Resistance to antineoplastic agents is the major obstacle to curative therapy of cancer. Tumor cell lines with acquired resistance to the antineoplastic agent cis-diamminedichloroplatinum(II) overexpressed metallothionein and demonstrated cross-resistance to alkylating agents such as chlorambucil and melphalan. Human carcinoma cells that maintained high levels of metallothionein because of chronic exposure to heavy metals were resistant to cis-diamminedichloroplatinum(II), melphalan, and chlorambucil. Furthermore, cells transfected with bovine papilloma virus expression vectors containing DNA encoding human metallothionein-IIA were resistant to cis-diamminedichloroplatinum(II), melphalan, and chlorambucil but not to 5-fluorouracil or vincristine. Thus, overexpression of metallothionein represents one mechanism of resistance to a subset of clinically important anticancer drugs.

Pak B with 5% E^O in hexane at 2 mL/min as the eluant and with the UV detector at 350 nm. The retention data are shown in Table VI. The solvents were from Burdick and Jackson, and they were degassed prior to use. Nuclear Overhauser Effect (NOE) Determinations. AllNOEs were measured on a Bruker WM-250 spectrophotometer operating in the pulse-FT mode. Each sample (ca. 5 mg) was dissolved in 0.5 mL of dry deuterioacetone (Merck acetone-d6 "100% "), degassed by several freeze-pump-thaw cycles and sealed.The NOE values were determined from the ratio between the relative peak intensities with the irradiating field on resonance and off resonance for the saturated signal. At least five NOE measurements were made for each signal of each sample studied. The standard deviation was always 2% or less. The field strength of the irradiating field was determined for each sample by setting the decoupling power level so that a maximum increase in intensity of interacting protons was obtained without affecting other proton signals. In all experiments the pulse delay time used was sufficiently long to allow complete recovery of all signals. This time ranged from 40 to 60 s, depending on the sample. The ambient probe temperature was 24 °C; the high-temperature experiments were run at 50 °C and the low temperature experiments at -50 °C. No significant changes were observed in the spectra or the NOE values at either the high or low temperatures.Acknowledgment. This work was supported in part by National Cancer Institute Contract No. N01-CP-75932.

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Synthetic procedures have been developed which lead to the 2-aza congeners 3 and several related N-oxides 4. The analogues 3 exhibited a wide range of in vitro cytotoxicity against L1210 leukemia, the human colon adenocarcinoma cell line LoVo, and the doxorubicin resistant LoVo/DX cell line. Selected analogues of 3 showed significant P388 antileukemic activity in mice with 3c exhibiting high activity. This activity was also retained in the related N-oxide 4a. These heterocyclic bioisosteric models are representative of the first anthracene-9,10-diones which display antileukemic activity comparable to mitoxantrone.

ChemInform Abstract The diamine(sulfoxide)-Pt(II) complexes (III) and analogues of (R,R)and (S,S)-trans-1,2-diaminocyclohexane are prepared as shown for (III) (no yields given). The complexes are the first well-defined antitumor Pt complexes containing sulfur as ligand. The antitumor activity( L 1210 leukemia) is dependent on both the nature of the amine and the nature of the sulfoxide. In the case of asym. sulfoxides such as methyl p-tolyl sulfoxide, preparation of the optically pure forms shows a distinct effect of chirality of the sulfoxide ligand on the biological activity. The possible mechanisms of antitumor action are discussed. The complexes may act by binding to DNA with subsequent loss of sulfoxide ligand.

The growth characteristics and colonization potential of a transplantable melanoma administered to young (3 mo) and old (24 mo) C57BL/6 mice were investigated. After sc injection of B16-F10 melanoma cells, tumor growth was slower, and final tumor volume was less in the older mice. Furthermore, after iv injection of B16-F1 melanoma cells, the number of pulmonary colonies was also less, and the survival was greater in the older mice. These findings indicate an age advantage in this experimental tumor model that may be attributed to either physical or immunologic factors.

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