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Oral administration of the PARP-1 inhibitor GPI 15427 increases the anti-tumor activity of irinotecan against colon carcinomas
No full textPoly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been investigated as enhancer of anticancer therapy. We recently demonstrated that the novel PARP-1 inhibitor GPI 15427 increases the anti-tumor efficacy of temozolomide (TMZ) against a variety of tumor types such as melanoma, lymphoma, glioblastoma multiforme, even when the tumors are located at the CNS site. Among the PARP-1 inhibitors tested so far as chemosensitizers in xenograft models, GPI 15427 is the first agent that achieved oral efficacy against tumors grown intracranially as well as subcutaneously in mice, while all the other PARP-1 inhibitors were administered intraperitoneally against subcutaneous tumors. In addition, oral administration of the GPI 15427 is well tolerated with an LD50 > 1000 mg/kg/day x 5 days po. Furthermore, at 40 mg/kg/day x 5 day po, GPI 15427 does not exacerbate reduction of white blood cells by the maximal tolerated dose of TMZ in mice.
To broaden the utility of GPI 15427 as a sensitizer for other chemotherapy, in this study we tested whether it can enhance the anti-tumor efficacy of topoisomerase I inhibitor irinotecan, a water-soluble analogue of the natural alkaloid camptothecin, with considerable therapeutic activity in advanced colorectal carcinoma. Irinotecan triggers tumor cell apoptosis by stabilizing the linkage between topoisomerase I and DNA, eventually resulting in lethal DNA breaks when the replication fork encounters the complex.
In in vitro testing, HT-29, HCT-116, HCT-15 and LoVo human colon carcinoma cells were exposed to graded concentrations of GPI 15427 to determine concentrations for maximal PARP inhibition without growth inhibitory effect. GPI 15427 was then tested for its ability to enhance tumor growth inhibition induced by 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan. The results of colony formation assay identified HT-29 as the most resistant colon carcinoma cell lines to SN-38. GPI 15427 increased the growth inhibitory effect of the topoisomerase I inhibitor on HT-29 by 2-3-fold.
We then tested GPI 15427 in HT-29 tumor bearing mice. GPI 15427 (40 mg/kg, po) was administered for five consecutive days 1 h before irinotecan (10 mg/kg/ip) for two cycles. Efficacy of treatments was evaluated by comparing tumor growth in untreated mice, mice treated with irinotecan, or mice treated with irinotecan + GPI 15427. The results indicated that GPI 15427 significantly increased antitumor efficacy of irinotecan (P<0.001).
In conclusion, these data suggest that oral administration of the PARP-1 inhibitor GPI 15427 might represent a suitable therapeutic strategy to enhance the anti-tumor efficacy of irinotecan against colon carcinomas
Oral administration of the PARP inhibitor GPI 15427 increases the activity of anticancer drugs with different mechanisms of action
No full textPoly(ADP-ribose) polymerase (PARP) inhibitors have been shown to enhance the antitumor activity of methylating agents and topoisomerase I inhibitors. We recently demonstrated that, among the PARP inhibitors tested so far as chemosensitizers in xenograft models, GPI 15427 is the first agent that has shown oral efficacy against tumors when administered in association with the methylating agent temozolomide (TMZ).
In this study we tested whether GPI 15427 can enhance the anti-tumor efficacy of the topoisomerase I inhibitor irinotecan, an analogue of camptothecin with considerable therapeutic activity in advanced colorectal carcinoma. The efficacy of GPI 15427 as chemosensitizer was also tested against irinotecan/TMZ combination. In fact, the combination of these drugs is currently evaluated in clinical trials for the treatment of solid tumors refractory to conventional chemotherapy.
A panel of human colon carcinoma cell lines including HT29, HCT116, HCT15 and LoVo, were exposed to graded concentrations of GPI 15427 to determine the dose capable of maximal PARP inhibition without growth inhibitory effect. GPI 15427 was then tested for its ability to enhance tumor growth inhibition induced by 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan. The results of colony formation assay identified HT-29, LoVo and HCT15 as the most resistant to SN-38; in all cell lines tested GPI 15427 increased the growth inhibitory effect of the topoisomerase I inhibitor. Similarly, GPI 15427 enhanced sensitivity of colon cancer cells to TMZ. Interestingly, the results indicated that GPI 15427 significantly potentiated the growth inhibitory effect of SN-38/TMZ combination (combination index ≤0.2).
