor cells, may therefore be able to control tumor initiation, growth and metastasis (Fig. 1) (5–17).

Figure 1 Pleiotropic effects of statins (5–17). Cyt, cytochrome c; FPP, farnesyl pyrophosphate; GGPP, geranylgeranyl pyrophosphate; p21WAF1/CIP1 and p27KIP1, two cyclin-dependent kinase inhibitors; JNK, c-jun NH2-terminal kinase; MC, mitochondria; MMP-9, matrix metalloproteinase-9; NF-κB, nuclear factor κB.

3. Antitumor effects of statins in preclinical studies

The in vitro preclinical studies in different cell lines have shown the ability of statins to suppress tumor growth and development. Statins exert antiproliferative, pro-apoptotic and anti-invasive effects in different cancer cell lines with varying sensitivity. The antimyeloma activity of statins in humans was first reported with the concomitant simvastatin administration in refractory multiple myeloma (MM), which showed reduced drug resistance (18). However, high-dose simvastatin treatment (15 mg/kg/day) in heavily pretreated MM patients transiently increased osteoclast activity and gastrointestinal side-effects, leading to premature discontinuation (19). A pre-operative study in primary invasive breast cancer patients investigated atorvastatin-induced effects on tumor proliferation and HMGCR expression‎‎ while analyzing HMGCR as a predictive marker for statin response. Results of that study suggest HMGCR is targeted by statins in breast cancer cells in vivo, and that statins may have an antiproliferative effect in HMGCR-positive tumors (20). Furthermore, fluvastatin reduced tumor proliferation and increased apoptotic activity in high-grade, stage 0/1 breast cancer in invasive breast cancer patients (21). Statin-induced effects and the underlined mechanism in different cancer cell lines are presented in Table I.

Table I Postulated molecular mechanisms of statin-induced anticancer activity in different cancer cell lines and animal models.

Besides their in vitro efficacy, statins have also been shown to have in vivo antitumor effects in various animal models of cancer. Their efficacy as chemopreventive agents has been demonstrated in radiation-induced mammary tumorigenesis (22), chemical-induced colon tumorigenesis in rodent models (23,24), human myeloid leukemia and glioma cancer cells inoculated in severe combined immunodeficient mice (25,26), and chemical-induced lung tumor in mice (27). Statins have also been shown to reduce metastasis in rat lymphoma (28), rat fibrosarcoma (29), mouse mammary tumor (30), murine colon tumor (31) and mouse melanoma (32). Furthermore, statins increased thein vivo antitumor effect of doxorubicin in three tumor models accompanied by attenuation of its cardiotoxicity (33). Similarly, statins increased the antitumor effect of tumor necrosis factor by inhibiting the tumor-induced angiogenesis in a murine tumor model (34). The effect of statin-induced anticancer activity in different animal models is presented in Table I.

4. Antitumor effects of statins in clinical studies

Observational and retrospective studies reporting cancer risk with statin usage

Accumulating evidence has focused on pre-diagnostic use of statins in reducing risk of lethal prostate cancer (35). In a prospective cohort study of 34,989 USA male health professionals, the use of statins was associated with a reduced risk of advanced prostate cancer. The risk of advanced disease was lower with longer statin use (P trend=0.003) vs. never use. The relative risk (RR) was 0.60 [95% confidence interval (CI), 0.35–1.03] for <5 years of use and 0.26 (95% CI, 0.08–0.83) for ≥5 years of use. There was no association between statin use and risk of total prostate cancer (RR, 0.96; 95% CI, 0.85–1.09) (36). In a Denmark-based case-control study (n=42,480), statin use was associated with an overall risk reduction (6%) that was specifically higher among patients with advanced prostate cancer (10%) (37). Similarly, a decreased risk in mortality was noted among 11,772 newly diagnosed non-metastatic prostate cancer patients in the UK. Furthermore, decreased risks of prostate cancer mortality and all-cause mortality were reported in patients who used statins prior to diagnosis [hazard ratio (HR), 0.55, 95% CI, 0.41–0.74; and HR, 0.66, 95% CI, 0.53–0.81, respectively]. The results were higher compared to those obtained from patients who initiated the treatment only after diagnosis (HR, 0.82, 95% CI, 0.71–0.96; and HR, 0.91, 95% CI, 0.82–1.01, respectively) (38). In another prospective, population-based cohort study (n=1001), statin use prior to prostate cancer diagnosis was unrelated to prostate cancer recurrence/progression, but was associated with a decrease in the risk of prostate cancer-specific mortality (39).

