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Purpose: 4'-Thio-β-D-arabinofuranosylcytosine (4'-thio-ara-C), which has shown a broad spectrum of antitumor activity against human tumor systems in mice and is undergoing clinical trials, was evaluated for cross-resistance to seven clinical agents in order to identify potentially useful guides for patient selection for further clinical trials of 4'-thio-ara-C and possible noncross-resistant drug combinations with 4'-thio-ara-C., Methods: A drug resistance profile for 4'-thio-ara-C, which was administered intraperitoneally daily for nine consecutive days, was obtained using seven drug-resistant P388 and L1210 leukemias that were implanted intraperitoneally in mice., Results: Multidrug-resistant P388 leukemias (leukemias resistant to doxorubicin, etoposide, or paclitaxel) exhibited no cross-resistance to 4'-thio-ara-C. Leukemias resistant to camptothecin, cisplatin, and 5-fluorouracil were also not cross-resistant to 4'-thio-ara-C. Only the leukemia resistant to 1-β-D-arabinofuranosylcytosine was cross-resistant to 4'-thio-ara-C., Conclusions: The data suggest that (1) it may be important to exclude or to monitor with extra care patients who have previously been treated with 1-β-D-arabinofuranosylcytosine and (2) the lack of cross-resistance seen with 4'-thio-ara-C may contribute to therapeutic synergism when 4'-thio-ara-C is combined with other agents.

Purpose: Clofarabine increases the activation of 1-beta-D-arabinofuranosyl cytosine (araC) in tumor cells, and combination of these two drugs has been shown to result in good clinical activity against various hematologic malignancies. 1-beta-D-[4-thio-arabinofuranosyl] cytosine (T-araC) is a new cytosine analog that has exhibited excellent activity against a broad spectrum of human solid tumors and leukemia/lymphoma xenografts in mice and is currently being evaluated in patients as a new drug for the treatment of cancer. Since T-araC has a vastly superior preclinical efficacy profile in comparison to araC, we have initiated studies to determine the potential value of clofarabine/T-araC combination therapy., Methods: In vitro studies have been conducted to determine the effect of clofarabine on the metabolism of T-araC, and in vivo studies have been conducted to determine the effect of the clofarabine/T-araC combination on five human tumor xenografts in mice., Results: Initial studies with various tumor cells in culture indicated that a 2-h incubation with clofarabine enhanced the metabolism of T-araC 24 h after its removal by threefold in three tumor cell types (HCT-116 colon, K562 leukemia, and RL lymphoma) and by 1.5-fold in two other tumor cell types (MDA-MB-435 breast (melanoma), and HL-60 leukemia). Pretreatment with clofarabine resulted in a slight decrease in metabolism of T-araC in RPMI-8226 myeloma cells (65% of control) and inhibited metabolism of T-araC in CCRF-CEM leukemia cells by 90%. In vivo combination studies were conducted with various human tumor xenografts to determine whether or not the modulations observed in vitro were reflective of the in vivo situation. Clofarabine and T-araC were administered on alternate days for five treatments each (q2dx5) with the administration of T-araC 24 h after each clofarabine treatment. Combination treatment of HCT-116, K562, HL-60, or RL tumors with clofarabine and T-araC resulted in dramatically superior anti-tumor activity than treatment with either agent alone, whereas this combination resulted in antagonism in CCRF-CEM tumors. The in vivo antitumor activity of clofarabine plus T-araC against HCT-116 tumors was much better than the activity seen with clofarabine plus araC., Conclusions: These studies provide a rationale for clinical trials using this combination in the treatment of acute leukemias as well as solid tumors and suggest that this combination would exhibit greater antitumor activity than that of clofarabine plus araC.

Purpose: Sorafenib tosylate (sorafenib, BAY 43-9006, Nexavar) is a multi-kinase inhibitor that targets tumor cell proliferation and angiogenesis. These studies evaluated the efficacy and tolerability of combinations of sorafenib plus agents used to treat non-small cell lung cancer (NSCLC) using preclinical models of that disease., Methods: Intravenous (iv) vinorelbine and interperitoneal (ip) cisplatin were administered intermittently (q4d x 3) in combination with sorafenib administered orally (po) once daily for 9 days starting on the same day as the standard agent. In studies with sorafenib and gefitinib, both agents were administered po daily for 10 days starting on the same day. Treatment in all studies was initiated against established sc tumors, and each study was conducted in duplicate. Efficacy was assessed as the delay in tumor growth to a specified size (TGD)., Results: Vinorelbine (6.7 mg/kg) and sorafenib (40 mg/kg) produced TGDs of 2.4 and 7.8 days, respectively, in the NCI-H460 NSCLC model. Combination therapy produced a 10.0-day TGD with no increase in toxicity. Combination therapy in the NCI-H23 NSCLC model with the highest evaluated dose levels of sorafenib plus cisplatin was well tolerated and produced TGDs equivalent to those produced by cisplatin alone. Lower dose levels of each agent produced approximately additive TGD's. Combination therapy in the A549 NSCLC model with sorafenib and gefitinib produced TGDs equivalent to that produced by sorafenib alone with no toxicity. Tumor growth in the MDA-MB-231 mammary tumor model, that contains mutations in signal transduction proteins downstream of the EGF receptor (the target of gefitinib) was also inhibited by sorafenib, but not by gefitinib., Conclusion: Concurrent administration of sorafenib and vinorelbine, cisplatin or gefitinib was at least as efficacious as the individual agents alone and was well tolerated. These results support the inclusion of sorafenib in clinical trials in NSCLC employing combinations of both cytotoxic and cytostatic agents.