We then tested the PARP inhibitor in HT-29 or LoVo xenografts. GPI 15427 (40 mg/kg, po) was administered 1 h before low doses of irinotecan (4 mg/kg), TMZ (10 mg/kg) or both and efficacy of treatments was evaluated by calibrating tumor nodules. The results indicated that oral GPI 15427 significantly delayed tumor growth when administered in combination with both drugs (P<0.001).
In conclusion, these data suggest that oral administration of the PARP-1 inhibitor GPI 15427 might represent a suitable therapeutic strategy to enhance the anti-tumor efficacy of irinotecan/TMZ combination against colon carcinomas.
Supported by: FIRB 2001, PRIN 2003 and PRIN 2004 projects to GG, LT
Systemic administration of GPI 15427, a novel Poly(ADP-Ribose) polymerase-1 inhibitor, increases the antitumor activity of temozolomide against intracranial melanoma, glioma, lymphoma
No full textPURPOSE: Temozolomide (TMZ) is a DNA methylating agent that has shown promising antitumor activity in recent clinical trials against high grade gliomas, metastatic melanoma, and brain lymphoma. In this study, we tested whether systemic administration of GPI 15427, a novel poly(ADP-ribose) polymerase (PARP-1) inhibitor capable of crossing the blood-brain barrier, could enhance the efficacy of TMZ against metastatic melanoma, glioblastoma multiforme, and lymphoma growing in the brain. EXPERIMENTAL DESIGN: Murine B16 melanoma or L5178Y lymphoma cells were injected intracranially in syngeneic mice. An orthotopic xenograft of the human SJGBM2 glioblastoma multiforme was implanted in nude mice. Animals were treated with TMZ + GPI 15427 using a schedule of 40 mg/kg/i.v. GPI 15427 + 100 mg/kg/i.p. TMZ for 3 days. The efficacy of drug treatment was assessed by: (a) the increase of mouse survival and life span; and (b) the suppression of melanoma metastases to lung after i.v. injection of B16 cells. RESULTS: In all models, systemic administration of GPI 15427 shortly before TMZ significantly increased life span of tumor-bearing mice with respect to untreated controls or to groups treated with either GPI 15427 or TMZ only. Moreover, GPI 15427 increased the antimetastatic effect of TMZ. CONCLUSIONS: These data indicate that systemic administration of the poly(ADP-ribose) polymerase-1 inhibitor GPI 15427 significantly enhances TMZ antitumor efficacy against solid or hematological neoplasias even when located at the central nervous system site
Systemic administration of GPI 15427, a novel Poly(ADP-Ribose) polymerase-1 inhibitor, increases the antitumor activity of temozolomide against intracranial melanoma, glioma, lymphoma
No full textPurpose: Temozolomide (TMZ) is a DNA methylating agent that has shown promising antitumor activity in recent clinical trials against high grade gliomas, metastatic melanoma, and brain lymphoma. In this study, we tested whether systemic administration of GPI 15427, a novel poly(ADPribose) polymerase (PARP-1) inhibitor capable of crossing the blood-brain barrier, could enhance the efficacy of TMZ against metastatic melanoma, glioblastoma multiforme, and lymphoma growing in the brain. Experimental Design: Murine B16 melanoma or L5178Y lymphoma cells were injected intracranially in syngeneic mice. An orthotopic xenograft of the human SJGBM2 glioblastoma multiforme was implanted in nude mice. Animals were treated with TMZ + GPI 15427 using a schedule of 40 mg/kg/i.v. GPI 15427 + 100 mg/kg/i.p. TMZ for 3 days. The efficacy of drug treatment was assessed by: (a) the increase of mouse survival and life span; and (b) the suppression of melanoma metastases to lung after i.v. injection of B16 cells. Results: In all models, systemic administration of GPI 15427 shortly before TMZ significantly increased life span of tumor-bearing mice with respect to untreated controls or to groups treated with either GPI 15427 or TMZ only. Moreover, GPI 15427 increased the antimetastatic effect of TMZ. Conclusions: These data indicate that systemic administration of the poly(ADP-ribose) polymerase-1 inhibitor GPI 15427 significantly enhances TMZ antitumor efficacy against solid or hematological neoplasias even when located at the central nervous system site
Systemic administration of GPI 15427, a novel Poly(ADP-Ribose) polymerase-1 inhibitor, increases the antitumor activity of temozolomide against intracranial melanoma, glioma, lymphoma