Data from observational studies have addressed the risk of glioma among statin users (40,41). The use of simvastatin and lovastatin for >6 months was inversely associated with glioma risk (40). A recent large nationwide case-control study (41) conducted in Denmark in patients with glioma (2,656 cases and 18,480 controls) also showed a reduction in the risk of glioma among long-term statin users compared with non-users, and the risk was inversely related to the intensity of statin treatment among users [odds ratio (OR), 0.71, 95% CI, 0.44–1.15 for highest intensity statin users]. This potential chemopreventive effect was limited to users of lipophilic statins (41).

Population-based studies have shown 19% reductions in esophageal cancer incidence where statins have been used. Observational studies have shown that statins reduced the incidence of adenocarcinoma in patients with Barrett’s esophagus (BE) by 43%; this effect was further enhanced by a 74% decrease in risk reduction in patients taking a combination of nonsteroidal anti-inflammatory drugs and statins (42).

Findings of a meta-analysis showed that statins are associated with a reduced risk of esophageal cancer, particularly in patients with BE. In a subset of patients with BE (5 studies, 312 esophageal adenocarcinomas in 2,125 patients), statins were associated with a significantly decreased risk (41%) of esophageal adenocarcinomas after adjusting for potential confounders (adjusted OR, 0.59, 95% CI, 0.45–0.78) (43). These findings were consistent with those of another meta-analysis of 11 observational studies. The pooled adjusted data showed statin use was associated with a lower incidence of the combined esophageal cancers (OR, 0.81, 95% CI, 0.75–0.88). Furthermore, their chemopreventive effect was increased in combination with cyclo-oxygenase inhibitors in reducing the risk of adenocarcinoma in BE (OR, 0.26, 95% CI, 0.1–0.68) (44).

A meta-analysis of 26 randomized controlled trials (RCTs) involving 290 gastric cancer and 8 observational studies, totaling 7,321 gastric cancers indicated a reduced risk of gastric cancer with statin use (45). In addition, a meta-analysis of published studies showed a modest reduction in colorectal cancer risk among statin users (46).

A review of 723 patients diagnosed with primary inflammatory breast cancer in 1995–2011 showed that hydrophilic statins were associated with significantly improved progression-free survival (PFS) rates (47). However, long-term use of statins was associated with increased risk of invasive ductal carcinoma (IDC; n=916) and invasive lobular carcinoma (ILC; n=1,068) in a contemporary population-based case-control study conducted in the Seattle-Puget Sound region. It was also reported that women diagnosed with hypercholesterolemia currently using statins for ≥10 years had more than double the risk of IDC (OR, 2.04, 95% CI, 1.17–3.57) and ILC (OR, 2.43, 95% CI, 1.40–4.21) compared with never users (48).

In the meta-analysis of all the observational studies published up to January 2012, statin use and long-term statin use did not significantly affect breast cancer risk. However, the cumulative meta-analysis showed a change in trend of reporting risk of breast cancer from positive to negative in statin users between 1993 and 2011. These findingd do not support the hypothesis that statins exert a protective effect against breast cancer (49).

The Cancer in The Ovary and Uterus Study (CITOUS; case-control study) assessed the use of statins prior to and following diagnosis in a subset of 424 cases of ovarian and endometrial cancers and 341 controls using pharmacy records. Use of statins >1 year prior to diagnosis was associated with risk reduction, whereas survival improvement was observed among the two malignancies when statins were ingested only after diagnosis (50).

The Nurses’ Health and Health Professionals Follow-Up Study investigated the association between statin use and renal cell carcinoma (RCC) risk. The reported results were similar between ever vs. never users of statins. The subgroup analyses of that study reported that statin use may be associated with a lower risk of RCC among women with no history of hypertension (51).

Statin use is associated with a reduced risk of hepatocellular cancer, most strongly in Asian, but also in Western populations (52). Similarly, another meta-analysis suggested a favorable effect of statins on hepatocellular carcinoma in the absence of a duration-risk relationship (53).

A meta-analysis of all the published articles up to December 2007 showed no association between statin use on pancreatic cancer risk among patients using statins daily for managing hypercholesterolemia (54). These findings were consistent with those from another meta-analysis, which reported no association between statin use and pancreatic cancer risk among patients using statins daily for preventing cardiovascular event (55).

A meta-analysis of observational trials and RCTs did not support a protective effect of statins on overall lung cancer risk, and the lung cancer risk among elderly people (56). Nineteen studies (5 RCTs and 14 observational studies) involving 38,013 lung cancer cases suggested no association between statin use and risk of lung cancer (57). Similarly, a meta-analysis of published literature did not support the role of statins in prevention of skin cancer (58).

A retrospective eval‎‎uation of 1,502 patients with urothelial carcinoma of the bladder treated with radical cystectomy and pelvic lymphadenectomy without neoadjuvant therapy showed statin users were at a higher risk for disease recurrence and cancer-specific mortality in a univariate, but not a multivariate analysis. However, the present study also reported that statin users were older (P=0.003), had higher body mass index (median 32 vs. 28 kg/m2, P<0.001), and were more likely to have positive soft tissue surgical margins (9 vs. 4%, P<0.001) (59). Another meta-analysis with limited RCTs suggested no association between statin use and risk of bladder cancer (60).

