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The efficiency of chemotherapy is limited by a resistance phenomena. The cancer cells possess or acquire the possibility to bypass the action mechanisms of chemotherapy drugs.

Some cancers are naturally chemoresistant to almost all drugs (for instance: kidney or thyroid cancers).

Others are initially sensitive, but develop resistance capacities during treatment. The drugs become less and less efficient with subsequent cycles. Many resistance phenomena are crossed among drugs: hence new drugs, as yet unadministered to this patient, are totally inefficient since the cancer cells have acquired protection.

Resistance mechanisms are the origin of primary or secondary chemotherapy failure. Although these mechanisms have been largely studied in vitro, the applications of such research remain uncertain.

Pharmacokinetic mechanisms

In order to be effective, the drug needs to reach the tumour in sufficient quantities. This depends:

• on its characteristics: absorption, distribution, metabolism, elimination,

• on the characteristics of the tumour or the organ:

  • very little access to non vascularised tumours,
  • sanctuary organs such as brain or testis.

• on individual characteristics related to
  • age,
  • sex,
  • weight,
  • renal and liver functions.
    
• on the adequacy between tumour kinetics and drug administration (phase dependent drugs should be delivered for prolonged periods of time).

Pharmacodynamic mechanisms

We can refer to many mechanisms:

Decrease in cellular input

Many drugs need a transport protein to penetrate cells: the loss of the transport protein’s activity leads to resistance against the drug.

Increase in cellular output

Many membrane transport proteins will expel the drug from the cell: glycoprotein P, protein MRP and LRP.

MDR or Multi-Drug Resistance

MDR explains the majority of primary and acquired resistance phenomena. It concerns drugs which are extracts from natural products such as anthracyclins, vinca alcaloids, taxanes, epidodophyllotoxin.

There is a cross resistance between all these drugs.

Glycoprotein P is the main transport molecule of these drugs and is coded by the MDR-1 gene. Certain tumours have spontaneously high levels of glycoprotein P, such as tumours of the colon, pancreas, kidney and hepatocarcinoma. Others initially express very low levels which increase, more or less rapidly, with treatment: tumours of the stomach, breast, ovary, lungs as well as sarcoma and lymphoma.

MDR is reversible in vitro: the transport of anticancer drugs is modified by a number of other drugs such as verapamil, quinine and certain experimental molecules: S-9788, PSC-833, GF-120418, VX-70.

The clinical applications to reverse MDR remain experimental.