No full textPurpose: Temozolomide (TMZ) is a DNA methylating agent that has shown promising antitumor activity in recent clinical trials against high grade gliomas, metastatic melanoma, and brain lymphoma. In this study, we tested whether systemic administration of GPI 15427, a novel poly(ADPribose) polymerase (PARP-1) inhibitor capable of crossing the blood-brain barrier, could enhance the efficacy of TMZ against metastatic melanoma, glioblastoma multiforme, and lymphoma growing in the brain. Experimental Design: Murine B16 melanoma or L5178Y lymphoma cells were injected intracranially in syngeneic mice. An orthotopic xenograft of the human SJGBM2 glioblastoma multiforme was implanted in nude mice. Animals were treated with TMZ + GPI 15427 using a schedule of 40 mg/kg/i.v. GPI 15427 + 100 mg/kg/i.p. TMZ for 3 days. The efficacy of drug treatment was assessed by: (a) the increase of mouse survival and life span; and (b) the suppression of melanoma metastases to lung after i.v. injection of B16 cells. Results: In all models, systemic administration of GPI 15427 shortly before TMZ significantly increased life span of tumor-bearing mice with respect to untreated controls or to groups treated with either GPI 15427 or TMZ only. Moreover, GPI 15427 increased the antimetastatic effect of TMZ. Conclusions: These data indicate that systemic administration of the poly(ADP-ribose) polymerase-1 inhibitor GPI 15427 significantly enhances TMZ antitumor efficacy against solid or hematological neoplasias even when located at the central nervous system site
Oral administration of the PARP-1 inhibitor GPI 15427 increases the anti-tumor activity of irinotecan and temozolomide combination against colon carcinoma
No full textBackground
Poly(ADP-ribose) polymerase (PARP) inhibitors have been shown to enhance the antitumor activity of methylating agents and topoisomerase I inhibitors. These anticancer drugs are currently evaluated in combination in clinical trials due to synergistic effects observed in preclinical models.
In this study we tested whether the PARP inhibitor GPI 15427 (10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen-3-one) can enhance the anti-tumor efficacy of temozolomide used in combination with irinotecan, a water-soluble analogue of the natural alkaloid camptothecin, with considerable therapeutic activity in advanced colorectal carcinoma.
Materials/Methods
Human colon carcinoma cells were exposed in vitro to GPI 15427 to determine concentrations for maximal PARP inhibition devoid of growth inhibitory effect. GPI 15427 was then tested for its ability to enhance tumor growth inhibition induced by temozolomide and 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan. Thereafter, the efficacy of GPI 15427 in combination with temozolomide and irinotecan was assayed in tumor xenografts.
Results
The results of colony formation assay indicated that GPI 15427 significantly potentiated the growth inhibitory effect of temozolomide and SN-38 combination (combination index ≤0.2).
In vivo efficacy of treatments was evaluated by comparing tumor growth in untreated mice, mice treated with temozolomide+irinotecan, or mice treated with both drugs in combination with GPI 15427. The results indicated that GPI 15427 significantly increased the antitumor efficacy of temozolomide and irinotecan combination (P<0.001).
In conclusion, these data suggest that oral administration of the PARP inhibitor GPI 15427 might represent a suitable therapeutic strategy to enhance the anti-tumor efficacy of temozolomide and irinotecan combination against colon carcinomas.
Supported by: Italian Ministry of Education and Research FIRB and PRIN projects to GG and LT
Oral administration of the PARP-1 inhibitor GPI 15427 increases the anti-tumor activity of temozolomide against melanoma growing at the CNS site
No full textTemozolomide (TMZ) is a DNA methylating agent with high oral bioavailability and ability to cross the blood brain barrier.
Recent clinical trials have shown that TMZ improves progression-free survival and reduces the incidence of CNS relapse in Stage IV melanoma patients in comparison to patients treated with Dacarbazine, the standard care for this malignancy.
This is particularly important for malignant melanoma in which brain metastases are common and can lead to patient death in few months.
Unfortunately, resistance to TMZ occurs relatively often and strongly affects the rate and durability of clinical response.
However, recent studies have demonstrated that inhibition of poly (ADP-ribose) polymerase-1 (PARP-1), an enzyme involved in the repair of methylpurines, may represent a potential strategy to improve TMZ efficacy.
In this study we tested whether oral administration of a novel PARP-1 inhibitor GPI 15427 is able to enhance the anti-tumor efficacy of TMZ against B16 melanoma growing at the CNS.
Pharmacokinetic studies revealed that GPI 15427 reached a Cmax of 4189 + 327 ng/ml in plasma after a single iv dose of 40 mg/kg in rats.
When the same dose was given orally, the plasma Cmax was 1041 + 516 ng/ml, indicating a substantial oral bioavailability of the compound.