Numerous population-based case-control studies conducted in Taiwan did not provide evidence to support an association between statin use and risk of breast cancer (n=565; control, n=2,260) (61), esophageal cancer (n=197; controls, n=788) (62), bladder cancer (n=325; controls, n=1,300) (63), kidney cancer (n=177; controls, n=708) (64), and female lung cancer (n=297; controls, n=1,188) (65).

Another retrospective eval‎‎uation of the entire Danish population diagnosed with cancer between 1995 and 2007 was performed on 18,721 patients using statins regularly before the cancer diagnosis vs. 277,204 patients who had never used statins. The present study concluded that statin use in cancer patients was associated with reduced cancer-associated mortality as compared to that in non-users (HR, 0.85, 95% CI, 0.82–0.87) for each of the 13 types of cancer (66). In another meta-analysis (27 randomized trials), a median of 5 years of statin therapy was reported to have no effect on the incidence of, or mortality from, any type of cancer, or the aggregate of all cancers (67). The effect of statins on the incidence of different types of cancer reported in various observational and retrospective studies is presented in Table II.

Table II Effect of the use of statins on different types of cancer reported in various observational and retrospective studies.

Antitumor effect of statins in experimental studies Lovastatin

In a phase I–II trial of lovastatin in anaplastic astrocytoma and glioblastoma multiforme, 18 patients received lovastatin between 20 and 30 mg/kg/day for 7 days followed by a 3-week rest. Lovastatin was considered well tolerated, as no patient reported myalgia and only 2 patients reported mild joint pain. Nine of 18 patients received concurrent radiation with no neurological toxicity, indicating that the combination was potentially safe. Of those who received concurrent radiation, 2 minor and 2 partial responses (duration range, 160–236 days) were observed. One patient each on lovastatin monotherapy showed partial and minor response, and stable disease. Notably, the patient who had partial response accomplished a response duration of >405 days, at which time lovastatin was discontinued due to cost-related issues (68).

Similarly, another phase I study eval‎‎uated the safety and tolerability of lovastatin using escalating doses in 88 cancer patients with advanced solid tumors. A majority of patients had prostate cancer or central nervous system tumors. Myopathy was found to be a dose-limiting toxicity and ubiquinone administration was associated with reversal of lovastatin-induced myopathy. Myopathy was prevented by its prophylactic administration in a 56-patient cohort. In the absence of supplementation, lovastatin was well tolerated up to 25 mg/kg/day for 7 days followed by a 3-week rest. One anaplastic astrocytoma patient treated with lovastatin at 30 and 35 mg/kg/day who progressed after surgical resection of the tumor, irradiation and 2 cycles of carmustine had a minor response (45% tumor size reduction) maintained for 8 months (69).

Prolongation of overall survival and PFS was documented in MM patients with lovastatin plus thalidomide and dexamethasone (TDL) vs. thalidomide and dexamethasone alone. The TDL regimen was safe and well tolerated (70).

Simvastatin

Simvastatin in combination with conventional FOLFIRI [irinotecan, 5-fluorouracil (5-FU), and leucovorin] in metastatic colorectal cancer patients showed promising antitumor activities (71). An exploratory subgroup analysis in non-small cell lung carcinoma patients with wild-type epidermal growth factor receptor (EGFR) non-adenocarcinomas showed higher RR, 40 vs. 0%, P=0.043) and longer PFS (3.6 vs. 1.7 months, P=0.027) with simvastatin plus gefitinib vs. gefitinib alone (72). Moreover, low-dose simvastatin to gemcitabine in advanced pancreatic cancer does not provide clinical benefit or results in increased toxicity (73).

Atorvastatin

The 6-month interventions with atorvastatin did not provide convincing evidence of colorectal cancer risk reduction in a multicenter phase II trial, although the relatively small sample size limited statistical power (74).

Fluvastatin

In patients with RCC and metastasis, zoledronate with fluvastatin or atorvastatin as bone-targeting therapy affected certain bone biomarkers and provided bone response in several patients. However, no statistically significant improvement in time to skeletal events was observed (75). The survival of pediatric brain stem tumor patients was significantly increased with metronomic treatment with carboplatin and vincristine associated with fluvastatin and thalidomide (76).

Pravastatin

In patients with acute myeloid leukemia (AML), pravastatin with idarubicin plus high-dose cytarabine (Ida-HDAC) decreased the total and low-density lipoprotein (LDL) cholesterol in almost all patients. The encouraging response rates suggest further trials eval‎‎uating the effect of cholesterol modulation on response in AML should be conducted (77). Chemoembolization and pravastatin combination significantly improved (P=0.003) survival of patients with advanced hepatocellular carcinoma vs. those receiving chemoembolization alone (78).

