Molecular Mechanisms of Cellular Transport, Resistance and Cytotoxic Side Effects of Platinum and Adjuvant Anti-cancer Drugs – A Molecular Orbital Study

The side effects, acquired resistance, reversal of resistance, and combination of Pt drugs with adjuvant drugs has been examined using an extensive review of the literature and molecular orbital computations. It is concluded that Pt chemotherapeutical regimes are dominated by side reactions, particularly hydrolysis in blood serum and delivery efficiency. For example, it is shown that transplatin is therapeutically inactive because it hydrolyses faster in blood serum than cisplatin, so little transplatin reaches its target DNA. The reactivity of charged hydrolysis products determines the severity of side effect. The reactivity determining properties of the approved Pt drugs and their various hydrolysed species are calculated. The cellular uptake of Pt and adjuvant drugs is fastest for neutral species, with high lipophilicity, since their desolvation penalties for crossing the cell membrane are lowest. Pt resistant cell lines generally have lower levels of drug uptake, indicating this is a dominant first order cause of cellular resistance. Resistance can be caused by complexation of charged Pt species to phosphatidylserine (PS) headgroups, or by Pt complexation to the inner terminii of the trans-membrane pore of the hCtr1 transporter. Drugs that are known to reverse induced Pt resistance can decomplex the Pt-PS or Pt-hCtr1 complexes, restoring normal PS or hCtr1 functions. Molecular biophysical properties of adjuvant drugs used in combination with Pt drugs (e.g., paclitaxel, doxorubicin, gemcitabine, Folfox) can assist the clinical evaluation of combinatorial Pt based chemotherapeutic regimes. These drugs have similar properties to the approved Pt drugs, and fit into the same “therapeutic window” in sterms of their likely cellular uptakes and reduction potentials. The role of free radical species involved in Pt drug induced apoptosis via electron transfer from the guanine base of DNA, and the reactions of oxidizing hydroxyl radicals and reducing hydrated electrons reactions with cisplatin, transplatin and carboplatin under physiological pH and Cl ion condition have been examined.

Free radical sensitisers such as TMPD and TETA when combined with Pt drugs may allow targeting of the more hypoxic environments in solid cancerous tumours (and less damage to normal cells). The calculated biophysical parameters ionization energy and electron affinity, which are related to the redox environments found in cells, may be useful predictors of likely cytotoxic efficacy of combination therapies involving sensitisers and Pt drugs.

Keywords: Adjuvant drugs, Anti-cancer, Cellular uptake, Combinatorial chemotherapies, Platinum drugs, Resistance, Reversal of resistance, Side effects.