The brain levels of GPI 15427 reached 1744 ng/g, 2301 ng/g at 0.5 and 1 h, respectively, post oral dosing of 40 mg/kg rats, indicating that the compound readily penetrates the blood brain barrier.
B16 melanoma cells (104) were injected intracranially into male B6D2F1 mice.
Tumor bearing mice were treated when neoplastic infiltration of the brain tissue was evident in histological sections.
GPI 15427 (10, 40, or 100 mg/kg/per os) was administered for three or five consecutive days 1 h before TMZ (100 mg/Kg IP).
Efficacy of treatments was evaluated by comparing the survival curves of untreated mice, mice treated with TMZ, or GPI 15427 alone to the survival curves of mice treated with TMZ + GPI 15427.
At all doses tested, no drug-related deaths were observed.
Moreover, GPI 15427 + TMZ significantly increased life span of tumor bearing mice compared to untreated mice, mice treated with GPI 15427 or with TMZ as single agents.
In conclusion, these data indicate that oral administration of the PARP-1 inhibitor GPI 15427 is well tolerated and induces significant enhancement of TMZ anti-tumor efficacy against melanoma at the CNS site
Systemic administration of the PARP-1 inhibitor GPI 15427 increases the antitumor activity of temozolomide against metastatic melanoma.
No full textWe previously demonstrated that the antitumor activity of temozolomide (TMZ) can be enhanced at the CNS site by intracerebral injection of a PARP-1 inhibitor that does not permeate the blood-brain barrier [1]. TMA is an anticancer agent with promising activity against metastatic melanoma [2,3]. Here we tested whether systemic administration of GPI 15427, a novel PARP inhibitor capable of crossing the blood-brain barrier, could enhance the anti-tumor efficacy of TMZ against melanoma involving the CNS site. The efficacy of the drug treatment was also tetsed against lung metastases.ùMurine B16 melanoma cells were injected intracranially in syngeneic mice. Animals were treated for three days with TMZ (100 mg/kg, i.p.) +/- GPI 15427 (1mg/mouse, i.v.) when neoplastin infiltration of the brain tissue was evident in histological sections. Administration of shortly before TMZ significantly increased life-span of tumor-bearing mice with respect to untreated controls, or to group treated with either GPI 15427 or TMZ only (P<0.0001). The increase in survival detected in the group treated with the drug combination was accompanied by a marked reduction of tumor ingiltration in the brain, as evidenced by histological studies.
GPI 15427 aslo enhanced the anti-metastatic acitivity of TMZ. In fact, the number of pulmonary metastases obtained after iv injection of B16 cells was significantly lower in mice treated with GPI 15427+TMZ than in those receiving TMZ only (P=0.004).
In conclusion, these data indicate that systemic administration of GPI 15427 induces significant enhancement of TMZ anti-tumor activity against melanoma, even at the CNS site
Brain distribution and efficacy as chemosensitizer of an oral formulation of PARP-1 inhibitor GPI 15427 in experimental models of CNS tumors.
No full textWe previously demonstrated that intravenous or intra-cerebral administration of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors increases the antitumor-activity of temozolomide (TMZ), an oral anticancer drug used for the treatment of malignant melanoma and primary or secondary brain tumors. Since the oral route has a number of advantages in terms of safety and convenience with respect to intravenous injection, ill this Study we tested whether administration per os of the novel PARP-I inhibitor GPI 15427 allows sufficient absorption of the compound and achievement of brain concentrations capable of enhancing the efficacy of TMZ against tumors growing at the CNS. Pharmacokinetics analysis of GPI 15427 levels In plasma and brain was assessed in Sprague-Dawley rats after oral dosing, by liquid chromatography and tandem mass spectrometry. Antitumor activity of oral GPI 15427 in association with TMZ was evaluated in BD2F1 mice injected intracranially with B16 melanoma or L5178Y lymphoma. Phamacokinetics studies revealed that GPI 15427 possesses a substantial oral bioavailability (plasma C-max after a single dose of 40 mg/kg: 1041+/-516 ng/ml). Moreover, the brain levels and brain/plasma ratios of GPI 15427 (3.37 at 0.5 h and 3.19 at 1 h) indicated that the compound readily penetrates the blood-brain barrier. GPI 15427 (10 or 40 mg/kg/per os) was then administered for five days, 1 h before TMZ (100 mg/kg/i.p.), to tumor-bearing mice. The The results indicated that GP1 was well tolerated and significantly increased life-span of the animals with respect to TMZ. In conclusion. PARP-1 inhibitor GPI 15427 is efficacious as chemosensitizer for the treatment of tumors located at the CNS site when it is administered by oral route
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