Pravastatin in combination with epirubicin, cisplatin, and capecitabine did not improve outcome in advanced gastric cancer patients in a randomized phase II trial (79). Summary of clinical trials that used statins as monotherapy or as a combination in patients with different cancer types are presented in Table III.

Table III Summary of clinical trials that used statins as monotherapy or as combination in patients with different types of cancer.

5. Synergism of statins with radiotherapy and chemotherapy

Statins act by arresting cells in the late G1 phase of the cell cycle and can affect cell synchronization in the radiosensitive phase (5). The late G1 and G2-M phases are most sensitive to radiation therapy; therefore, statins potentially sensitized cells to radiation in the late G1 phase (80,81). The antitumor effect of lovastatin as a radiosensitizer on B-cell rat lymphoma (L-TACB) was higher than that of individual therapy (82). The underlying molecular mechanism involved Ras, which confers intrinsic resistance to radiation since in vitro studies using osteosarcoma cells demonstrated that lovastatin decreases this radiation resistance (80,81). Furthermore, HMGCR may serve as a predictive marker of response to postoperative radiotherapy in ductal carcinoma in situ(DCIS) (83). A retrospective cohort study suggested an association between statin therapy and improvement in response of rectal cancer to neoadjuvant chemoradiation (84).

Statins have shown anticancer potential with numerous chemotherapeutic agents. Simvastatin showed additive activity and mutual sensitization with doxorubicin by triggering caspase activation in human rhabdomyosarcoma cells (85). When combined with 5-FU or cisplatin as chemotherapy, lovastatin acts by inhibiting geranylgeranylation but not farnesylation of target protein(s) in colon cancer cells (10). Lovastatin or simvastatin with cytosine arabinoside significantly enhances the antiproliferative effect of each drug in leukemia cell lines and this may be beneficial in the leukemia treatment (86,87). A similar synergy of simvastatin with N,N′-bis(2-chloroethyl)-N-nitrosourea or β-interferon produces antiproliferative activity in human glioma cells (88). Cerivastatin also increases the cytotoxicity of 5-FU in chemoresistant colorectal cancer cell lines by inhibiting nuclear factor-κB DNA-binding activity (89).

A phase I study in AML patients showed synergistic effects of the addition of pravastatin to a conventional chemotherapy regimen (idarubicin and high-dose cytarabine) (77). Statin use in combination with concurrent chemoradiotherapy in preoperative rectal carcinoma patients was associated with improved pathologic complete response at the time of surgery (90). HMGCR expression‎‎ was reported as an independent predictor of prolonged recurrence-free survival in primary ovarian cancer. Future studies are required to eval‎‎uate HMGCR expression‎‎ as a surrogate marker of response to statin treatment, particularly in conjunction with current chemotherapeutic regimens (91). Synergistic effects are observed in patients with relapsed or refractory myeloma by the addition of lovastatin to thalidomide and dexamethasone (70).

6. Conclusion

Preclinical data based on cancer cell lines and animal models demonstrate encouraging anticancer activity of statins. Similarly, several population-based and retrospective studies demonstrate chemopreventive and survival benefit of statins in various types of cancer. However, this benefit has not been confirmed/proven or validated in clinical trials, and is attributed to the absence of well-conducted large-scale phase III RCTs that have addressed the antitumor effects of statins in cancer. In fact, a majority of the trials thus far are phase I and/or small or poorly conducted phase II clinical trials with a small sample size and inadequate power. Moreover, genetic and non-genetic factors also may contribute to the inter-individual variation in statin response. In ovarian cancer, HMGCR expression‎‎ was reported as an independent predictor of prolonged recurrence-free survival (91). Lipkin et al, identified a single-nucleotide polymorphism in the HMGCR gene that significantly modified the chemopreventive activity of statins for colorectal cancer risk (92). Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) overexpression‎‎ was recently reported to reduce HMGCR enzyme activity, enhance LDL-C uptake, and increase cellular apolipoprotein B (93). This may explain the inter-individual variation of drug response to statins. Advances in molecular biology may be useful to identify markers responsive to statin treatment and tailor base statin treatment based on genotypic profile, in the direction of personalized medicine.

Studies suggest statins can modulate the outcome of various cancer types and notably can target cancer vs. normal cells. The microenvironments seem to regulate the statin effect in different types of cancer. The side-effects appear to be limited, manageable and may be associated with genetic and non-genetic factors. Future studies should concentrate on eval‎‎uating statins in large-scale phase III RCTs in cancer patients to establish the precise effect of stains in cancer prevention and treatment.

Acknowledgements

This study was supported in part by King Fahad Medical City, Riyadh, Saudi Arabia.

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