Table 2. . Most relevant cross-resistance mechanisms against first-line chemotherapeutic agents and drugs used for second-line treatment in high-grade osteosarcoma.

	Mechanisms of resistance
	ABCB1-mediated increased efflux	ABCC transporters-mediated increased efflux	ABCG2-mediated increased efflux	Increased DNA damage repair	Increased GSTs-mediated detoxification	Increased CYPs-mediated detoxification	Increased UGTs-mediated detoxification
First-line drugs
Doxorubicin
Cisplatin
Methotrexate
Ifosfamide
Second-line drugs
Vinca alkaloids
Taxanes
Gemcitabine
Etoposide
Bleomycin
Dactinomycin (Actinomycin D)
Cyclophosphamide
Carboplatin
Topotecan
Irinotecan
	Moderately relevant or to be confirmed			Relevant		Highly relevant