Purpose: 4'-Thio-beta -d-arabinofuranosylcytosine (4'-thio-ara-C), which has shown significant cytotoxicity against a panel of human tumor lines, was evaluated for antitumor activity against a spectrum of human tumor systems in mice., Methods: Antitumor activity was evaluated in 15 subcutaneously implanted human tumor xenografts. 4'-Thio-ara-C was administered intraperitoneally using either q1dx9 (daily treatment for nine consecutive days) or q4hx3/q1dx9 (three treatments each day separated by 4-h intervals for nine consecutive days)., Results: 4'-Thio-ara-C exhibited an excellent spectrum of activity. Treatment with the compound was curative against HCT-116 colon, SW-620 colon, NCI-H23 NSCL, and CAKI-1 renal tumors and resulted in partial/complete regressions in the DLD-1 colon, NCI-H522 NSCL, DU-145 prostate, and PANC-1 pancreatic tumor models. Tumor stasis was noted for HT29 colon and NCI-H460 NSCL tumors. Tumor inhibition was observed for A549 NSCL, PC-3 prostate, LNCAP prostate, and MDA-MB-435 breast tumors. Of the 15 tumors examined, only CFPAC-1 pancreatic was unresponsive to the compound. In contrast, 1-beta -d-arabinofuranosylcytosine was minimally active at best against CAKI-1 renal, HCT-116 colon, NCI-H460 NSCL, and SW-620 colon tumors. Schedule- and route-dependency studies were conducted using the NCI-H460 NSCL tumor. The activity of 4'-thio-ara-C was independent of schedule when comparing q2dx5 (every other day for five treatments), q1dx9, and q4hx3/q1dx9 treatment schedules. 4'-Thio-ara-C was equally effective by the intravenous and intraperitoneal routes of administration, with the oral route being less efficacious., Conclusions: On the basis of these results, 4'-thio-ara-C appears to have a profile distinct from other nucleoside antitumor agents and is being advanced to clinical trials.

Gemcitabine, a novel pyrimidine nucleoside antimetabolite, has shown clinical antitumor activity against several tumors (breast, small-cell and non-small-cell lung, bladder, pancreatic, and ovarian). We have developed a drug-resistance profile for gemcitabine using eight drug-resistant P388 leukemias in order to identify potentially useful guides for patient selection for further clinical trials of gemcitabine and possible noncrossresistant drug combinations with gemcitabine. Multidrug-resistant P388 leukemias (leukemias resistant to doxorubicin or etoposide) exhibited no crossresistance to gemcitabine. Leukemias resistant to vincristine (not multidrug resistant), cyclophosphamide, melphalan, cisplatin, and methotrexate were also not crossresistant to gemcitabine. Only the leukemia resistant to 1-beta-D-arabinofuranosylcytosine was crossresistant to gemcitabine. The results suggest that (1) it may be important to exclude or to monitor with extra care patients who have previously been treated with 1-beta-D-arabinofuranosylcytosine and (2) the lack of crossresistance seen with gemcitabine may contribute to therapeutic synergism when gemcitabine is combined with other agents.

The antimicrotubule agent taxol (NSC 125973) has shown clinical antitumor activity against several classically refractory tumors. We developed a drug-resistance profile for taxol using ten drug-resistant P388 leukemias to identify potentially useful guides for patient selection for further clinical trials of taxol and possible non-cross-resistant drug combinations with taxol. Multidrug-resistant P388 leukemias exhibited either clear (leukemia resistant to amsacrine) or marginal cross-resistance (leukemias resistant to doxorubicin, actinomycin D, and mitoxantrone) to taxol. Leukemias resistant to vincristine (non-multidrug-resistant leukemia), camptothecin, melphalan, cisplatin, 1-beta-D-arabinofuranosylcytosine, and methotrexate were not cross-resistant to taxol. The data suggest that (1) it may be important to exclude or to monitor with extra care patients who have previously been treated with amsacrine, doxorubicin, actinomycin D, or mitoxantrone and (2) a combination of one of the non-cross-resistant drugs and taxol might exhibit therapeutic synergism.

Since 1978, over 50 clinically useful antitumor drugs or new candidate antitumor agents have been evaluated in vivo against cisplatin-resistant P388 leukemia (P388/DDPt) in our laboratories. Analysis of this data base has yielded insights into the cross-resistance, collateral sensitivity, and mechanisms of resistance of P388/DDPt. P388/DDPt was cross-resistant or marginally cross-resistant to eight agents [carmethizole.HCl, rhizoxin, dibromodulcitol, spirohydantoin mustard, hepsulfam, arabinosyl-5-azacytosine (ara-AC), tiazofurin, and deoxyspergualin]. Of these eight agents, the latter six have entered various phases of clinical trials. For these trials, it may be important to exclude or to monitor with extra care patients who have previously been treated with cisplatin. P388/DDPt was collaterally sensitive to six agents [fludarabine phosphate (2-F-ara-AMP), amsacrine (AMSA), mitoxantrone, etoposide (VP-16), batracylin, and flavone acetic acid] and, possibly, to two others (merbarone and echinomycin). These observations of collateral sensitivity suggest that a combination of cisplatin plus any one of these drugs might exhibit therapeutic synergism. Therapeutic synergism has been observed in animal models for combinations of cisplatin plus VP-16, AMSA, or mitoxantrone. The observation of collateral sensitivity for P388/DDPt to four agents (AMSA, mitoxantrone, merbarone, and VP-16) that have been reported to interact with DNA topoisomerase II suggests the possible involvement of the latter in cisplatin resistance. Both the increased sensitivity of P388/DDPt to these agents and a portion of its resistance to cisplatin could be the result of an increase in DNA topoisomerase II activity.