The antitumor effect of cyclophosphamide (CPM) and paclitaxel was investigated in BALB/c mice bearing EMT6 tumors, in combination with the bioreductive compound NLCPQ-1 by using the in vivo/in vitro assay as the endpoint. An optimum administration schedule for a synergistic interaction between NLCPQ-1 and CPM/paclitaxel was determined and dose modification factors (DMF) were calculated for antitumor effect and bone marrow toxicity. All drugs were given by IP injection; NLCPQ-1 at 15 mg/kg, which is much less than its maximally tolerated dose (MTD greater than 50 mg/kg), paclitaxel up to 25 mg/kg, and CPM up to 200 mg/kg. Bone marrow toxicity studies were performed in parallel by using a modified CFU-GM assay. A schedule-dependent synergistic interaction was observed for both chemotherapeutic agents combined with NLCPQ-1 but with entirely different patterns, as has been previously seen with the analog NLCQ-1. The optimal degree of potentiation, P (percentage of tumor cells that were killed due to clear potentiation), was 31 and 33 when NLCPQ-1 was administered 2 h before CPM and 3-3.5 h after paclitaxel, respectively. At the above time schedules, NLCPQ-1 modified the dose of CPM and paclitaxel, for 60% tumor cell killing, by a factor of 1.8 and 2.1, respectively. Bone marrow toxicity was not enhanced by combining either chemotherapeutic agent with NLCPQ-1. Comparison with results from previous similar studies with NLCQ-1 revealed that, on a molar basis, NLCPQ-1 was a less potent chemosensitizer than NLCQ-1. However, the results still suggest a potential clinical use of NLCPQ-1 as an adjuvant to CPM or paclitaxel therapy against solid tumors.

01 Jan 1998·Oncology research

9-[3-(2-Nitro-1-imidazolyl)propylamino]-cyclopenteno[b]quinoline hydrochloride (NLCPQ-1). A novel DNA-affinic bioreductive agent as chemosensitizer: mechanistic studies. II.

Article

Author: Khan, S H ; Bloomer, W D ; Rosenzweig, H S ; Papadopoulou, M V ; Ji, M

NLCPQ-1 is a novel, weak, DNA-affinic bioreductive compound with enhanced chemosensitizing ability for commonly used chemotherapeutic agents, both in vitro and in vivo. In the present report we investigated possible mechanisms involved in the potentiation of cis-DDP and L-PAM in V79 cells. Potentiation was observed when cells were pretreated under hypoxic conditions with NLCPQ-1 prior to their aerobic exposure to each chemotherapeutic agent studied and in the presence of NLCPQ-1. The dominant mechanisms, under hypoxic pretreatment conditions, participating in the potentiation were: a) extensive DNA damage, as measured by the comet and alkaline elution assays, b) DNA, RNA, and protein synthesis inhibition, c) significant delay in the traverse through the S phase, as observed by flow cytometry, and possibly d) suppression of PLD repair. Apoptosis was also detected 36 h posttreatment in the chemotherapeutic drug-treated as well as the combination drug-treated cells. Glutathione depletion by NLCPQ-1 metabolites under hypoxic conditions was also involved in the potentiation process, but its contribution in potentiation was minimal.

01 Jan 1997·Oncology research

9-[3-(2-Nitro-1-imidazolyl)propylamino]-cyclopenteno[b]quinoline hydrochloride (NLCPQ-1): a novel DNA-affinic bioreductive agent as chemosensitizer. I.

Article

Author: Ji, M ; Rao, M K ; Bloomer, W D ; Papadopoulou, M V

9-(3-(2-Nitro-1-imidazolyl)propylamino]-cyclopentano[b]quinoline hydrochloride (NLCPQ-1) is one member of a limited series of 2-nitroimidazole-linked derivatized quinolines we have synthesized to be weak DNA binding compounds. On a concentration basis, NLCPQ-1 is the most potent analogue of the series as a radiosensitizer and cytotoxin of hypoxic cells in vitro and in vivo. This improved efficacy compared to untargeted nitroimidazolic bioreductive compounds has been mainly attributed to its weak DNA binding. In the present study, we investigated the ability of NLCPQ-1 to act synergistically with 4-[bis(2-chloroethyl)amino]-L-phenylalanine (L-PAM, melphalan) or cis-diamminedichloroplatinum (cis-DDP, cisplatin) against tumor cells in vitro and in vivo. We demonstrated that 7 microM NLCPQ-1 potentiated the toxic effect of cis-DDP and L-PAM against V79 cells under hypoxic pretreatment conditions with dose modification factors (DMF) of 2.6 and 2.4, respectively, measured at 0.1 survival. Potentiation was dependent on the concentrations of both the chemotherapeutic agent and NLCPQ-1 as well as on the duration of the hypoxic pretreatment with NLCPQ-1. No potentiation was observed under aerobic cotreatment conditions in vitro. Significant synergism was observed when 15 mg/kg NLCPQ-1 was administered IP at various time intervals before a single dose of L-PAM (5 mg/kg) or cis-DDP (5 mg/kg) in Balb/c mice bearing EMT6 tumors. The in vivo/in vitro assay was used as the investigational endpoint and either the fractional product or isobologramic analysis was used to determine synergistic interactions.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Discovery	US	Evanston Hospital Corp.	-

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